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What you need to know about covid-19 vaccines, answers to the most common questions about coronavirus vaccines..

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Vaccines save millions of lives each year. The development of safe and effective COVID-19 vaccines are a crucial step in helping us get back to doing more of the things we enjoy with the people we love.

We’ve gathered the latest expert information to answer some of the most common questions about COVID-19 vaccines. Keep checking back as we will update this article as more information becomes available.

What are the benefits of getting vaccinated?

Vaccines save millions of lives each year and a COVID-19 vaccine could save yours. The COVID-19 vaccines are safe and effective, providing strong protection against serious illness and death. WHO reports that unvaccinated people have at least 10 times higher risk of death from COVID-19 than someone who has been vaccinated. 

It is important to be vaccinated as soon as it’s your turn, even if you already had COVID-19. Getting vaccinated is a safer way for you to develop immunity from COVID-19 than getting infected.

The COVID-19 vaccines are highly effective, but no vaccine provides 100 per cent protection. Some people will still get ill from COVID-19 after vaccination or pass the virus onto someone else. 

Therefore, it is important to continue practicing safety precautions to protect yourself and others, including avoiding crowded spaces, physical distancing, hand washing and wearing a mask.

Who should be vaccinated first?

Each country must identify priority populations, which WHO recommends are frontline health workers (to protect health systems) and those at highest risk of death due to COVID-19, such as older adults and people with certain medical conditions. Other essential workers, such as teachers and social workers, should then be prioritized, followed by additional groups as more vaccine doses become available.

The risk of severe illness from COVID-19 is very low amongst healthy children and adolescents, so unless they are part of a group at higher risk of severe COVID-19, it is less urgent to vaccinate them than these priority groups.

Children and adolescents who are at higher risk of developing severe illness from COVID-19, such as those with underlying illnesses, should be prioritized for COVID-19 vaccines.  

When shouldn’t you be vaccinated against COVID-19?

If you have any questions about whether you should receive a COVID-19 vaccine, speak to your healthcare provider. At present, people with the following health conditions should not receive a COVID-19 vaccine to avoid any possible adverse effects:

• If you have a history of severe allergic reactions to any ingredients of a COVID-19 vaccine.
• If you are currently sick or experiencing symptoms of COVID-19 (although you can get vaccinated once you have recovered and your doctor has approved).

Should I get vaccinated if I already had COVID-19?

Yes, you should get vaccinated even if you’ve previously had COVID-19. While people who recover from COVID-19 may develop natural immunity to the virus, it is still not certain how long that immunity lasts or how well it protects you against COVID-19 reinfection. Vaccines offer more reliable protection, especially against severe illness and death. Vaccination policies after COVID-19 infection vary by country. Check with your health care provider on the recommendation where you live.

Which COVID-19 vaccine is best for me?

All WHO-approved vaccines have been shown to be highly effective at protecting you against severe illness and death from COVID-19. The best vaccine to get is the one most readily available to you.

You can find a list of those approved vaccines on WHO’s site .  

Remember, if your vaccination involves two doses, it’s important to receive both to have the maximum protection. 

How do COVID-19 vaccines work?

Vaccines work by mimicking an infectious agent – viruses, bacteria or other microorganisms that can cause a disease. This ‘teaches’ our immune system to rapidly and effectively respond against it.

Traditionally, vaccines have done this by introducing a weakened form of an infectious agent that allows our immune system to build a memory of it. This way, our immune system can quickly recognize and fight it before it makes us ill. That’s how some of the COVID-19 vaccines have been designed.

Other COVID-19 vaccines have been developed using new approaches, which are called messenger RNA, or mRNA, vaccines. Instead of introducing antigens (a substance that causes your immune system to produce antibodies), mRNA vaccines give our body the genetic code it needs to allow our immune system to produce the antigen itself. mRNA vaccine technology has been studied for several decades. They contain no live virus and do not interfere with human DNA.

For more information on how vaccines work, please visit WHO .

Are COVID-19 vaccines safe?

Yes, COVID-19 vaccines have been safely used to vaccinate billions of people. The COVID-19 vaccines were developed as rapidly as possible, but they had to go through rigorous testing in clinical trials to prove that they meet internationally agreed benchmarks for safety and effectiveness. Only if they meet these standards can a vaccine receive validation from WHO and national regulatory agencies.

UNICEF only procures and supplies COVID-19 vaccines that meet WHO’s established safety and efficacy criteria and that have received the required regulatory approval.

How were COVID-19 vaccines developed so quickly?

Scientists were able to develop safe effective vaccines in a relatively short amount of time due to a combination of factors that allowed them to scale up research and production without compromising safety: 

• Because of the global pandemic, there was a larger sample size to study and tens of thousands of volunteers stepped forward 
• Advancements in technology (like mRNA vaccines) that were years in the making 
• Governments and other bodies came together to remove the obstacle of funding research and development 
• Manufacturing of the vaccines occurred in parallel to the clinical trials to speed up production 

Though they were developed quickly, all COVID-19 vaccines approved for use by the WHO are safe and effective.

What are the side effects of COVID-19 vaccines?

Vaccines are designed to give you immunity without the dangers of getting the disease. Not everyone does, but it’s common to experience some mild-to-moderate side effects that go away within a few days on their own.

Some of the mild-to-moderate side effects you may experience after vaccination include:

• Arm soreness at the injection site
• Muscle or joint aches

You can manage any side effects with rest, staying hydrated and taking medication to manage pain and fever, if needed.

If any symptoms continue for more than a few days then contact your healthcare provider for advice. More serious side effects are extremely rare, but if you experience a more severe reaction, then contact your healthcare provider immediately.

>> Read: What you need to know before, during and after receiving a COVID-19 vaccine

How do I find out more about a particular COVID-19 vaccine?

You can find out more about COVID-19 vaccines on WHO’s website .  

Can I stop taking precautions after being vaccinated?

Keep taking precautions to protect yourself, family and friends if there is still COVID-19 in your area, even after getting vaccinated. The COVID-19 vaccines are highly effective against serious illness and death, but no vaccine is 100% effective.  

The vaccines offer less protection against infection from the Omicron variant, which is now the dominant variant globally, but remain highly effective in preventing hospitalization, severe disease, and death. In addition to vaccination, it remains important to continue practicing safety precautions to protect yourself and others. These precautions include avoiding crowded spaces, physical distancing, hand washing, and wearing a mask (as per local policies).  

Can I still get COVID-19 after I have been vaccinated? What are ‘breakthrough cases’?

A number of vaccinated people may get infected with COVID-19, which is called a breakthrough infection. In such cases, people are much more likely to only have milder symptoms. Vaccine protection against serious illness and death remains strong.

With more infectious virus variants such as Omicron, there have been more breakthrough infections. That’s why it's recommended to continue taking precautions such as avoiding crowded spaces, wearing a mask and washing your hands regularly, even if you are vaccinated. 

And remember, it’s important to receive all of the recommended doses of vaccines to have the maximum protection.

How long does protection from COVID-19 vaccines last?

According to WHO, the effectiveness of COVID-19 vaccines wanes around 4-6 months after the primary series of vaccination has been completed. Taking a booster to strengthen your protection against serious disease is recommended if it is available to you. 

Do the COVID-19 vaccines protect against variants?

The WHO-approved COVID-19 vaccines continue to be highly effective at preventing severe illness and death.

However, the vaccines offer less protection against infection from Omicron, which is the dominant variant globally. That's why it's important to get vaccinated and continue measures to reduce the spread of the virus – which helps to reduce the chances for the virus to mutate – including physical distancing, mask wearing, good ventilation, regular handwashing and seeking care early if you have symptoms. 

Do I need to get a booster shot?  

Booster doses play an important role in protecting against severe disease, hospitalization and death. 

WHO recommends that you take all COVID-19 vaccine doses recommended to you by your health authority as soon as it is your turn, including a booster dose if recommended. 

Booster shots should be given first to high priority groups. Data shows that a booster shot plays a significant role in boosting waning immunity and protecting against severe disease from highly transmissible variants like Omicron. 

If available, an additional second booster shot is also recommended for some groups of people, 4-6 months after the first booster. That includes older people, those who have weakened immune systems, pregnant women and healthcare workers. 

Check with your local health authorities for guidance and the availability of booster shots where you live.  

What do we know about the bivalent COVID-19 booster doses that have been developed to target Omicron?

Bivalent COVID-19 booster shots have now been developed with both the original strain of the coronavirus and a strain of Omicron. These have been designed to better match the Omicron subvariants that have proven to be particularly transmissible. Lab studies have shown that these doses help you to mount a higher antibody response against Omicron. Both Moderna and Pfizer have developed these bivalent vaccines, and some countries have now approved their use.  

Check with your local health authorities for information about the availability of these doses and who can get them where you live. And it’s important to note that the original COVID-19 vaccines continue to work very well and provide strong protection against severe illness from Omicron.  

Can I receive different types of COVID-19 vaccines?  

Yes, however, policies on mixing vaccines vary by country. Some countries have used different vaccines for the primary vaccine series and the booster. Check with your local health authorities for guidance where you live and speak with your healthcare provider if you have any questions on what is best for you. 

I’m pregnant. Can I get vaccinated against COVID-19?

Yes, you can get vaccinated if you are pregnant. COVID-19 during pregnancy puts you at higher risk of becoming severely ill and of giving birth prematurely. 

Many people around the world have been vaccinated against COVID-19 while pregnant or breastfeeding. No safety concerns have been identified for them or their babies. Getting vaccinated while pregnant helps to protect your baby. For more information about receiving a COVID-19 vaccination while pregnant, speak to your healthcare provider.

>> Read: Navigating pregnancy during the COVID-19 pandemic

I’m breastfeeding. Should I get vaccinated against COVID-19?

Yes, if you are breastfeeding you should take the vaccine as soon as it is available to you. It is very safe and there is no risk to the mother or baby. None of the current COVID-19 vaccines have live virus in them, so there is no risk of you transmitting COVID-19 to your baby through your breastmilk from the vaccine. In fact, the antibodies that you have after vaccination may go through the breast milk and help protect your baby. >> Read: Breastfeeding safely during the COVID-19 pandemic

Can COVID-19 vaccines affect fertility?

No, you may have seen false claims on social media, but there is no evidence that any vaccine, including COVID-19 vaccines, can affect fertility in women or men. You should get vaccinated if you are currently trying to become pregnant.

Could a COVID-19 vaccine disrupt my menstrual cycle?

Some people have reported experiencing a disruption to their menstrual cycle after getting vaccinated against COVID-19. Although data is still limited, research is ongoing into the impact of vaccines on menstrual cycles.

Speak to your healthcare provider if you have concerns or questions about your periods.

Should my child or teen get a COVID-19 vaccine?

An increasing number of vaccines have been approved for use in children. They’ve been made available after examining the data on the safety and efficacy of these vaccines, and millions of children have been safely vaccinated around the world. Some COVID-19 vaccines have been approved for children from the age of 6 months old. Check with your local health authorities on what vaccines are authorized and available for children and adolescents where you live.  

Children and adolescents tend to have milder disease compared to adults, so unless they are part of a group at higher risk of severe COVID-19, it is less urgent to vaccinate them than older people, those with chronic health conditions and health workers. 

Remind your children of the importance of us all taking precautions to protect each other, such as avoiding crowded spaces, physical distancing, hand washing and wearing a mask. 

It is critical that children continue to receive the recommended childhood vaccines. 

How do I talk to my kids about COVID-19 vaccines?

News about COVID-19 vaccines is flooding our daily lives and it is only natural that curious young minds will have questions – lots of them. Read our explainer article for help explaining what can be a complicated topic in simple and reassuring terms.

It’s important to note that from the millions of children that have so far been vaccinated against COVID-19 globally, we know that side effects are very rare. Just like adults, children and adolescents might experience mild symptoms after receiving a dose, such as a slight fever and body aches. But these symptoms typically last for just a day or two. The authorized vaccines for adolescents and children are very safe.  

My friend or family member is against COVID-19 vaccines. How do I talk to them?

The development of safe and effective COVID-19 vaccines is a huge step forward in our global effort to end the pandemic. This is exciting news, but there are still some people who are skeptical or hesitant about COVID-19 vaccines. Chances are you know a person who falls into this category.

We spoke to Dr. Saad Omer, Director at the Yale Institute for Global Health, to get his tips on how to navigate these challenging conversations. >> Read the interview

How can I protect my family until we are all vaccinated?

Safe and effective vaccines are a game changer, but even once vaccinated we need to continue taking precautions for the time being to protect ourselves and others. Variants like Omicron have proven that although COVID-19 vaccines are very effective at preventing severe disease, they’re not enough to stop the spread of the virus alone. The most important thing you can do is reduce your risk of exposure to the virus. To protect yourself and your loved ones, make sure to:

• Wear a mask where physical distancing from others is not possible.
• Keep a physical distance from others in public places.
• Avoid poorly ventilated or crowded spaces.
• Open windows to improve ventilation indoors.
• Try and focus on outdoor activities if possible.  
• Wash your hands regularly with soap and water or an alcohol-based hand rub.

If you or a family member has a fever, cough or difficulty breathing, seek medical care early and avoid mixing with other children and adults.  

Can COVID-19 vaccines affect your DNA?

No, none of the COVID-19 vaccines affect or interact with your DNA in any way. Messenger RNA, or mRNA, vaccines teach the cells how to make a protein that triggers an immune response inside the body. This response produces antibodies which keep you protected against the virus. mRNA is different from DNA and only stays inside the cell for about 72 hours before degrading. However, it never enters the nucleus of the cell, where DNA is kept.

Do the COVID-19 vaccines contain any animal products in them?

No, none of the WHO-approved COVID-19 vaccines contain animal products.

I’ve seen inaccurate information online about COVID-19 vaccines. What should I do?

Sadly, there is a lot of inaccurate information online about the COVID-19 virus and vaccines. A lot of what we’re experiencing is new to all of us, so there may be some occasions where information is shared, in a non-malicious way, that turns out to be inaccurate.

Misinformation in a health crisis can spread paranoia, fear and stigmatization. It can also result in people being left unprotected or more vulnerable to the virus. Get verified facts and advice from trusted sources like your local health authority, the UN, UNICEF, WHO.

If you see content online that you believe to be false or misleading, you can help stop it spreading by reporting it to the social media platform.

What is COVAX?

COVAX is a global effort committed to the development, production and equitable distribution of vaccines around the world. No country will be safe from COVID-19 until all countries are protected.

There are 190 countries and territories engaged in the COVAX Facility, which account for over 90 per cent of the world’s population. Working with CEPI, GAVI, WHO and other partners, UNICEF is leading efforts to procure and supply COVID-19 vaccines on behalf of COVAX.  

Learn more about COVAX .

This article was last updated on 25 October 2022. It will continue to be updated to reflect the latest information. 

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• Zhongguo Dang Dai Er Ke Za Zhi
• v.23(3); 2021 Mar 15

Language: English | Chinese

Efficacy and safety of COVID-19 vaccines: a systematic review

Covid-19疫苗的有效性和安全性的系统评价.

Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan 430060, China, 武汉大学人民医院儿科, 湖北武汉 430060

Xiao-Yan TU

Zhang-wu liang, jiang-nan chen, jiao-jiao li, li-guo jiang, fu-qiang xing.

To evaluate systematically the efficacy and safety of COVID-19 vaccines.

PubMed, Embase, Cochrane Library, Clinicaltrial.gov, CNKI, Wanfang Data, China Biomedical Literature Service System, and China Clinical Trial Registry were searched for randomized controlled trials of COVID-19 vaccines published up to December 31, 2020. The Cochrane bias risk assessment tool was used to assess the quality of studies. A qualitative analysis was performed on the results of clinical trials.

Thirteen randomized, blinded, controlled trials, which involved the safety and efficacy of 11 COVID-19 vaccines, were included. In 10 studies, the 28-day seroconversion rate of subjects exceeded 80%. In two 10 000-scale clinical trials, the vaccines were effective in 95% and 70.4% of the subjects, respectively. The seroconversion rate was lower than 60% in only one study. In six studies, the proportion of subjects who had an adverse reaction within 28 days after vaccination was lower than 30%. This proportion was 30%-50% in two studies and > 50% in the other two studies. Most of the adverse reactions were mild to moderate and resolved within 24 hours after vaccination. The most common local adverse reaction was pain or tenderness at the injection site, and the most common systemic adverse reaction was fatigue, fever, or bodily pain. The immune response and incidence of adverse reactions to the vaccines were positively correlated with the dose given to the subjects. The immune response to the vaccines was worse in the elderly than in the younger population. In 6 studies that compared single-dose and double-dose vaccination, 4 studies showed that double-dose vaccination produced a stronger immune response than single-dose vaccination.

Conclusions

Most of the COVID-19 vaccines appear to be effective and safe. Double-dose vaccination is recommended. However, more research is needed to investigate the long-term efficacy and safety of the vaccines and the influence of dose, age, and production process on the protective efficacy.

目的

系统评价新型冠状病毒肺炎(COVID-19)疫苗的有效性和安全性。

方法

通过计算机检索有关COVID-19疫苗的临床随机对照试验文献，对临床试验结果进行定性分析。检索时间为各数据库建库至2020年12月31日。所检索的数据库包括PubMed、Embase、Cochrane图书馆、Clinicaltrial.gov、中国知网、万方数据、中国生物医学文献服务系统和中国临床试验注册中心。使用Cochrane偏倚风险评估工具评估文献质量。

结果

纳入了13项随机、盲法、对照试验，涉及11种COVID-19疫苗接种的安全性和有效性。在其中10项研究中，受试者的28 d血清转化率超过80%；2项万人规模的临床试验中，分别取得了95%和70.4%的有效率；1项研究的血清转化率低于60%。在对接种后28 d内不良反应发生率的分析显示，6项研究不良反应发生率低于30%，2项研究为30%~50%，2项研究高于50%。在13项研究中，疫苗接种不良反应事件绝大部分为轻度到中度，在接种后24 h内缓解；最常见的局部不良反应为注射部位疼痛或压痛，最常见的系统性不良反应为疲劳、发热或躯体痛。受试者对疫苗的免疫反应和不良反应发生率与接种剂量呈正相关。老年人对疫苗的免疫反应较年轻人差。6项研究比较了疫苗单剂量与双剂量接种的效应，其中4项研究显示双剂量接种比单剂量接种产生更强的免疫反应。

结论

大部分COVID-19疫苗具有较好的有效性和安全性；推荐双剂量接种。然而COVID-19疫苗的长期有效性、安全性及剂量、年龄和工艺差异对保护效力的影响需要更多的研究证实。

It has been more than a year since the outbreak of the novel coronavirus pneumonia (COVID-19). Although the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused COVID-19 in China was effectively controlled, the global epidemic has not stopped. According to data from the World Health Organization, as of 16:05 on February 15, 2021, Central European Time, the cumulative number of confirmed COVID-19 cases worldwide reached 108, 579, 352, and the cumulative deaths reached 2, 396, 408 [ 1 ] . The COVID-19 epidemic as a major global public health event has become the primary health threat for all mankind, and impacted the world's political, economic and cultural greatly [ 2 - 3 ] . SARS-CoV-2 is a β-coronavirus with RNA as genetic material, which enters cell through a spike protein combined with angiotensin converting enzyme 2 [ 4 - 5 ] . COVID-19 generally manifests as fever and dry cough, and injuries multiple organ, especially the lungs [ 2 , 5 - 6 ] . Wearing mask and maintaining social distancing have been confirmed as the most effective measures to stop the spread of the virus form China's experience of fighting the epidemic [ 3 , 7 - 9 ] , and isolation and symptomatic supportive treatment still dominate for COVID-19 patients [ 5 ] . However, the efficacy of antiviral drugs and traditional Chinese medicines needs more evidence [ 10 - 11 ] . Due to the low penetration rate of masks and the limitations of treatment options abroad [ 12 - 13 ] , more and more hopes are pinned on the development of a COVID-19 vaccine. According to different targets and technologies, vaccines can be divided into the following categories: inactivated vaccines, recombinant spike protein vaccines, viral vector vaccines, RNA vaccines, live attenuated vaccines and virus-like particle vaccines, etc [ 14 - 16 ] . Currently, hundreds of COVID-19 candidate vaccine projects have been registered in the US clinical trial database (clinicaltrials.gov) [ 15 , 17 ] . Results of phase 3 clinical trials of several vaccines are published [ 18 - 22 ] . As of January 1, 2021, China, Russia, the United States, Britain and other countries have approved their own mass vaccination plans for the population. This study evaluated the safety and effectiveness of the COVID-19 vaccine through systematic literature review and qualitative analysis for the published COVID-19 vaccine clinical trial results.

1. Information and methods

This systematic review was completed in accordance with the guidelines in the "Preferred Reporting Project for Systematic Evaluation and Meta-Analysis (PRISMA)" [ 23 - 24 ] .

1.1. Literature inclusion criteria

The literature inclusion criteria: (1) The healthy men or non-pregnant women aged 18 and above; (2) COVID-19 vaccination as the intervention measure; (3) The randomized, controlled, and blinded trials; (4) The clinical trial results indicators include at least one or more as following: local adverse reactions (pain, itching, redness, swelling and induration, etc.), systemic adverse reactions (fever, diarrhea, fatigue, nausea/vomiting, etc.), the last vaccine neutralizing antibody geometric mean titer (GMT), seroconversion rate and other laboratory test indicators measured by live virus neutralization test 14 days or 28 days after inoculation.

1.2. Literature exclusion criteria

Documents that meet one of the following conditions were excluded: (1) Medical news, popular science articles, non-medical papers, reviews, letters, comments, basic research, case reports, conference abstracts; (2) No full text or literature published in a third language other than Chinese and English; (3) One of overlapping two studies were excluded; (4) If the data of the literature included in the later published literature, The former was excluded.

1.3. Literature search

The English databases PubMed, Embase, Cochrane Library and clinicaltrials.gov databases were searched. The Chinese databases searched included CNKI, Wanfang Database, China Biomedical Literature Service System and China Clinical Trial Registration Center. In order to ensure the comprehensiveness of the search results, this system evaluation used Boolean logic to search by "subject words + free words". The main search terms include: COVID-19, 2019-nCoV, SARS-CoV-2, 2019 novel coronavirus, vaccines, vaccination, COVID-19 vaccines, mRNA-1273 vaccine, Ad5-nCoV vaccine, ChAdOx1 COVID-19 vaccine, BNT162 vaccine, controlled clinical trial, randomized controlled trials, controlled clinical trial, random, blind, placebo, trial, Meta, and etc. Chinese search terms include: 新型冠状病毒、新冠肺炎、新型冠状病毒肺炎、疫苗、试验、随机对照试验、随机对照研究、随机对照、随机、元分析、Meta、荟萃, etc.

1.4. Literature screening and data extraction

The literature screening and data extraction were done independently by two researchers. Differences in the summary of the results will be discussed and dealt with by the two researchers or the third researcher. All results obtained in the database were imported into Note Express (Wuhan University Library Edition) software, and duplicate documents were removed mechanically using the software's duplicate check function. The initial screening by reading the title and abstract, and the secondary screening by reading the full text were completed. The extracted data included: the first author, vaccine type, inoculation dose, interval between inoculations, number of subjects and baseline characteristics (race, sex ratio, age range or average age), research design, local and systemic adverse reactions, laboratory indicators, as well as funds, sponsors and registration number.

1.5. Methodological quality evaluation

Assess the risk of bias according to the Cochrane Systematic Review Manual [ 25 - 26 ] .

1.6. Statistical analysis

The main results of this systematic review included the safety and effectiveness of the vaccine. Indicators for evaluating safety included local adverse reactions (pain, itching, redness, induration, etc.) and systemic adverse reactions (cough, diarrhea, fatigue, fever, headache, nausea/vomiting, itching, muscle pain, joint pain/discomfort, anorexia, etc.). The immunogenicity indicators included GMT, seroconversion rate, and the response of IgG or other specific antibodies to the receptor binding domain.

2.1. Literature search results

There were 753 relevant articles published before December 31, 2020. After screening, 13 papers were included in the system evaluation [ 19 - 22 , 27 - 35 ] . The process of document screening was shown in Figure 1 .

A flow diagram of literature screening

2.2. Methodological quality evaluation

The 13 included studies all adopted a randomized control method [ 19 - 22 , 27 - 35 ] , with a double-blind method in 10 studies [ 21 - 22 , 27 - 32 , 34 - 35 ] , and a single-blind method in 2 studies [ 20 , 33 ] , and bothsingle-blind method and double-blind methodin one study [ 19 ] . All trials hid the allocation plan. Nine trials had incomplete data or selective reports [ 19 , 22 , 27 , 29 - 31 , 33 - 35 ] , of which 2 had more missing data in the preprint [ 22 , 29 ] , and the remaining 7 missed individual data [ 19 , 27 , 30 - 31 , 33 - 35 ] ; 9 trials had other types of bias [ 19 - 20 , 22 , 29 - 32 , 34 - 35 ] , for example, Keech et al. [ 30 ] did not perform virus neutralization test in the experimental design. In general, the included literature had a low risk of bias ( Figure 2 & Table 1 ).

Risk assessment of literature bias

Methodological quality evaluation of included studies

2.3. The characteristics of the included studies

The 13 included studies were randomized, blinded, and controlled trials, involving 5 inactivated vaccines [ 21 - 22 , 27 - 29 , 34 ] , 2 recombinant spike protein vaccines [ 30 , 32 ] , 2 RNA vaccines [ 20 , 31 , 33 ] and 2 adenovirus vector vaccines [ 19 , 35 ] . Table 2 for details of vaccine characteristics and developer information). There were 6 studies comparing the effects of single-dose and double-dose vaccination [ 19 , 27 , 30 - 31 , 33 , 35 ] . Most of the 13 studies compared the difference of two doses of vaccine at intervals of 2, 3 or 4 weeks. Most studies also compared the difference between low, medium and high injection doses. Participants in all trials were adults, and 5 articles reported the results of vaccines in the elderly population [ 19 - 20 , 32 - 33 , 35 ] . The baseline characteristics of the participants were shown in Table 3 .

Experimental design and developers of the included studies

Baseline characteristics of the participants

2.4. Qualitative analysis

2.4.1. the effectiveness and safety of vaccines.

In 10 studies, the 28-day seroconversion rate of testee exceeded 80% [ 21 - 22 , 27 - 34 ] . The RNA vaccine (BNT162b2) reported by Polack achieved 95% efficiency [ 20 ] , the recombinant adenovirus vector vaccine (ChAdOx1 nCoV-19) reported by Voysey achieved an effective rate of 70.4% [ 19 ] , but Zhu reported that the 28-day seroconversion rate of the adenovirus recombinant vector vaccine in testee was less than 60% [ 35 ] .

In 6 studies, the incidence of adverse reactions in volunteers within 28 days for vaccination was less than 30% [ 20 - 22 , 27 - 28 , 34 ] . The adverse reaction rates of the recombinant spike protein vaccine (SCB-2019) reported by Richmond [ 32 ] and the RNA vaccine reported by Walsh [ 33 ] were 34.7% and 39.1%, respectively, and the adverse reaction rates of the RNA vaccine (BNT162b1) reported by Mulligan [ 31 ] and the adenovirus recombinant vector vaccine reported by Zhu [ 35 ] were 52.8% and 73.0%, respectively. Three studies could not obtain the adverse reaction rate [ 19 , 29 - 30 ] . The adverse reactions of all vaccinated testee were mostly mild to moderate, and could be relieved within 24 hours after vaccination. The most common local adverse reaction included pain or tenderness at the injection site [ 19 - 22 , 27 - 35 ] . Fatigue was reported as the most common systemic adverse reaction in 9 studies [ 19 - 20 , 22 , 28 - 29 , 31 , 33 - 35 ] . In addition, fever was reported as the most common systemic adverse reaction in 2 studies [ 21 , 27 ] , and 2 studies reported somatic pain as the most common systemic adverse reaction [ 30 , 32 ] ( Table 4 ).

Effectiveness and safety of vaccines

2.4.2. Dose difference

The difference in injection dose is an important factor affecting the immunogenicity and safety of the vaccine. A total of 9 studies [ 21 - 22 , 27 - 29 , 32 - 35 ] found significant differences in GMT and seroconversion rates obtained from testee with different doses of vaccination, 8 of which [ 20 - 22 , 28 - 29 , 31 , 34 - 35 ] found that GMT increased, and 4 [ 22 , 28 - 29 , 32 ] found that the seroconversion rate of testee increased with the increase of vaccine dose, but the incidence of adverse reactions also increases relatively [ 22 , 28 - 29 , 32 ] . Therefore, when the clinical trial entered Phase III, the researchers set the medium dose as the standard dose of the vaccine [ 19 - 20 ] .

2.4.3. Difference of age

Four studies specifically recruited the elderly 60 years and older, and conducted a special subgroup analysis in the results. Richmond [ 32 ] reported that the GMT range measured by the micro-neutralization test in the elderly group was 1567-3625, which was lower than 2510-4452 in the 18-59-year-old group. The incidence of systemic adverse reactions in the elderly after the first injection was 17%, which was lower than 38% in the 18-59 years-old group. Xia [ 27 ] also reported that the GMT of the elderly group was lower than that of the 18-59 years-old group, and the seroconversion time was later than that of the 18-59 years-old group. The incidence of systemic adverse reactions in the elderly within 7 days after vaccination was 28.6%, which was lower than 41.7% of the 18-59 years-old group. Polack [ 20 ] and Walsh [ 33 ] also reported similar results. In short, compared with healthy people aged 18 to 59, the GMT detected in the serum was significantly lower in elderly population vaccinated with the same vaccine according to the same procedure, but the incidence of adverse reactions in the elderly population was also significantly lower [ 20 , 27 , 32 - 33 ] .

2.4.4. Differences in vaccination procedures

Although a number of studies designed a comparison of different vaccination procedures, the results of the experiment were complicated. Zhang 's research showed that testee who vaccinated at 2-week intervals got a faster immune response, but a stronger immune response at 4-week intervals [ 34 ] . Che detected a stronger immune response in testee who were vaccinated at 2-week intervals [ 28 ] . Xia also found that the incidence of adverse reactions in testee vaccinated at 2-week intervals was lower than that at 4-week intervals [ 21 ] . In 6 studies that compared single-dose and double-dose vaccination, 4 studies showed that double-dose vaccination produced a stronger immune response than single-dose vaccination [ 19 , 31 , 33 , 35 ] .

2.4.5. Differences of vaccine type

The RNA vaccine (BNT162b2) reported by Polack [ 20 ] and the recombinant adenovirus vector vaccine (ChAdOx1 nCoV-19) reported by Voysey [ 19 ] involved more than 10, 000 people, and two both used relative risk to calculate the effective rate, showing that effective rate of the former was 95% [ 20 ] , and the latter was 70.4% [ 19 ] . Owing to differences in the design, the small sample size, and different outcome indicators of other clinical trials, their effective rates were not yet comparable.

3. Discussion

The system evaluation draws the following conclusions: (1) All candidate vaccines have a good immunogenicity and safety except the vaccine reported by Zhu [ 35 ] . Within 28 days after vaccination, the testee' serum GMT increased significantly, and the seroconversion rate was mostly greater than 80%. The adverse reaction rate of most vaccines was less than 30%, degree was mild to moderate, and symptoms were alleviated within 24 hours. (2) The potency and adverse reaction rate after vaccination were positively related to the dose. Most clinical trials chose the middle dose when the phase III. This might be the result of comprehensive consideration of effectiveness and safety. (3) Under the same conditions, the vaccine had poor immunogenicity to elderly people over 60, but the adverse reaction rate was also low. One of the possible reasons was low immunity of the older. A lot of studies on the tolerance of the elderly population to the vaccine still are needed. In addition, there are currently no published results of clinical trials targeting juveniles. (4) Most studies recommend double-dose vaccination, but the interval needs further study.

However, this systematic review has some limitations: (1) No evidence of the long-term effectiveness and safety of the vaccine. Due to the urgency of vaccine development, most trials only followed up to 28 days after vaccination. Whether neutralizing antibodies can be maintained for a long time and whether there are delayed adverse reactions after vaccination still require a longer period. (2) In order to get more up-to-date evidence, this systematic review also includes preprinted documents, which have not been peer reviewed and some of the data are not available. (3) Only randomized, double-blind, and controlled trials were included, while observational studies, retrospective case analysis, and early animal experiments were all excluded. For example, an open label trial conducted by Anderson [ 36 ] found that mRNA-1273 vaccine had a good safety in the elderly population. Logonov [ 37 ] reported two adenovirus recombinant vector vaccine preparations (rAd26) in a non-random clinical trial (rAd26-S and rAd5-S) had a good safety and immunogenicity in healthy people aged 18 to 60. (4) There were differences in the design of various clinical trials, which made it impossible to compare the advantages and disadvantages of different types of vaccines. For example, Voysey [ 19 ] and Polack [ 20 ] used relative risk to calculate the effective rate. Although the remaining 10 studies have completed the virus neutralization test, the experimental design schemes were quite different [ 21 - 22 , 27 - 29 , 31 - 35 ] . (5) Only Chinese and English documents were searched in this systematic review, and documents published in other languages such as Japanese and French were excluded.

In conclusion, this systematic review summarized the results of clinical trials related to the COVID-19 vaccine, showing that most vaccines had a good safety and effectiveness. It is believed that with the widespread vaccination of COVID-19, it is possible to control and end the global pandemic of COVID-19.

Conflict of interest: The authors have no conflicts of interest to disclose.

新型冠状病毒肺炎(COVID-19)疫情暴发至今已1年余。虽然COVID-19疫情在我国已经得到了有效控制, 但全球整体疫情形势依然严峻。根据世界卫生组织的数据, 截至欧洲中部时间2021年2月15日16 : 05, 全球累计COVID-19确诊病例达到108 579 352例, 累计死亡人数达到2 396 408人 [ 1 ] 。作为全球的重大公共卫生事件, COVID-19疫情成为全人类首要的健康威胁, 世界政治经济文化也受到巨大冲击 [ 2 - 3 ] 。导致COVID-19的严重急性呼吸综合征冠状病毒2(SARS-CoV-2)是以RNA为遗传物质的β属冠状病毒, 通过刺突蛋白结合血管紧张素转化酶2进入细胞 [ 4 - 5 ] 。COVID-19患者的首发症状以发热和干咳多见, 在多脏器损伤中, 肺脏受损最为严重 [ 2 , 5 - 6 ] 。在疫情控制上, 佩戴口罩和保持社交距离已经在中国抗击疫情的实践中被确认为阻断病毒传播最为有效的措施 [ 3 , 7 - 9 ] 。在对COVID-19患者的治疗上, 隔离和对症支持治疗仍占主要地位 [ 5 ] , 而关于抗病毒药物和中药等的疗效还需更多证据的支持 [ 10 - 11 ] 。由于口罩在国外普及率的低下和治疗方案的局限性 [ 12 - 13 ] , 越来越多的希望被寄托在COVID-19疫苗的开发上。根据靶点和技术的不同, 疫苗可以被分为以下几类: 灭活疫苗、重组刺突蛋白疫苗、病毒载体疫苗、RNA疫苗、减毒活疫苗和病毒样颗粒疫苗等 [ 14 - 16 ] 。目前, 已有数百项COVID-19候选疫苗的项目在美国临床试验数据库(clinicaltrials.gov)注册 [ 15 , 17 ] , 数种疫苗的3期临床试验结果予以发表 [ 18 - 22 ] 。截至2021年1月1日, 中、俄、美、英等国家先后批准了本国疫苗在人群中的大规模接种计划。本研究通过系统文献复习及定性分析已发表的COVID-19疫苗临床试验结果, 评估COVID-19疫苗的安全性与有效性。

1. 资料与方法

本系统评价遵循《系统评价和Meta分析的首选报告项目(PRISMA)》中的准则完成 [ 23 - 24 ] 。

1.1. 文献纳入标准

文献纳入标准包括: (1)试验对象为18岁及以上的健康男性或未孕女性; (2)干预措施为接种COVID-19疫苗; (3)试验类型为随机、对照、盲法试验; (4)临床试验结果指标至少包括以下一项或几项: 局部不良反应(疼痛、瘙痒、发红、肿胀和硬结等)、全身不良反应(发热、腹泻、疲劳、恶心/呕吐等)、末次疫苗接种14 d或28 d后以活病毒中和试验测得的中和抗体几何平均滴度(GMT)、血清转化率及其他实验室检测指标。

1.2. 文献排除标准

具备以下条件之一的文献被排除: (1)文献类型为医学新闻、科普文章、非医学类论文、综述、信件、评论、基础研究、病例报告、会议摘要; (2) 无法获取全文或以中文、英文外的第三种语言发表的文献; (3)若两项研究的受试者存在重叠, 则其中之一被排除; (4)若文献的数据被之后发表的文献包含在内, 前者予以排除。

1.3. 文献检索

对英文数据库PubMed、Embase、Cochrane图书馆和clinicaltrials.gov数据库进行了检索。检索的中文数据库包括中国知网、万方数据库、中国生物医学文献服务系统和中国临床试验注册中心。为了保证检索结果的全面性, 本系统评价运用布尔运算逻辑, 采取"主题词+自由词"方式进行了检索。主要检索词包括: COVID-19、2019-nCoV、SARS-CoV-2、2019 novel coronavirus、vaccines、vaccination、COVID-19 vaccines、mRNA-1273 vaccine、Ad5-nCoV vaccine、ChAdOx1 COVID-19 vaccine、BNT162 vaccine、controlled clinical trial、randomized controlled trials、controlled clinical trial、random、blind、placebo、trial、Meta等。中文检索词包括新型冠状病毒、新冠肺炎、新型冠状病毒肺炎、疫苗、试验、随机对照试验、随机对照研究、随机对照、随机、元分析、Meta、荟萃等。

1.4. 文献筛选和资料提取

文献筛选和资料提取工作由两位研究者独立完成。若结果汇总时出现分歧, 由两位研究者讨论处理或交由第3位研究者决定。在数据库中获得的所有检索结果导入NoteExpress(武汉大学图书馆版)软件中, 使用软件的查重功能机械地去除重复文献。然后通过阅读标题和摘要完成初次筛选, 通过阅读全文完成二次筛选。在第二次筛选中, 每一篇文献被剔除的原因均被记录。所提取数据包括: 第一作者、疫苗类型、接种剂量、接种间隔时间、受试者人数及基线特征(种族、性别比例、年龄范围或平均年龄)、研究设计方案、局部和全身不良反应、实验室检查指标, 以及基金、赞助商和注册号等。

1.5. 方法学质量评价

依据Cochrane系统评价手册评估偏倚风险 [ 25 - 26 ] 。

1.6. 统计学分析

本系统评价的主要结果包括疫苗的安全性和有效性。评估安全性的指标包括局部不良反应(疼痛、瘙痒、红肿、硬结等)及全身不良反应(咳嗽、腹泻、疲倦、发烧、头痛、恶心/呕吐、瘙痒、肌肉疼痛、关节痛/不适、厌食等)。评估免疫原性的指标包括GMT、血清转化率、IgG或其他特异性抗体对受体结合域的反应。

2. 结果

2.1. 文献检索结果.

检索了截至2020年12月31日之前发表的所有相关文献, 共得到753篇。经过筛选后纳入13篇 [ 19 - 22 , 27 - 35 ] 进入本系统评价。文献筛选的具体流程见 图 1 。

文献筛选流程图

2.2. 纳入研究的方法学质量评价

纳入的13项研究 [ 19 - 22 , 27 - 35 ] 均采用了随机对照的方法, 其中10项 [ 21 - 22 , 27 - 32 , 34 - 35 ] 实施了双盲法, 2项 [ 20 , 33 ] 实施了单盲法, 1项 [ 19 ] 在不同试验地点分别使用了单盲法和双盲法; 所有试验均隐藏了分配方案; 9项 [ 19 , 22 , 27 , 29 - 31 , 33 - 35 ] 数据不完整或选择性报告, 其中2项 [ 22 , 29 ] 预印本缺失数据较多, 其余7项 [ 19 , 27 , 30 - 31 , 33 - 35 ] 缺失个别数据; 9项 [ 19 - 20 , 22 , 29 - 32 , 34 - 35 ] 存在其他类型偏倚, 如Keech等 [ 30 ] 在试验设计中未做病毒中和试验。总的来讲, 所纳入文献的偏倚风险较低。见 图 2 和 表 1 。

文献偏倚风险评估

纳入研究的方法学质量评价

2.3. 纳入研究的基本特征

所纳入的13项研究均为随机、盲法、对照试验, 共涉及灭活疫苗5种 [ 21 - 22 , 27 - 29 , 34 ] 、重组刺突蛋白疫苗2种 [ 30 , 32 ] 、RNA疫苗2种 [ 20 , 31 , 33 ] 和腺病毒载体疫苗2种 [ 19 , 35 ] , 疫苗特性、开发者等信息见 表 2 。有6项研究比较了疫苗单剂量与双剂量接种的效应 [ 19 , 27 , 30 - 31 , 33 , 35 ] 。大部分研究比较了以2周、3周或4周为间隔注射两剂疫苗的差别。大部分研究也比较了低、中、高不同注射剂量的差别。所有试验的参与者均为成年人, 有5篇文献报道了疫苗在老年人群体中的结果 [ 19 - 20 , 32 - 33 , 35 ] 。所纳入研究参与者的基线特征见 表 3 。

纳入研究的基线特征

纳入研究的试验设计和开发者

2.4. 定性分析结果

2.4.1. 疫苗的有效性和安全性.

在10项研究中, 受试者的28 d血清转化率超过80% [ 21 - 22 , 27 - 34 ] ;在两项万人规模的临床试验中, Polack等 [ 20 ] 报道的RNA疫苗(BNT162b2)取得了95%的有效率, Voysey等 [ 19 ] 报道的腺病毒重组载体疫苗(ChAdOx1 nCoV-19)取得了70.4%的有效率; Zhu等 [ 35 ] 报道的腺病毒重组载体疫苗在受试者中的28 d血清转化率低于60%。见 表 4 。

疫苗的有效性和安全性

在6项研究中, 志愿者在接种疫苗后的28 d内不良反应发生率低于30% [ 20 - 22 , 27 - 28 , 34 ] ;Richmond等 [ 32 ] 报道的重组刺突蛋白疫苗(SCB-2019)和Walsh等 [ 33 ] 报道的RNA疫苗的不良反应率分别为34.7%和39.1%;Mulligan等 [ 31 ] 报道的RNA疫苗(BNT162b1)和Zhu等 [ 35 ] 报道的腺病毒重组载体疫苗的不良反应率分别为52.8%和73.0%;3项研究无法获取不良反应率 [ 19 , 29 - 30 ] 。所有疫苗接种的受试者发生不良反应事件绝大部分都是轻度到中度, 且在接种后24 h内可缓解; 所有疫苗接种最常见的局部不良反应均为注射部位疼痛或压痛 [ 19 - 22 , 27 - 35 ] ;疲劳在9项研究中被报道为最常见的系统性不良反应 [ 19 - 20 , 22 , 28 - 29 , 31 , 33 - 35 ] 。此外, 发热在2项研究中被报道为最常见的系统性不良反应 [ 21 , 27 ] , 也有2项研究报道躯体痛为最常见的系统性不良反应 [ 30 , 32 ] 。见 表 4 。

2.4.2. 剂量差异的影响

注射剂量的不同是影响疫苗免疫原性和安全性的重要因素。共有9项研究 [ 21 - 22 , 27 - 29 , 32 - 35 ] 发现接受不同剂量疫苗接种的受试者获得的GMT和血清转化率存在显著性差异, 其中8项 [ 20 - 22 , 28 - 29 , 31 , 34 - 35 ] 发现GMT随着疫苗剂量的增加而增加, 4项 [ 22 , 28 - 29 , 32 ] 发现受试者血清转化率随疫苗剂量的增加而增加。但随着接种剂量的加大, 不良反应的发生率也相对增加 [ 22 , 28 - 29 , 32 ] 。因此, 当临床试验进入Ⅲ期阶段, 研究者将中等剂量设定为疫苗的标准剂量 [ 19 - 20 ] 。

2.4.3. 年龄差异的影响

有4项研究专门招募了60岁及以上的老年人群, 并在结果中进行了专门的亚组分析。Richmond等 [ 32 ] 报道使用微量中和试验在老年人组测得的GMT范围为1 567~3 625, 低于18~59岁组的2 510~4 452;而老年人在第1次注射后的全身不良反应发生率为17%, 低于18~59岁组的38%。Xia等 [ 27 ] 也报道老年人组GMT低于18~59岁组, 且达到血清转化时间晚于18~59岁组; 而老年人在接种后7 d内的全身不良反应发生率为28.6%, 低于18~59岁组的41.7%。Polack等 [ 20 ] 和Walsh等 [ 33 ] 两项研究也报道了相似结果。总之, 相比于18~59岁的健康人群, 老年人群按照相同的程序接种同种疫苗后, 血清中所检测到的GMT显著偏低, 但相应地老年人群中不良反应发生率也显著偏低 [ 20 , 27 , 32 - 33 ] 。

2.4.4. 接种程序差异的影响

虽然多项研究设计了不同接种程序的对比, 但试验结果是复杂的。Zhang等 [ 34 ] 的研究表明, 以2周为间隔接种疫苗的受试者获得了更快的免疫反应, 但以4周为间隔接种疫苗的受试者获得了更强的免疫反应。但Che等 [ 28 ] 在以2周为间隔接种疫苗的受试者中检测到了更强的免疫反应, Xia等 [ 21 ] 也发现以2周为间隔接种疫苗的受试者不良反应发生率低于以4周为间隔接种疫苗的受试者。在6项比较了疫苗的单剂量与双剂量接种的研究中, 4项研究显示疫苗双剂量接种比单剂量接种产生更强的免疫反应 [ 19 , 31 , 33 , 35 ] 。

2.4.5. 疫苗类型差异的影响

Polack等 [ 20 ] 报道的RNA疫苗(BNT162b2)和Voysey等 [ 19 ] 报道的腺病毒重组载体疫苗(ChAdOx1 nCoV-19)受试者人数超过10 000人, 都采用相对危险度计算有效率, 显示前者有效率为95% [ 20 ] , 后者有效率为70.4% [ 19 ] 。其他临床试验的设计存在差异, 受试者规模较小, 结局指标也有所不同, 其有效率尚无法比较。

3. 讨论

本系统评价得出以下结论: (1)除了Zhu等 [ 35 ] 报道的疫苗外, 所有候选疫苗都具有良好的免疫原性和安全性。接种后28 d内, 受试者血清GMT显著增加, 血清转化率大多大于80%, 大部分疫苗的不良反应率低于30%, 且以轻到中度为主, 24 h内缓解。(2)接种后产生的效价和不良反应率与剂量呈正相关, 因此, 大部分临床试验进入Ⅲ期阶段后, 选择了中等剂量作为标准剂量, 这可能是对有效性和安全性综合考虑的结果。(3) 相同条件下, 疫苗对60岁以上的老年人的免疫原性较差, 但不良反应率也偏低, 一种可能的解释是这与人体的免疫衰老有关。老年人群对疫苗的耐受性需要继续研究。此外, 目前尚没有针对未成年人的临床试验结果发表。(4)大部分疫苗研究都推荐双剂量接种, 但接种间隔时间需进一步研究。

然而, 本系统评价有一定的局限性: (1)缺乏疫苗的长期有效性和安全性的证据。由于疫苗研发的急迫性, 大部分试验只随访到了接种后28 d, 中和性抗体能否长期维持, 接种疫苗后是否有迟发的不良反应, 仍需要更长时间的随访。(2)为了纳入更多最新证据, 本系统评价也将预印本文献包含在内, 这些文献没有经过同行评议, 且其中一些数据无法获取。(3)本系统评价只纳入了随机、双盲、对照试验, 而观察性研究、回顾性病例分析及早期的动物试验均被排除在外。如Anderson等 [ 36 ] 实施的一项开放标签试验发现mRNA-1273疫苗在老年人群体具有较好的安全性, Logunov等 [ 37 ] 在非随机临床试验中报道了两种腺病毒重组载体疫苗制剂(rAd26-S和rAd5-S)在18~60岁健康人群具有较好的安全性和免疫原性。(4)各项临床试验的设计存在差异, 导致无法对不同类型疫苗的优劣进行比较, 如Voysey等 [ 19 ] 和Polack等 [ 20 ] 采用相对危险度计算有效率, Keech等 [ 30 ] 未做病毒中和试验, 其余10项研究虽然均完成了病毒中和试验, 但试验设计方案差异较大 [ 21 - 22 , 27 - 29 , 31 - 35 ] 。(5)本系统评价只检索了中英文文献, 以日文、法文等其他语言发表的文献被排除在外。

综上所述, 本系统评价总结了COVID-19疫苗相关的临床试验结果, 表明大部分疫苗都具有较好的安全性和有效性。这让我们有理由相信, 随着COVID-19疫苗的广泛接种, 有望控制、终结COVID-19的全球大流行。

利益冲突声明：所有作者均声明不存在利益冲突。

Biographies

邢凯, 男, 本科生

Jiang Y, Email: moc.361@dwiygnaij

Funding Statement

中央高校基本科研业务费专项资金资助项目(2042020kf1011)

Fundamental Research Funds for the Central Universities (2042020kf1011)

Essay on Coronavirus Vaccine

500+ words essay on  coronavirus vaccine.

The Coronavirus has infected millions of people so far all over the world. In addition to that, millions of people have lost their lives to it. Ever since the outbreak, researchers all over the world have been working constantly to develop vaccines that will work effectively against the virus. We will take a look at the Coronavirus vaccine that is present today. Vaccines have the ability to save people’s lives. Developing the vaccine for Coronavirus was a huge step to end the pandemic.

Working of Coronavirus Vaccine

As Coronavirus caused a lot of confusion and fear amongst people, it is natural people were not aware of how the vaccine works. To begin with, a vaccine will work by mimicking an infectious agent.

The agent can be viruses, bacteria or any other microorganisms. They carry the potential of causing disease. When it mimics that, our immune system learns how to respond against it rapidly and efficiently.

As per the traditional methods, vaccines have managed to do this as they introduce a weakened form of an infectious agent. It enables our immune system to basically build its memory.

As a result, our immune system can then identify it quickly and fight against it before it gets the chance to harm us or make us ill. Similarly, some of the coronavirus vaccines have been made like that.

On the other hand, there are other coronavirus vaccines that researchers have developed by making use of new approaches. We refer to them as messenger RNA or mRNA vaccines.

Over here, they do not introduce antigens in our bodies. Instead, mRNA vaccines give the genetic code our body needs to enable our immune system for producing the antigen itself.

For several years, researchers have been studying mRNA vaccine technology. Thus, they do not contain any live virus and also do not interfere with the human DNA .

Get the huge list of more than 500 Essay Topics and Ideas

Safety of Coronavirus Vaccine

While the vaccines are being developed at a fast pace, they also require rigorous testing. The tests are done in clinical trials to ensure that they meet the benchmarks for the safety and efficiency of international standards.

When they meet the standards, then only can they get the go-ahead from WHO and national regulatory agencies. UNICEF has said that it will attain and supply only those vaccines that meet the WHO guidelines and have met the regulatory approval.

As of now, the vaccine doses are limited in number. Thus, the healthcare workers, first responders, people over the age of 75 and residents of long-term care facilities will receive the first doses.

After that, everyone will be able to get it once more of them are available. To get the vaccine, a person may require to pay a fee. However, some government institutions are providing it free of cost.

In order to get the vaccine, one must check with their local and state health departments on a regular basis. When they get the chance, they must get the dose right away.

The Coronavirus outbreak has challenged the whole world. Constantly, the experts and authorities are working to develop the vaccines. Therefore, we can also do our bit and adopt preventive measures to limit the spread of this disease. The major goal is to get the vaccine to everyone so that we can go on and about with our normal lives.

FAQ on Essay on Coronavirus Vaccine

Question 1: What are some common side effects of the Coronavirus vaccine?

Answer 1:  The most common side effect includes a sore arm, fever , headache, and fatigue. However, not to worry, side effects are good in this case. They indicate that your vaccine is starting to work as it triggers your immune system.

Question 2: When do Coronavirus vaccine side effects kick in?

Answer 2: Usually, most of the side effects start to kick in within the first 3 days after you get your vaccine. Moreover, they will last up to 1 to 2 days only.

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How Pfizer Makes Its Covid-19 Vaccine

By Emma Cott ,  Elliot deBruyn and Jonathan Corum April 28, 2021

• Share full article

Inside this facility in Chesterfield, Missouri, trillions of bacteria are producing tiny loops of DNA containing coronavirus genes — the raw material for the Pfizer-BioNTech vaccine .

It’s the start of a complex manufacturing and testing process that takes 60 days and involves Pfizer facilities in three states. The result will be millions of doses of the vaccine, frozen and ready to ship.

Pull DNA from Cold Storage

A scientist removes vials of DNA from the master cell bank, the source of every batch of Pfizer’s Covid-19 vaccine. The vials are kept at –150°C (–238°F) or below, and contain small rings of DNA called plasmids.

Coronavirus

spike protein

spike proteins

Each plasmid contains a coronavirus gene, the genetic instructions for a human cell to build coronavirus proteins and trigger an immune response to the virus.

Scientists thaw the plasmids and modify a batch of E. coli bacteria to take the plasmids inside their cells.

A single vial can eventually produce up to 50 million doses of the vaccine.

Grow the Cells

The vial of modified bacteria is swirled into a flask of amber-colored growth medium, a sterile and warm environment that encourages the bacteria to multiply.

Multiplying

Ferment the Mixture

The bacteria are allowed to grow overnight and then moved into a large fermenter that contains up to 300 liters of a nutrient broth.

The bacterial broth spends four days in the fermenter, multiplying every 20 minutes and making trillions of copies of the DNA plasmids.

Harvest and Purify the DNA

When the fermentation is complete, scientists add chemicals to break open the bacteria and release the plasmids from their enclosing cells.

The mixture is then purified to remove the bacteria and leave only the plasmids.

Test for Quality

The plasmids are tested for purity, and compared against previous samples to confirm that the coronavirus gene sequence has not changed.

for comparison

Cut the Plasmids

If the plasmids pass the quality checks, proteins called enzymes are added to the mixture. The enzymes cut the circular plasmids and separate the coronavirus genes into straight segments, a process called linearization that takes about two days.

cutting the

Filter the DNA

Any remaining bacteria or plasmid fragments are filtered out, leaving one-liter bottles of purified DNA.

The DNA sequences are tested again, and will serve as templates for the next stage of the process. Each bottle of DNA will produce about 1.5 million doses of the vaccine.

The Chesterfield facility is Pfizer’s only source of plasmids for its Covid-19 vaccine. But finishing the vaccine requires several more steps in two other facilities.

Freeze, Pack and Ship

Each bottle of DNA is frozen, bagged, sealed and packed with a small monitor that will record its temperature in transit.

Up to 48 bottles are packed in a container with enough dry ice to keep them frozen at –20°C (–4°F) . The containers are locked to prevent tampering and shipped to a Pfizer research and manufacturing facility in Andover, Mass.

The Andover plant will process the DNA into messenger RNA, or mRNA, the active ingredient of the Pfizer-BioNTech vaccine.

Chesterfield

Other bottles are flown to BioNTech facilities in Mainz, Germany, where they are processed for Europe and other markets.

Transcribe the DNA into mRNA

Inside the Andover facility, yellow walls mark the mRNA suite. Five bottles of DNA are thawed for a day, then mixed with the building blocks of messenger RNA.

Over several hours, enzymes pry open the DNA templates and transcribe them into strands of mRNA. The finished vaccine will carry the mRNA into human cells, which will read the coronavirus gene and begin producing coronavirus proteins.

Transcribing

DNA into mRNA

The mixture is moved into a holding tank, then filtered to remove any unwanted DNA, enzymes or other impurities. Each batch will eventually yield up to 7.5 million doses of the vaccine.

Test the mRNA

The Pfizer-BioNTech vaccine was the first mRNA vaccine to be authorized for emergency use in people.

Analytical scientists repeatedly test the filtered mRNA to verify its purity and confirm the genetic sequence is correct.

The result is 10 bags of coronavirus mRNA. Each bag holds 16 liters and represents the raw material for about 750,000 doses of the vaccine.

Freeze, Pack and Ship (Again)

The bags of mRNA are frozen to –20°C (–4°F) and shipped to a Pfizer facility in Kalamazoo, Mich., where they will be processed into the finished vaccine and packaged in vials. Samples are also sent back to Pfizer’s Chesterfield facility, where they are tested again.

The Andover plant can produce two batches of mRNA a week, each about 10 bags. The facility made its first test batch last July, and recently doubled its mRNA capacity by adding a second suite.

A parallel process in Mainz, Germany, processes DNA from the Chesterfield facility and sends bags of filtered mRNA to Puurs, Belgium.

Prepare the mRNA

The Kalamazoo facility receives the bags of mRNA, keeps them frozen until needed and then thaws enough to produce 3.6 million doses of the vaccine, or 600,000 vials.

The thawed mRNA is mixed with water in preparation for making the vaccine.

Prepare the Lipids

In a separate process, scientists prepare the oily lipids that will protect the mRNA and help it enter human cells.

The lipids are measured out and mixed with ethanol, which will eventually be removed from the finished vaccine.

Assemble the mRNA Vaccine

A rack of 16 pumps precisely controls the flow of the mRNA and lipid solutions, then mixes them together to create lipid nanoparticles.

Lipids enveloping

nanoparticles

When the lipids come into contact with the naked strands of mRNA, electric charge pulls them together in a nanosecond. The mRNA is enveloped in several layers of lipids, forming an oily, protective vaccine particle.

Synchronizing eight pairs of pumps is not an ideal solution, but Pfizer engineers chose to scale up existing technology instead of trying to build a larger, unproven type of precision mixing device.

The newly made vaccine is filtered to remove the ethanol, concentrated and filtered again to remove any impurities, and finally sterilized.

Prepare the Vials

Hundreds of thousands of empty vials are washed and heat sterilized.

A set of 13 cameras performs a high-speed visual inspection, taking more than 100 photographs of each vial. Any vials with cracks, chips or other imperfections are removed from the line.

A separate machine puts each vial under vacuum to confirm it doesn’t leak.

Rush to Fill the Vials

The flow of vials is narrowed to a single-file line. Machines inject 0.45 ml of a concentrated vaccine solution into each vial, enough for six doses after dilution. The vials are sealed with foil and capped with purple lids, at a pace of up to 575 vials per minute. (The footage above shows a test run, with empty vials.)

The vaccine is chilled but warms up quickly during the bottling process, and the mRNA will deteriorate if left unfrozen for too long. Kalamazoo has limited time, about 46 hours, to get the liquid vaccine into vials and then into deep freeze.

Package, Freeze and Test

The filled vials are inspected again, and then labeled and packed into “pizza boxes,” small plastic trays that hold 195 vials each.

The trays are bundled in stacks of five and loaded into one of 350 industrial freezers. Each freezer holds 300 trays.

It takes a couple of days for the vaccine to reach the –70°C (–94°F) required for long-term storage, and each freezer is tested to ensure that every shelf can maintain that ultracold temperature.

Once frozen, the vials of vaccine are held for four weeks of testing. Samples are sent back to the Andover facility that produced the mRNA, and to the Chesterfield site that provided the DNA templates.

Pfizer currently operates on a 60-day timeline from start to finish, and more than half of that time is dedicated to testing.

Pack and Ship the Finished Vaccine

After weeks of testing, the vaccine is ready to ship. Workers pull trays from the freezers and pack them in shipping boxes with temperature and location sensors. The minimum order is one tray of 195 vials, and a box holds up to five trays.

Each box contains 45 pounds of dry ice — so much that Pfizer’s Kalamazoo facility now makes dry ice on site. Pfizer is also evaluating different formulations of the vaccine, including freeze-dried and ready-to-use versions that would not require ultracold storage.

Commercial production of the vaccine began in September. As of April 22, the plant had delivered more than 150 million vaccine doses to the United States. Pfizer expects to deliver 220 million doses by the end of May, and 300 million by mid-July.

THE LAST STEP

Administer the vaccine.

Some 141 million people in the United States — more than half of the nation’s adults — have received at least one dose of a Covid-19 vaccine. More than a billion doses have been administered worldwide.

The City of Los Angeles hosts a mass vaccination site at Dodger Stadium, above. On Feb. 5, health care workers gave thousands of shots of the Moderna vaccine , which also uses mRNA to build immunity. (Moderna declined to provide filming access to their facilities.)

The single-dose Johnson & Johnson vaccine uses an adenovirus to carry DNA into human cells. A facility in Baltimore run by Emergent BioSolutions had to throw out up to 15 million doses of Johnson & Johnson’s vaccine because of possible contamination.

A Vaccine for Variants

Many of the coronavirus variants now in circulation have key mutations in their spike proteins that help the virus bind more tightly to human cells or evade some kinds of antibodies.

Pfizer and BioNTech are developing and testing new versions of their vaccine against recent variants, and might eventually alter their genetic recipe to mass-produce Covid-19 vaccines that target specific variants.

To do that, Pfizer would go back to where their vaccine production began, to the master cell bank in Chesterfield that keeps rings of DNA in deep freeze.

A new batch of DNA carrying modified coronavirus genes could eventually produce a slightly different vaccine, one that encourages the immune system to better recognize recent coronavirus mutations.

Chesterfield video by Elliot deBruyn. Dodger Stadium video by Luisa Conlon. Video editing by Meg Felling. Cinematography directed by Jonah M. Kessel. Additional video production by Alexandra Eaton and Sarah Kerr.

Andover and Kalamazoo video provided by Pfizer, with some barcodes and other identifying information obscured.

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Disclaimer: This translation was last updated on August 2, 2022. For up-to-date content, please visit the English version of this page.

Disclaimer: The Spanish COVID-19 site is currently undergoing significant updates which may lead to a delay in translated content. We apologize for any inconvenience.

Understanding How COVID-19 Vaccines Work

What you need to know.

COVID-19 vaccines help our bodies develop immunity to the virus that causes COVID-19 without us having to get the illness.

• Different COVID-19 vaccines may work in our bodies differently but all provide protection against the virus that causes COVID-19.
• None of the COVID-19 vaccines can give you COVID-19.
• Bringing new vaccines to the public involves various steps, all which must be followed to ensure they are safe and effective before they are made available for use.

How COVID-19 Vaccines Work

Different types of vaccines work in different ways to offer protection. But with all types of vaccines, the body is left with a supply of “memory” T-lymphocytes as well as B-lymphocytes that will remember how to fight that virus in the future.

It typically takes a few weeks after vaccination for the body to produce T-lymphocytes and B-lymphocytes.

Sometimes after vaccination, the process of building immunity can cause symptoms, such as fever. These symptoms are normal signs the body is building immunity.

Types of Vaccines: mRNA, and Protein Subunit

There are different types of vaccines.

• All COVID-19 vaccines prompt our bodies to recognize and help protect us from the virus that causes COVID-19.
• Currently, there are two types of COVID-19 vaccines for use in the United States: mRNA , and protein subunit vaccines.

None of these vaccines can give you COVID-19.

• Vaccines do  not  use any live virus.
• Vaccines  cannot  cause infection with the virus that causes COVID-19 or other viruses.

They do not affect or interact with our DNA.

• These vaccines do  not  enter the nucleus of the cell where our DNA (genetic material) is located, so it cannot change or influence our genes.

mRNA vaccines (Pfizer-BioNTech or Moderna)

To trigger an immune response, many vaccines put a weakened or inactivated germ into our bodies. Not mRNA vaccines. Instead, mRNA vaccines use mRNA created in a laboratory to teach our cells how to make a protein—or even just a piece of a protein—that triggers an immune response inside our bodies. This immune response, which produces antibodies, is what helps protect us from getting sick from that germ in the future.

Research for mRNA technology

Researchers have been studying and working with mRNA vaccines for decades .

• In fact, mRNA vaccines have been studied before for flu, Zika, rabies, and cytomegalovirus (CMV).
• Beyond vaccines, cancer research has also used mRNA to trigger the immune system to target specific cancer cells.
• First, mRNA COVID-19 vaccines are given in the upper arm muscle or upper thigh, depending on the age of who is getting vaccinated.
• After vaccination, the mRNA will enter the muscle cells. Once inside, they use the cells’ machinery to produce a harmless piece of what is called the spike protein. The spike protein is found on the surface of the virus that causes COVID-19. After the protein piece is made, our cells break down the mRNA and remove it, leaving the body as waste.
• Next, our cells display the spike protein piece on their surface. Our immune system recognizes that the protein does not belong there. This triggers our immune system to produce antibodies and activate other immune cells to fight off what it thinks is an infection. This is what your body might do if you got sick with COVID-19.
• At the end of the process, our bodies have learned how to help protect against future infection with the virus that causes COVID-19. The benefit is that people get this protection from a vaccine, without ever having to risk the potentially serious consequences of getting sick with COVID-19. Any side effects  from getting the vaccine are normal signs the body is building protection.

How mRNA COVID-19 Vaccines Work

PDF infographic explaining how mRNA COVID-19 vaccines work.

• English [128 KB, 1 page]
• Other Languages

Protein subunit vaccines (Novavax)

Protein subunit vaccines contain pieces (proteins) of the virus that causes COVID-19. These virus pieces are the spike protein. The vaccine also contains another ingredient called an adjuvant that helps the immune system respond to that spike protein in the future. Once the immune system knows how to respond to the spike protein, the immune system will be able to respond quickly to the actual virus spike protein and protect you against COVID-19.

Research for protein subunit technology

Protein subunit vaccines have been used for years.

• More than 30 years ago, a hepatitis B vaccine became the first protein subunit vaccine to be approved for use in people in the United States.
• Another example of other protein subunit vaccines used today include whooping cough vaccines.
• Protein subunit COVID-19 vaccines are given in the upper arm muscle. After vaccination, nearby cells pick up these proteins.
• Next, our immune system recognizes that these proteins do not belong there. Another ingredient in the vaccine, the adjuvant, helps our immune system to produce antibodies and activate other immune cells to fight off what it thinks is an infection. This is what your body might do if you got sick with COVID-19.
• At the end of the process, our bodies have learned how to help protect against future infection with the virus that causes COVID-19. The benefit is that people get this protection from a vaccine, without ever having to risk the potentially serious consequences of getting sick with COVID-19. Many side effects  from getting the vaccine are normal signs the body is building protection.

How Protein Subunit COVID-19 Vaccines Work

PDF infographic explaining how Protein Subunit COVID-19 vaccines work.

• English [953 KB, 1 page]

Developing COVID-19 Vaccines

While COVID-19 vaccines were developed rapidly, all steps have been taken to ensure their safety and effectiveness. Bringing a new vaccine to the public involves many steps including:

• vaccine development,
• clinical trials,
• U.S. Food and Drug Administration (FDA) authorization or approval,
• and development and approval of vaccine recommendations through the Advisory Committee on Immunization Practices (ACIP) and CDC.

As vaccines are distributed outside of clinical trials, monitoring systems are used to make sure that COVID-19 vaccines are safe.

New vaccines are first developed in laboratories. Scientists have been working for many years to develop vaccines against coronaviruses, such as those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). SARS-CoV-2, the virus that causes COVID-19, is related to these other coronaviruses. The knowledge that was gained through past research on coronavirus vaccines helped speed up the initial development of the current COVID-19 vaccines.

After initial laboratory development, vaccines go through three phases of clinical trials  to make sure they are safe and effective. No trial phases have been skipped.

The clinical trials for COVID-19 vaccines have involved tens of thousands of volunteers of different ages, races, and ethnicities.

Clinical trials for vaccines compare outcomes (such as how many people get sick) between people who are vaccinated and people who are not. Results from these trials have shown that COVID-19 vaccines are safe and effective , especially against severe illness, hospitalization, and death.

Before vaccines are made available to people in real-world settings, FDA assesses the findings from clinical trials. Initially, they determined that COVID-19 vaccines  met FDA’s safety and effectiveness standards and granted those vaccines  Emergency Use Authorizations (EUAs) . The EUAs allowed the vaccines to be quickly distributed for use while maintaining the same high safety standards required for all vaccines. Learn more in this  video about EUAs .

FDA has granted full approval for some COVID-19 vaccines. Before granting approval, FDA reviewed evidence that built on the data and information submitted to support the EUA. This included:

• preclinical and clinical trial data and information,
• as well as details of the manufacturing process,
• vaccine testing results to ensure vaccine quality, and
• inspections of the sites where the vaccine is made.

These vaccines were found to meet the high standards for safety, effectiveness, and manufacturing quality FDA requires of an approved product. Learn more about the process for FDA approval .

When FDA authorizes or approves a COVID-19 vaccine, ACIP reviews all available data about that vaccine to determine whether to recommend it and who should receive it. These vaccine recommendations then go through an approval process that involves both ACIP and CDC.

  Watch Video: Understanding ACIP and How Vaccine Recommendations are Made [00:05:02]

Hundreds of millions of people in the United States have received COVID-19 vaccines under the most intense safety monitoring in U.S. history.

Several monitoring systems continue to track outcomes from COVID-19 vaccines to ensure their safety. Some people have no side effects. Many people have reported common side effects after COVID-19 vaccination , like pain or swelling at the injection site, a headache, chills, or fever. These reactions are common and are normal signs that your body is building protection.

Reports of serious adverse events after vaccination are rare .

• How can you prepare for vaccination?
• What can you expect during and after your vaccination?
• Uninsured? You can still get a free COVID-19 vaccine. Learn more about CDC’s Bridge Access program .

COVID-19 Clinical and Professional Resources

• Coronaviruses
• Vaccine Development Process: How Was Time Saved [779 KB, 1 Page]

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• Published: 03 May 2022

COVID-19 vaccine development: milestones, lessons and prospects

• Maochen Li   ORCID: orcid.org/0000-0001-8786-5039 1   na1 ,
• Han Wang   ORCID: orcid.org/0000-0001-5298-8194 2   na1 ,
• Lili Tian 1   na1 ,
• Zehan Pang   ORCID: orcid.org/0000-0003-4537-2441 1   na1 ,
• Qingkun Yang   ORCID: orcid.org/0000-0002-1548-498X 3 ,
• Tianqi Huang 1 ,
• Junfen Fan 4 ,
• Lihua Song 1 ,
• Yigang Tong 1 , 5 &
• Huahao Fan   ORCID: orcid.org/0000-0001-5007-2158 1  

Signal Transduction and Targeted Therapy volume  7 , Article number:  146 ( 2022 ) Cite this article

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With the constantly mutating of SARS-CoV-2 and the emergence of Variants of Concern (VOC), the implementation of vaccination is critically important. Existing SARS-CoV-2 vaccines mainly include inactivated, live attenuated, viral vector, protein subunit, RNA, DNA, and virus-like particle (VLP) vaccines. Viral vector vaccines, protein subunit vaccines, and mRNA vaccines may induce additional cellular or humoral immune regulations, including Th cell responses and germinal center responses, and form relevant memory cells, greatly improving their efficiency. However, some viral vector or mRNA vaccines may be associated with complications like thrombocytopenia and myocarditis, raising concerns about the safety of these COVID-19 vaccines. Here, we systemically assess the safety and efficacy of COVID-19 vaccines, including the possible complications and different effects on pregnant women, the elderly, people with immune diseases and acquired immunodeficiency syndrome (AIDS), transplant recipients, and cancer patients. Based on the current analysis, governments and relevant agencies are recommended to continue to advance the vaccine immunization process. Simultaneously, special attention should be paid to the health status of the vaccines, timely treatment of complications, vaccine development, and ensuring the lives and health of patients. In addition, available measures such as mix-and-match vaccination, developing new vaccines like nanoparticle vaccines, and optimizing immune adjuvant to improve vaccine safety and efficacy could be considered.

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Safety, immunogenicity and efficacy of an mRNA-based COVID-19 vaccine, GLB-COV2-043, in preclinical animal models

Felipe Lelis, Laura A. Byk, … Antu K. Dey

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Nikolaos C. Kyriakidis, Andrés López-Cortés, … Esteban Ortiz Prado

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious positive-sense, single-stranded RNA virus that spreads rapidly worldwide. The resulting infection, known as coronavirus disease 2019 (COVID-19), can cause several symptoms, such as cough, fever, chest discomfort, and even respiratory distress syndrome in severe cases. 1 , 2 As of March 28, 2022, there were 480,905,839 confirmed cases of COVID-19 worldwide, and 6,123,493 patients died of viral infection or other related complications ( https://coronavirus.jhu.edu/ ).

Effective and safe vaccines are essential to control the COVID-19 pandemic. 3 , 4 Several studies have reported the progress in developing SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) vaccines. 5 , 6 , 7 , 8 The preclinical data of these candidate vaccines partly saved the time for developing the current marketed SARS-CoV-2 vaccines and would provide platforms for the future widespread application of SARS-CoV-2 vaccines. The World Health Organization (WHO) classifies COVID-19 vaccines that have been analyzed or approved for clinical trials into the following categories: inactivated vaccine, live attenuated, vector, RNA, DNA, protein subunit, and virus-like particle (VLP) vaccines.

Animal experiments play a critical role in vaccine development, including evaluating the safety and protective efficacy, determining the injection schedule, and establishing the effective dosage. Small animals, especially rodents, are the foundation of biological and immunological studies in vaccine development. 9 , 10 Generally, rats, mice, guinea pigs, rabbits, and other animals can be used as animal models to evaluate candidate vaccines’ immunogenicity, tolerance, and safety. However, due to species differences between these animals and humans, similar biological effects may not be produced after vaccination. The studies of non-human primates (NHPs) are helpful in understanding and illustrating human immune responses, owing to similar innate and adaptive immune responses. 9 Many reagents used to identify human immune molecules also show similar effects on NHPs. In addition to preclinical trials (animal experiments), clinical trials are essential for developing vaccines. The safety, dosage, and tolerance of vaccines are assessed in the Phase I trial, efficacy and adverse effects are investigated in Phase II and III trials.

Vaccination is a pivotal means to prevent the spread of SARS-CoV-2 and ultimately quell the pandemic. However, vaccine performance is affected by the constant acquisition of viral mutations due to the inherent high error rate of virus RNA-dependent RNA polymerase (RdRp) and the existence of a highly variable receptor-binding motif in the spike (S) protein. 11 , 12 , 13 We have previously noted that the B.1.351 (Beta) variant significantly reduces the neutralizing geometric mean antibody titers (GMT) in recipients 14 of mRNA and inactivated vaccines and may cause breakthrough infections. 15 The reduction in neutralization activity has raised concerns about vaccine efficacy. Thus, rapid virus sequence surveillance (e.g. the identification of E484 mutations in new SARS-CoV-2 variants 16 ) and vaccine updates are crucial.

This review systematically introduces the existing COVID-19 vaccine platforms, analyzes the advantages and disadvantages of the vaccine routes, and compares the efficacy and safety of various vaccines, including the possible complications and different protective efficacies in special populations. Moreover, given the continuous mutation of SARS-CoV-2, we analyze the neutralization activities of various vaccines according to the latest research and propose ideas to improve and optimize existing vaccines, including changing the administration route, adopting more vaccination strategies, and applying more vaccine development methods (Fig. 1 ).

The milestones of COVID-19 vaccine development. With the maturity of vaccine platforms, more and more COVID-19 vaccines have entered clinical trials and been approved for emergency use in many countries. However, the appearance of VOCs has brought great challenges to existing COVID-19 vaccines. By changing the administration route, the protection provided by vaccines can be enhanced, and more vaccination strategies are applied to cope with VOCs. In addition, more vaccine development methods are applied, such as developing polyvalent vaccines and improving adjuvant and delivery systems. These enormous changes form a milestone in the COVID-19 vaccine progress compared with post-years

Vaccine-induced immunity

The immune response elicited by the body after vaccination is termed active immunity or acquired immunity. In this process, the immune system is activated. CD4 + T cells depend on antigen peptide (AP)-MHC (major histocompatibility complex) class II molecular complex to differentiate into helper T cells (Th cells). CD8 + T cells depend on AP-MHC class I molecular complex and differentiate into cytotoxic T lymphocytes (CTL). B cells are activated with the help of Th cells to produce antibodies. After antigen stimulation, B and T cells form corresponding memory cells to protect the body from invading by the same pathogen, typically for several years. The development of COVID-19 vaccines is mainly based on seven platforms, which can be classified into three modes according to the antigen category. 17 , 18 The first mode is based on the protein produced in vitro, including inactivated vaccines (inactivated SARS-CoV-2), VLP vaccines (virus particles without nucleic acid), and subunit vaccines (S protein or receptor-binding domain (RBD) expressed in vitro). The second model is based on the antigen gene expressed in vivo, including viral vector vaccines (using replication-defective engineered viruses carrying the mRNA of S protein or RBD), DNA vaccines (DNA sequences of S protein or RBD), and mRNA vaccines (RNA sequences of S protein or RBD). The third mode is the live-attenuated vaccine. These vaccines can induce neutralizing antibodies to protect recipients from viral invasion. Moreover, some mRNA and viral vector vaccines can induce Th1 cell responses 19 , 20 and persistent human germinal center responses, 21 , 22 which provide more efficient protection. In addition, memory cells induced by COVID-19 vaccines play an important role in vaccine immunity. 23 , 24 , 25

Vaccine-induced Th1 cell response

ChAdOx1 nCoV-19 (AZD1222, viral vector vaccine), NVX-CoV2373 (protein subunit vaccine), mRNA-1273(mRNA vaccine), BNT162 (including BNT162b1 and BNT162b2, mRNA vaccine), and other COVID-19-candidate vaccines were reported to induce Th1 cell responses. 19 , 26 , 27 , 28 After recognition of the AP-MHC class II complex and T-cell receptor (TCR), CD4 + T cells distributed in peripheral lymphoid organs can differentiate into Th1 cells, which secrete various cytokines, such as interleukin 2 (IL-2), and simultaneously upregulate the expression of related receptors (IL-2R). After IL-2 binds to IL-2R, T-cell proliferation and CD8 + T-cell activation are promoted. Both CD4 + and CD8 + T-cell responses have been observed in Ad26.COV-2-S recipients. 29 , 30 The activated CD8 + T cells differentiate into CTLs to further induce cellular immunity. In addition, Th1 cells can secrete interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). 31 The former also induces the differentiation of CD4 + T cells and enhances the intensity of the immune response (Fig. 2 ).

Vaccine-induced Th1 cell response. Some COVID-19 vaccines would induce Th1 cell responses. After recognition of the AP-MHC class II complex and T-cell receptor (TCR), CD4 + T cells distributed in peripheral lymphoid organs can differentiate into Th1 cells, which secrete various cytokines, such as interleukin 2 (IL-2), and simultaneously upregulate the expression of related receptors (IL-2R). Through IL-2 and IL-2R, T-cell proliferation and CD8 + T-cell activation are promoted, CD8 + T-cell can differentiate into cytotoxic T lymphocytes (CTLs) through the activation, producing perforin and other cytokines, which may improve the efficacy of vaccines

When the effector cells (Th cells and CTLs) clear the antigen, the signal maintaining the survival and proliferation of T cells no longer exists, the cell responses are reduced, and the immune system returns to homeostasis. However, antigen-specific memory T cells are crucial for long-term protection, typically formed during T-cell-mediated immunity. 23

Vaccine-induced germinal center response and humoral immune regulation

In addition to T-cell responses, follicular helper T cells (Tfh cells) induced by mRNA vaccines can trigger effective SARS-CoV-2 antigen-specific germinal center B-cell (GC B-cell) responses (Fig. 3 ). 21 , 22 , 32 Upon the interaction of T cells and B cells, some activated Th cells move to the lymphatic follicles and then differentiate into Tfh cells. Activated B cells proliferate and divide in lymphatic follicles to form the germinal center. With the help of Tfh cells, high-frequency point mutations occur in the variable region of the antibody gene of GC B cells, and antibody category transformation occurs, finally forming memory B cells and plasma cells, which can produce high-affinity antibodies. In one study, the GC B-cell response of BALB/c mice peaks between 7 and 14 days after the injection of the mRNA vaccine based on full-length S protein. However, the ability of the RBD-based mRNA vaccine to induce GC B-cell response was poor, indicating that the full-length S protein may play an important role in vaccine-induced GC B-cell response. 22 In addition, a strong SARS-CoV-2 S protein-binding GC B-cell response was detected in lymph node fine-needle aspirates of BNT162b2 (based on full-length S protein) vaccine recipients. The GC B-cell response was detected after the first dose and greatly enhanced after the second dose. 21

Vaccine-induced germinal center response. Some COVID-19 vaccines would induce a germinal center response. Upon the interaction of T cells and B cells, some activated Th cells move to the lymphatic follicles and then differentiate into Tfh cells. Activated B cells proliferate and divide in lymphatic follicles to form the germinal center. With the help of Tfh cells, high-frequency point mutations occur in the variable region of the antibody gene of GC B cells, and antibody category transformation occurs, finally forming memory B cells and plasma cells, which can produce high-affinity antibodies

The continuous existence of GC B cells is the premise for inducing long-lived plasma cells. 33 GC B cells that are not transformed into plasma cells will form memory B cells, and memory B cells are activated rapidly with the help of memory Th cells when encountering the same antigen and then produce plenty of antigen-specific antibodies. It can be concluded that the sustained GC B-cell response induced by the vaccine can secrete potent and persistent neutralizing antibodies and trigger strong humoral immunity. 21

COVID-19 vaccine-induced memory cell responses

The COVID-19 vaccine-induced memory cell responses can induce Th1 and sustained germinal center responses, triggering strong cellular and humoral immunity. In this process, antigen-specific memory T cells and B cells are usually formed, significant for long-term protection (Fig. 4 ). 23 Unlike initial T-cell activation, the activation of memory T cells no longer depends on antigen-presenting cells and can induce a stronger immune response. Most memory B cells enter the blood to participate in recycling and are rapidly activated to produce potent antibodies upon encountering the same antigen. The mRNA-1273 and BNT162b2 induced higher-level production of antibodies and stronger memory B-cell response. 24 Moreover, memory B cells could also be detected in patients who have recovered from COVID-19, and a single dose of mRNA vaccine can induce the memory B-cell response to reach the peak in these patients, 24 , 34 indicating that both previous infection and vaccination can induce memory cell responses.

Vaccine-induced memory cell response. In the Th1 and GC B-cell processes, antigen-specific memory T cells and memory B cells are usually formed. Unlike initial T-cell activation, the activation of memory T cells no longer depends on antigen-presenting cells and can induce a stronger immune response. Most memory B cells enter the blood to participate in recycling and are rapidly activated to produce potent antibodies upon encountering the same antigen

Existing vaccine platforms for COVID-19 vaccines

According to WHO data released on March 28, 2022, 153 vaccines have been approved for clinical trials, and 196 vaccines are in preclinical trials. These vaccines mainly include inactivated vaccines (accounting for 14% of the total), live attenuated vaccines (1%), viral vector vaccines (replication and non-replication; 17% of the total), RNA vaccines (18%), DNA vaccines (11%), protein subunit vaccines (34%), and VLP vaccines (4%) ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ). As of March 28, 2022, a total of ten vaccines (including three India vaccines), including inactivated vaccines, viral vector vaccines, mRNA vaccines, and protein subunit vaccines, have been approved for emergency use by WHO (Fig. 5 ) ( https://extranet.who.int/pqweb/vaccines/vaccinescovid-19-vaccine-eul-issued ). The features, advantages, and disadvantages of different COVID-19 vaccines are shown in Tables 1 , 2 .

A timeline of critical events in the COVID-19 vaccine development progress. WHO has approved the emergency use of ten vaccines (including three India vaccines, COVISHIELD, COVAXIN, and COVOVAX). Vaccination plays a critical role in protecting people from SARS-CoV-2 infections. However, the appearance of VOCs brought big challenges to the efficacy of approved COVID-19 vaccines. These events were summarized and displayed in the form of a timeline

COVID-19 inactivated vaccines

Inactivated vaccines are produced by inactivating the in vitro cultured viruses using chemical reagents. 35 The vaccine can maintain the integrity of virus particles as immunogens. 17 Wang et al. introduced the manufacturing process of the SARS-CoV-2 inactivated vaccine. In this process, SARS-CoV-2 from throat swabs of COVID-19 patients were used to infect Vero cells, and the HB02 strain with the strongest replication ability was selected from three isolated strains (HB02, CQ01, and QD01). After purification, the P1 library was obtained by subculturing in Vero cells with adaptive culturing, subculturing, and amplification. The seventh-generation virus, BJ-P-0207, was selected as the original strain of the COVID-19 inactivated vaccine, 36 , 37 and then β-propiolactone was used to inactivate the virus. 37

An advantage of inactivated vaccines is using the entire virus as an immunogen. Compared with vaccines based on the SARS-CoV-2 S protein or partial protein fragments, such as RBD, inactivated vaccines can induce a wider range of antibodies against more epitopes. 17 In addition, the overall adverse reaction rate of inactivated vaccines in clinical trials is low, and no deaths have been reported in clinical trials, indicating their good safety. 38 , 39 , 40 However, the production of inactivated vaccines are limited because the production of such vaccines must be carried out in biosafety level-3 laboratory or higher biosafety level. 3

The BBIBP-CorV and CoronaVac inactivated vaccines approved by WHO are independently developed in China. A total of 21 candidate COVID-19 inactivated vaccines have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines ).

COVID-19 live attenuated vaccines

Live attenuated vaccines are based on the virus obtained by reverse genetics or adaptation to reduce virulence and are used as non-pathogenic or weakly pathogenic antigens. 17 Currently, the main manufacturing processes include codon pair deoptimization (CPD) and virulence gene knockout. 3 , 41 , 42 Wang et al. and Trimpert et al. reported the CPD-based methods to modify SARS-CoV-2 genes genetically. In their studies, amino acid (aa) 283 deletion was introduced into the S protein, and the furin site was also deleted to attenuate the virulence of the virus but retain its replication ability. 43 , 44

Through the CPD-based method, most of the viral amino acid sequences can be retained and induce extensive responses, including innate, humoral, and cellular immunity against viral structural and nonstructural proteins in the recipient. 3 , 43 The extensive response is unlikely to diminish in efficacy due to antigen drift. In addition, live attenuated vaccines can induce mucosal immunity through nasal inhalation to protect the upper respiratory tract. 3 In contrast, other types of vaccines, such as inactivated and mRNA vaccines, are usually administered intramuscularly and only protect the lower respiratory tract. However, after weakening the virulence gene of the virus, virulence may be restored during replication and proliferation in the host. Thus, the reverse genetic method remains challenging.

Currently, there is no WHO-approved COVID-19 live attenuated vaccine for emergency use. Two candidate COVID-19 live attenuated vaccines, COVI-VAC and MV-014-212, have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines ).

COVID-19 viral vector vaccines

Viral vector vaccines are based on replication-attenuated engineered viruses carrying genetic material of viral proteins or polypeptides. 35 The particular antigen is produced by host cells after immune transduction. 17 Zhu et al. reported the manufacturing process of a viral vector vaccine based on human adenovirus type-5 (Ad5). In this process, the signal peptide gene and optimized full-length S protein gene based on the Wuhan-Hu-1 strain were introduced into a human Ad5 engineering virus with E1 and E3 gene deletions to produce a vector expressing S protein. 45 A recombinant chimpanzee Ad25 vector expressing full-length S protein was used to prepare the ChAdOx1 nCoV-19 vaccine. 46 Recombinant vectors based on the combination of human Ad5 and Ad26 were also used to prepare the Sputnik V vaccine. 47 , 48 In addition, the Ad26.COV-2-S vaccine developed by Janssen is based on the S protein modified by the Ad26 expression gene, with the deletion of the furin site and the introduction of aa986-987 mutations. 48 Besides adenovirus, vesicular stomatitis virus can also be modified and used to produce the COVID-19 vaccine, inducing a stronger humoral immune response via intranasal and intramuscular routes. 49

Except for inactivated vaccines and partially attenuated vaccines, there is no need to deal with live SARS-CoV-2 in manufacturing other types of vaccines (e.g., viral vector, protein subunit, mRNA, DNA, and VLP vaccines), so the manufacturing process of these vaccines is relatively safe. 3 In addition, viral vector vaccines can induce Th1 cell responses, 29 , 50 thus inducing strong protective effects. However, adenovirus-based viral vector vaccines can induce complications, especially thrombocytopenia. Thus, it is necessary to pay attention to the platelet levels of the relevant recipients in case of thrombocytopenia. 51 , 52 Although adenovirus is not easily neutralized by pre-existing immunity, the pre-existing Ad5 antibodies (46.4, 80, 78, 67, 64, 60, 45% and less than 30% of the population with neutralizing antibodies titers for Ad5 of >1:200 in China, India, Kenya, Thailand, Uganda, South Africa, Sierra Leone, and America, respectively, 26 , 53 ) these pre-existing adenoviruses antibodies in the serum may reduce the immunogenicity of such vaccines. Thus an additional flexible dose might be needed as a solution. 26 , 54

The WHO has approved two viral vector vaccines (Ad26.COV-2-S and AZD1222). As of March 28, 2022, 25 candidates’ clinical trials for COVID-19 viral vector vaccines have been approved, with four using replicating vectors and 21 using non-replicating vectors. Moreover, 3 viral vectors (a type of nonreplicable vector and two types of replicable vectors) + antigen-presenting cells and a vaccine based on the bacterial antigen-spore expression vector are also approved for clinical trials ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 protein subunit vaccine

Protein subunit vaccines are based on systemically expressed viral proteins or peptides using various cell-expressing systems, such as bacteria, yeasts, insects, and mammalian cells (such as human embryonic kidney cells). 17 , 35 , 55 , 56 , 57 These vaccines can be divided into recombinant S protein and RBD vaccines. 3 The ZF2001 vaccine adopts the dimer form of the S protein RBD of SARS-CoV-2 as an antigen. 58 Another subunit vaccine (NVX-CoV2373) adopts a full-length S protein with a pre-fusion conformation containing a furin site mutation, and the modified S protein was produced by the Sf9 insect cell expression system. The S protein with a pre-fusion conformation is usually metastable and easily transformed into the post-fusion conformation. The pre-fusion conformation can be stabilized by mutating two residues (K986 and V987) to proline. 17 , 59 In addition, a recombinant vaccine comprising residues 319–545 of the RBD was manufactured using insect cells and a baculovirus expression system, and the purity of the recombinant protein was more than 98% by adding a GP67 signal peptide in the expression system. 60

The protein subunit can also induce Th1 cell responses. 31 In addition, NVX-CoV2373 can induce higher titer neutralizing antibodies than inactivated and Ad5 viral vector vaccines. 3 However, the S protein has a large molecular weight, and the expression efficiency of the S protein is relatively low compared with that of RBD. Although the RBD has a small molecular weight and is easy to express, it lacks other immune epitopes on the S protein and thus is prone to antigen drift. 3

For emergency use, the WHO has authorized only one COVID-19 protein subunit vaccine (NVX-CoV2373). Furthermore, 51 candidate COVID-19 protein subunit vaccines were approved for clinical trials on March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 DNA vaccines

DNA vaccines are based on viral antigens encoded by a recombinant plasmid. Viral proteins or polypeptides are produced by transcription and translation processes in host cells. 17 Smith et al. synthesized the INO-4800 COVID-19 DNA vaccine based on a previously prepared MERS-CoV vaccine. 61 The main steps are as follows: (1) acquisition of the S protein sequence from GISAID; (2) addition of the N-terminal IgE leading sequence; (3) optimization of the IgE-Spike sequence with algorithms to enhance its expression and immunogenicity and synthesize the optimized sequence; (4) ligation of the fragment into the expression vector pGX0001 after digestion. 62 , 63 Brocato et al. constructed the DNA encoding SARS-CoV-2 S protein into the pWRG skeleton plasmid by cloning the gene with optimized human codons, and this skeleton plasmid was used to produce a DNA vaccine against hantavirus. 64

Compared with mRNA vaccines, DNA vaccines have higher stability and can be stored for a long time. 65 Escherichia coli can be used to prepare plasmids with high stability. 3 However, the immunogenicity of the DNA vaccine is low. Furthermore, different injection methods, such as intramuscular or electroporation injection, also affect the vaccine’s efficacy. 3

There is no COVID-19 DNA vaccine authorized by the WHO for emergency use. Sixteen candidate COVID-19 DNA vaccines have been approved for clinical trials on March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 mRNA vaccines

mRNA vaccines are based on mRNA encapsulated by vectors (usually lipid nanoparticles), viral proteins, or polypeptides produced during the translation process in the host cells. 17 , 35 In addition to mRNA itself, the 5′ Cap and 3′ Poly (A) also play important roles in regulating the efficiency and stability of translation. 66 , 67 At present, mRNA vaccines usually adopt the Cap 1 structure (m 7 GpppN 1 mp, with an additional 2′ methylated hydroxyl compared with Cap 0), improving translation efficiency. 66 There are two ways of mRNA tailing: use traditional polyadenylate tails to add the 3′ tail of poly (A) or design the DNA template with a proper length of poly (A), and the latter can obtain a length-controlled poly (A) tail. 67 , 68 Corbett et al. introduced a manufacturing process for the mRNA-1273 vaccine. The optimized mRNA encoding SARS-CoV-2 S-2P protein with stable pre-fusion conformation was synthesized (2 P represents double proline mutations of the K986 and V987 residues mentioned above). The synthesized mRNA sequence was purified by oligo-dT affinity purification, and encapsulated in lipid nanoparticles. 69 The BNT162b2 vaccine also adopts a similar mRNA encoding S-2P, 17 , 70 whereas the BNT162b1 vaccine adopts the mRNA encoding RBD and fuses the trimer domain of T4 fibrin to the C-terminus. Furthermore, a proper delivery system like LNP can protect mRNA against the degradation of nuclease 71 and further enhance the efficacy of mRNA vaccines. The capsulation of mRNA with LNP can effectively transfer mRNA into cells and induce a strong immune response; thus is widely used in most mRNA vaccines, including BNT162b2 and mRNA-1273. 71 , 72 In addition, other delivery systems like lipopolyplexes, polymer nanoparticles, cationic polypeptides, and polysaccharide particles also provide unlimited possibilities for the improvement of mRNA vaccine . 72 , 73

The mechanism of mRNA vaccine-induced immunity is similar to that of the DNA vaccines. Both BNT162b1 and BNT162b2 vaccines transmit the genetic information of the antigen rather than the antigen itself, 3 so they only need to synthesize the corresponding RNA of viral proteins, improving the production speed. 35 In addition, mRNA vaccines can induce strong Th1 cell responses and GC B-cell responses and simultaneously produce long-lived plasma cells and memory cells, continuously eliciting SARS-CoV-2 neutralizing antibodies. 21 , 24 However, mRNA vaccines may cause complications, especially myocarditis, 54 , 74 , 75 , and have a higher storage requirement due to the instability of mRNA. 3

The WHO has approved two types of mRNA vaccines: mRNA-1273 and BNT162b2, and a total of 28 candidate COVID-19 mRNA vaccines have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 VLP vaccines

VLP vaccines are based on noninfectious particles consisting of in vitro-expressed viral structural proteins and decorated viral polypeptides on the surface. 74 Tan et al. used Spy Tag technology to modify the SARS-CoV-2 RBD on the surface of protein particles by forming covalent iso-peptide bonds based on the previous protein nanoparticle platform and obtained an RBD-Spy VLP. 76 Moreover, a self-assembled VLP vaccine based on the expression of modified full-length S proteins, including R667G, R668S, R670S, K971P, and V972P mutations, has also been developed using a plant expression system. 77

VLP vaccines do not contain viral genomes, and plant-based VLP vaccines have the potential of oral delivery vaccines. 65 By loading a variety of antigens, such as the RBD from different variants on the protein particles, neutralizing antibodies against multi-immune epitopes can be induced to improve the neutralizing activity against SARS-CoV-2 variants. However, the manufacturing process of the VLP vaccine is more complex, and no relevant data was published for human clinical trials.

There is no COVID-19 VLP vaccine authorized by the WHO for emergency use. Six candidates' COVID-19 VLP vaccines have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

Efficacy of covid-19 vaccines

Animal studies of covid-19 vaccines approved by the who.

Several SARS-CoV-2 animal models have been developed, including mice expressing human ACE2, 78 , 79 , 80 SARS-CoV-2-adaptive mouse, 81 , 82 ferret, 83 hamster, 84 , 85 and NHP models. 86 , 87 , 88 Although mice can be infected with SARS-CoV-2 by transferring the human ACE2 gene or designing a virus-adapted mouse, no mouse model can simulate all the characteristics of human COVID-19, especially pulmonary vascular disease, hyperinflammatory syndrome, observed in adults and children, respectively. 10 The hamster model can simulate serious COVID-19 diseases. Syrian hamsters show mild to severe symptoms 1–2 days after nasal infection, 89 , 90 and progressive weight loss and dyspnea. The NHP model can reflect mild-to-moderate SARS-CoV-2 infection and can be used to test many candidate vaccines. However, due to different adjuvants and vaccine dosages, the use of serum-neutralizing antibody titer as a direct basis for comparing the efficacy of different vaccines is still limited. In addition, different analytical methods, such as 50% plaque reduction neutralization test (PRNT 50 ), 80% plaque reduction neutralization test (PRNT 80 ), and enzyme-linked immunosorbent assay (ELISA), may also affect the final experimental results. These data can objectively show the efficacy of each vaccine. Here, we summarize the immunogenicity, neutralizing activity, and cell response data from animal experiments for the BBIBP-CorV, CoronaVac, AZD1222, Ad26.COV-2-S, NVX-CoV2373, mRNA-1273, and BNT162b2 vaccines (Fig. 6 ).

A timeline of the preclinical and clinical trials of approved COVID-19 vaccines. Preclinical and clinical trials play important roles in evaluating the safety and protective efficacy of COVID-19 vaccines. The information of preclinical to clinical trials of several WHO-approved COVID-19 vaccines are provided in the form of a timeline, and partial Phase III clinical trials’ data were also displayed to show the total efficacy

Immunogenicity testing of BBIBP-CorV was performed in BALB/c mice, rabbits, and guinea pigs. 36 The animals were classified into three groups according to the doses: high (8 μg), medium (4 μg), and low (2 μg). All dosages produced good immunogenicity, and the serum conversion rate reached 100% on day 21 after immunization. In different dosage groups of BALB/c mice, the immunogenicity of the three-dose group was significantly higher than the two- and single-dose groups. In the NHP experiment, after vaccination, the neutralizing GMTs in rhesus monkeys were 1:860 in the high-dose group and 1:512 in the low-dose group, respectively, indicating BBIBP-CorV can effectively prevent SARS-CoV-2 infection in rhesus monkeys.

The PiCoVacc inactivated vaccine, also known as CoronaVac, is highly immunogenic in BALB/c mice. 37 After the injection of PiCoVacc, the serum S-specific antibody level of mice was ten times higher than that of convalescent serum obtained from COVID-19 patients. PiCoVacc could induce high RBD antibodies, 30 times higher than the induced NTD antibodies. The neutralizing antibody titer in rhesus monkeys was 1:50 in the third week after one dose of PiCoVacc, similar to the titers in the convalescent serum of COVID-19 patients. One week after the third dose of PiCoVacc, viral infection was induced through intranasal and organ routes. The viral load of all vaccinated animals decreased significantly 3–7 days after infection, indicating that PiCoVacc played an important anti-SARS-CoV-2 role in the NHP model.

Compared with BBIBP-CorV and CoronaVac, viral vector vaccines and mRNA vaccines can simultaneously induce T-cell responses, 46 , 48 , 69 , 70 mainly a Th1 cell response, while Th2 responses are related to vaccine-induced respiratory diseases, and were not detected. Viral-specific neutralizing antibodies were detected in all BALB/c mice following inoculation with ChAdOx1 nCoV-19 (AZD1222). On day 14, after the first or second dose, the neutralizing antibody titers in rhesus monkey serum were 1:5 to 1:40 (single dose) and 1:10 to 1:160 (two doses). In addition, cytokines, including IL-4, IL-5, and IL-13, in rhesus monkey serum after a single dose or two doses injection were low, indicating the safety of ChAdOx1 nCoV-19 in NHPs.

Another viral vector vaccine, Ad26.COV-2-S (Ad26-S.PP) induced similar neutralizing antibody titers in the NHP model. 48 RBD-specific neutralizing antibodies were detected in 31 of 32 rhesus monkeys (96.9%) 2 weeks after Ad26-S.PP inoculation and the induced titers were 1:53 to 1:233 (median 1:113) 4 weeks after vaccination. In addition, Ad26-S.PP also induced S-specific IgG and IgA responses in bronchoalveolar lavage (BAL) obtained from rhesus monkeys, indicating that Ad26-S.PP has a protective effect on rhesus monkeys’ upper and lower respiratory tracts. 6 weeks after vaccination, 1.0 × 10 5 50% tissue culture infectious dose (TCID 50 ) of SARS-CoV-2 was challenged in intranasal and tracheal routes, and 17 of 32 rhesus monkeys inoculated with Ad26-S.PP were completely protected, and no viral RNA was detected in BAL or nasal swabs, indicating that Ad26-S.PP protects the upper and lower respiratory tracts in the NHP model.

Besides Ad26.COV-2-S, another protein subunit vaccine NVX-CoV2373, also showed the protection efficacy of both upper and lower respiratory tracts in the cynomolgus macaque model. 91 The vaccine induced a remarkable level of anti-S IgG in mice with the titers of 1:84,000-1:139,000 on the 15th day after the single injection. 59 Meanwhile, NVX-CoV2373 also elicits multifunctional CD4 + and CD8 + T-cell responses. In the NHP model, the serum neutralizing antibody titers produced after the second dose of 2.5, 5, 25 μg vaccine could achieve 1:17,920-1:23,040 CPE 100 , which was 7.1–10 times higher than those in convalescent serum. SARS-CoV-2 was challenged in the upper and lower respiratory tract routes after NVX-CoV2373 vaccination, and 91.6% (11 in 12) immunized animals were free of infection. No viral RNA was detected in the nasal swabs, indicating the broader protection of NVX-CoV2373.

The mRNA-1273 vaccine is most immunogenic in the NHP model. The GMTs of rhesus monkey serum obtained from injection dosages of 10 and 100 μg were 1:501 and 1:3,481, respectively, which were 12 times and 84 times higher than that of human convalescent serum. 69 It has been shown that mRNA-1273 induces a strong S-specific neutralizing antibody response. Rhesus monkeys also showed a dose-dependent Th1 cell response after the injection of mRNA-1273, which was similar to the phenomenon observed after the injection of ChAdOx1 nCoV-19. Intranasal and tracheal routes administered all rhesus monkeys 1.0 × 10 6 TCID 50 of SARS-CoV-2 in the 4th week after the second dose. Four days after infection, only low-level viral RNA in two of eight animals in the 10-μg-dose group and one of eight in the 100-μg-dose groups could be detected, indicating good antiviral activity of mRNA-1273 in the NHP model.

BNT162b1 and BNT162b2 (especially the former) also showed high immunogenicity in BALB/c mice while lower than mRNA-1273. 70 On day 28, after single-dose injection, the serum neutralizing antibody titers of mice with BNT162b1 and BNT162b2 reached 1:1056 and 1:296, respectively. Additionally, both vaccines induced high CD4 + and CD8 + T-cell responses. In the NHP model, the neutralizing antibody titers of rhesus monkey serum obtained from 100 μg-dose 14 days after vaccination with the second dose of BNT162b1 and BNT162b2 were 1:1714 and 1:1689, respectively, which were significantly higher than those in the convalescent serum of COVID-19 patients (1:94). All rhesus monkeys were administered 1.05 × 10 6 plaque-forming units of SARS-CoV-2 by intranasal and tracheal routes on 41–55 days after the second dose of BNT162b1 or BNT162b2. On the third day after infection, viral RNA was detected in the BAL of two of the six rhesus monkeys injected with BNT162b1. Viral RNA was not detected in BAL of the BNT162b2 injected monkeys at any time point.

mRNA, viral vector, and protein subunit vaccines showed higher induced-antibody titers than inactivated vaccines and could induce Th1 cell responses. These vaccines mainly induced IgG production and showed a protective effect on the upper respiratory tract. However, the Ad26.S-PP and NVX-CoV2373 vaccines exerted a protective effect on both the upper and lower respiratory tracts. In addition, all injection groups showed significant virus clearance ability after the virus challenge, demonstrating the protection provided by these vaccines in NHPs. Furthermore, all experimental animals injected with the vaccine showed no pathological changes in the lungs and normal tissues, providing strong support for follow-up clinical trials.

Clinical trials of COVID-19 vaccines approved by the WHO

The safety and effectiveness of vaccines are evaluated in preclinical trials. Clinical trials of candidate vaccines can be carried out only after the relevant data meet the standards for such trials. Ten candidate vaccines have been approved for Phase IV clinical trials. They include three inactivated vaccines (BBIBP-CorV, WIBP COVID-19 vaccine, and CoronaVac), three viral vector vaccines (AZD1222, Ad5-nCoV, and Ad26.COV-2-S), one protein subunit vaccine (MVC-COV1901), and three mRNA vaccines (mRNA-1273, BNT162b2, and mRNA-1273.351) ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ). Data from Phase I, I/II, II, II/III, and III trials and some data from Phase IV clinical trials have been released (Fig. 6 ). Here, the neutralization efficacy, adverse reactions, and cell responses, mainly Th1 cell responses of some vaccines in different clinical trial stages, are discussed. Because of the different adjuvants used and different dosages of the vaccines, the titer of serum neutralizing antibodies cannot be used as a direct reflection of neutralization ability. Moreover, different analysis methods also affect the trial results.

Sinopharm announced the results of a randomized, double-blind, placebo-controlled Phase I/II clinical trial of the BBIBP-CorV vaccine (ChiCTR2000032459). 38 The Phase I and Phase II trials included 192 and 448 healthy aged 18–80 participants, respectively. All participants were negative for serum-specific SARS-CoV-2 IgG or IgM. In the Phase I trial, the vaccine group was injected with 2–8 μg BBIBP-CorV on day 0 and day 28. The control group was injected with two doses of normal saline placebo containing aluminum hydroxide adjuvant. In the Phase II trial, the vaccine group was divided into single-dose (day 0, 8 μg) and two doses (day 0, day 14, 21, 28; 4 μg at each time). In the Phase II trial, on day 28, after the second dose in the two-dose group or after the single dose in the single-dose group, serum neutralizing antibody titers against SARS-CoV-2 were detected based on PRNT 50 . The antibody titer in the single-dose group was 1:14.7, and the titers range of the two-dose group were 1:169.5-1:282.7. The serum titers after two doses on days 0 and 21 were the highest, indicating that two doses of vaccination could induce a higher neutralizing antibody level. In addition, the Phase I trial showed that the serum titer of subjects >60 years old after 28 days of the second dose was less than that of subjects aged 18–59, indicating that the elderly may need higher doses or adjuvants with stronger immunogenicity. None of the subjects in Phase I/II trials displayed severe adverse reactions within 28 days after vaccination. BBIBP-CorV was demonstrated safe for humans. Currently, several Phase IV clinical trials of the vaccine are underway (NCT04863638, NCT05075070, NCT05075083, NCT05104333, NCT05105295, and NCT05104216) ( https://clinicaltrials.gov ).

Huang et al. showed that the neutralization ability of serum neutralizing antibody induced by both BBIBP-CorV inactivated vaccine and ZF2001 subunit vaccine to the Beta variant was reduced by 1.6 times. 92 It is worth noting that serum neutralization activity obtained from BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group were increased, while 80% of samples still failed to neutralize B.1.1.529(Omicron) variant. 93 The results showed that it is necessary to closely monitor the neutralization efficacy of the vaccine against variants, especially those with strong immune escape ability, such as Beta and Omicron, and update the sequence of seed strain in time. 94

Sinovac conducted several randomized, double-blind, placebo-controlled Phase I/II clinical trials for the CoronaVac vaccine (NCT04551547, NCT04352608, NCT04383574). 39 , 95 , 96 Two groups received 3–6 μg of the CoronaVac vaccine, and participants aged 3–17 years received 1.5–3 μg. The control group received the same amount of aluminum hydroxide diluent. None of the participants had a history of SARS-CoV-2 exposure or infection, their body temperature was <37 °C, and none was allergic to the vaccine components. The serum neutralizing antibody titer of the subjects was analyzed with a minimum quadruple dilution using microcytosis. The vaccine induced higher titers in children and adolescents groups in the Phase II trial (3 μg adolescent group, 1:142.2; 6 μg adult group, 1:65.4; 6 μg elderly group, 1:49.9). One case of severe pneumonia unrelated to the vaccine was reported in the placebo group in children and adolescents, one case of acute hypersensitivity after the first dose of injection was reported in the adult group, and seven cases of severe adverse reactions were reported in the elderly group. The remaining adverse events were mild or non-toxic. These findings indicated that CoronaVac could be used in children and adolescents, and it is safe for children, adolescents, and adults.

Furthermore, Sinovac performed Phase III (NCT04582344) and IV clinical trials of CoronaVac for patients with autoimmune diseases and rheumatism (NCT04754698). 40 , 97 In the Phase III trial, 1413 participants, were analyzed for immunogenicity; 880 of 981 (89.7%) serum samples in the vaccine group were positive for RBD-specific antibodies, compared to 4.4% in the control group. The titer of neutralizing antibodies in 387 sera samples in the vaccine group ranged from 1:15–1:625 (1:15, 16%; 1:75, 38.7%; 1:375, 21%), indicating that most vaccine recipients could produce neutralizing antibodies after vaccination. No deaths or grade IV adverse events occurred in the Phase III trial. In the Phase IV clinical trial, using the above analysis based on microcytosis, the serum neutralizing antibody titer of vaccines with rheumatism was only 1:27 6 weeks after the second dose, which was lower than healthy subjects (1:67). These findings indicated that the dose should be increased for individuals with immune diseases, or the immune adjuvant should be replaced to improve protection. Seven Phase IV clinical trials of the vaccine are in progress (NCT04911790, NCT04953325, NCT04962308, NCT04993365, NCT05107557, NCT05165732, and NCT05148949) ( https://clinicaltrials.gov ).

According to the study of Chen Y and colleagues, 98 serum-neutralizing activity against D614G, B.1.1.7(Alpha), and B.1.429 variants after inoculation with CoronaVac were equally effective, while B.1.526, P.1(Gamma) and Beta significantly reduced serum neutralization efficiency. Fernández et al. tested serum neutralization in 44 individuals after two doses of the CoronaVac vaccine. Alpha and Gamma variants could escape from the neutralization of antibodies induced by the vaccine, with escape rates of 31.8 and 59.1% in the subjects, respectively. 99 Estofolete et al. 100 reached a similar conclusion that although the CoronaVac vaccine cannot completely inhibit the infection caused by the Gamma variant, the vaccination can help to reduce patients’ clinical symptoms and the rate of death and hospitalization. The Omicron variant can escape neutralizing antibodies elicited by BNT162b2 or CoronaVac, bringing a challenge to existing vaccines. 101

Phase I/II clinical trials of AZD1222 were divided into two stages (NCT04324606). 50 , 102 In the first stage, 1077 healthy subjects aged 18–55 years with negative laboratory-confirmed SARS-CoV-2 infection or COVID-19 symptoms were recruited. Ten individuals were injected with two doses of 5 × 10 10 viral particles (VPs), the remainders were injected with a single dose of 5 × 10 10 VPs. Those in the placebo group were injected with a licensed meningococcal group A, C, W-135, and Y conjugate vaccine (MenACWY). Serum neutralizing antibody levels were evaluated using a standardized ELISA protocol. The median level of serum samples on day 28 after one dose was 157 ELISA units (EU). The median level of 10 individuals injected with the enhancer dose was 639 EU on day 28 after the second dose, indicating that two injection doses can induce higher neutralizing antibodies. In the second stage of the trial, 52 subjects who had been injected with the first dose received a full-dose (SD) or half-dose (LD) of AZD1222(ChAdOx1 nCoV-19) vaccine on days 28 and 56. The titers of 80% virus inhibition detected by the microneutralization assay (MNA80) were 1:274 (day 0, 28 SD), 1:170 (day 0, 56 LD), and 1:395 (day 0, 56 SD) respectively. The highest titer was produced after the full-second dose injection on day 56. In addition, the AZD1222 vaccine can also induce Th1 biased CD4 + and CD8 + T-cell responses and further promote cellular immunity. No serious adverse reactions were reported in any phase of the trial, and prophylactic paracetamol treatment reduced the rate of mild or moderate adverse reactions. 103

In a single-blind, randomized, controlled Phase II/III trial of AZD1222 (NCT04400838), 104 participants were divided into three groups based on age: 18–55, 56–69, and >70 years. The 18–55 years old group was allocated two low doses (2.2 × 10 10 VPs)/two standard doses (3.5–6.5 × 10 10 VPs) ChAdOx1 nCoV-19 and placebo at 1:1 and 5:1, respectively. The 56–69-year-old group was injected with a single dose of ChAdOx1 nCoV-19, a single dose of placebo, two doses of ChAdOx1 nCoV-19, and two doses of placebo (3:1:3:1, respectively). The >70-year-old group was administered a single dose of ChAdOx1 nCoV-19, a single dose of placebo, two doses of ChAdOx1 nCoV-19, and two doses of placebo (5:1:5:1, respectively). All placebo groups received the aforementioned MenACWY vaccine. MNA80 was used to evaluate the titer of serum neutralizing antibodies. The titer of the low-dose group ranged from 1:143 to 1:161, and that of the standard-dose group ranged from 1:144 to 1:193, indicating that ChAdOx1 nCoV-19 can induce high-level neutralizing antibody in all age groups and that two doses of injection can produce higher antibody levels. Thirteen serious adverse events were reported as of October 26, 2020, and none related to vaccine injection. Phase IV clinical trials of the vaccine are in progress (NCT04760132, NCT04914832, NCT05057897, and NCT05142488) ( https://clinicaltrials.gov ).

Supasa et al. tested the neutralizing effect of AZD1222 on the Alpha variant. GMTs of serum neutralizing antibody decreased by 2.5 times on day 14 and 2.1 times on day 28 after the second dose, while no immune escape was observed. 105 Subsequently, the neutralization effect of AZD1222 on the Beta variant was tested. On day 14 or 28 after the second dose, the GMTs of the subjects’ serum neutralizing antibodies against the Beta variant were approximately nine times lower than that of the Victoria variant (an early Wuhan-related viral isolate). 106 In addition, the serum neutralizing antibody GMTs of AZD1222 subjects against the Delta variant decreased by ~4 times compared with the wild type. 107 On the 28th day after the booster dose, the neutralization ability against Omicron was reduced by about 12.7-fold compared with Victoria and 3.6-fold with B.1.617.2 (Delta). 108 These findings indicate that the Omicron and Beta variants have stronger immune escape ability than the Alpha and Delta variants. Monitoring vaccine neutralization ability should be highlighted, and existing vaccines should be optimized or strengthened to maintain vaccine efficacy for emerging SARS-CoV-2 variants.

Ad26.COV-2-S

Janssen performed Phase I and Phase I-II clinical trials of Ad26.COV-2-S (NCT04436276). 29 , 30 A total of 25 healthy adults aged 18–55 with negative nasopharyngeal PCR and serum IgG results participated in the Phase I trial. The participants were equally allocated to receive two doses of low-dose (5 × 10 10 VPs) Ad26.COV-2-S (low-dose/low-dose, LL), one dose of low-dose vaccine and one dose of placebo (low-dose/placebo, LP), two doses of high-dose (1 × 10 11 VPs) (high-dose/high-dose, HH), one dose of high-dose vaccine and one dose of placebo (high-dose/placebo, HP), or two doses of placebo (placebo/placebo, PP). The placebo group received a 0.9% sodium chloride solution. The GMTs of serum neutralizing antibody based on the inhibition of 50% of pseudovirus (ID 50 ) were detected 14 days after the second dose. The ID 50 values were 1:242 (LL), 1:375 (LP), 1:449 (HH), and 1:387 (HP) in the vaccine groups. Moreover, Ad26.COV-2-S induced CD4 + and CD8 + T-cell responses, simultaneously inducing cellular immunity. Adverse events after vaccination were not evaluated in this study.

In the Phase I-IIa clinical trial, 805 healthy adults aged 18–55 and >65 years were equally divided into LL, LP, HH, HP, and PP groups (low-dose: 5 × 10 10 VPs, high-dose: 1 × 10 11 VPs). On day 71 or 72 (2 weeks after the injection of the second dose), serum neutralizing antibody GMT based on 50% virus inhibition (IC 50 ) of the 18–55-year-old group was 1:827 (LL, day 72), 1:1266 (HH, day 72), 1:321 (LP, day 71), and 1:388 (HP, day 71). On day 29, the serum GMT of the participants injected with a single dose of low-dose or high-dose vaccine in the >65-year-old group was 1:277 or 1:212, respectively. These findings indicated that two injection doses significantly improved antibody titers and enhanced protection. On day 15, 76–83% of the participants in the 18–55 age group and 60–67% of participants in the >65 age group had a Th1 biased CD4 + T-cell response, consistent with the results observed in the Phase I trial. After the first dose, most of the reported local adverse events were grade 1 or 2. The most common event was injection site pain. These collective findings indicated that Ad26.COV-2-S is safe. Four Phase IV clinical trials of the vaccine are ongoing (EUCTR2021-002327-38-NL, NCT05030974, NCT05037266, and NCT05075538) ( https://www.ncbi.nlm.nih.gov , https://clinicaltrials.gov ).

Alter et al. systematically evaluated the neutralization efficacy of the Ad26.COV-2-S vaccine against SARS-CoV-2 variants. 109 Pseudovirus neutralization test results showed the neutralization titer of the antibody induced by the Ad26.COV-2-S to Gamma variant was 3.3 times lower than the wild type. The neutralization of the Beta variant was five times lower than that of the wild type. The live virus neutralization test showed that the neutralization activity of this variant (Beta) dropped approximately ten times in titers. Garcia Beltran et al. found the neutralization activity of serum samples from Ad26. COV-2 vaccinees against the Omicron variant was reduced by 17 times. 110

NVX-CoV2373

NVX-CoV2373 is a protein subunit vaccine based on the full-length S protein of pre-fusion conformation (rSARS-CoV-2). Relevant Phase I-II clinical trial (NCT04368988) data has been released. 31 A total of 131 healthy men and non-pregnant women aged 18–59 years were enrolled. All participants had no history of COVID-19 infection and had a low risk of COVID-19 exposure. Among them, six participants were assigned 5 μg/25 μg rSARS-CoV-2 + Matrix-M1 at a ratio of 1:1 as an initial safety measure and were observed for 48 h. The remaining 125 participants received 9% saline (placebo) as group A, two doses of 25 μg rSARS-CoV-2 without adjuvant Matrix-M1 as group B, two doses of 5 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group C, two doses of 25 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group D, and one dose of 25 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group E, at a ratio of 1:1:1:1:1, respectively. ELISA-based neutralization test was used to detect the antibody titers on the 14th day after the second dose. Group C and D showed the most efficacy with the titers of 1:3906 and 1:3305, respectively, four to six times more than convalescent serum. In addition, T-cell responses were also induced and boosted by the adjuvant Matrix-M1. No serious adverse event was reported in this trial except a subject terminated the second dose due to mild cellulitis.

Results of the Phase III clinical trial of NVX-CoV2373 have also been released. 111 This trial included 16,645 healthy men, non-pregnant women, and people with chronic diseases aged 18–84 without COVID-19 infection and immune disease history. The recipients received two doses of 5 μg NVX-CoV2373 or equivalent placebo (0.9% saline) at a ratio of 1:1. The rate of COVID-19 or SARS-CoV-2 infection 7 days after the vaccination was ~6.53 per thousand in the vaccine group versus 63.43 per thousand in the control group, indicating an overall efficacy of 89.7%. Based on the analysis of subgroups, the effectivity of NVX-CoV2373 in people aged over 65 was 88.9%, and the efficacy against the Alpha variant was 86.3%. The overall rate of adverse events among the recipients was higher in the vaccine group than in the placebo group (25.3 vs. 20.5%). The proportion of serious adverse events was similar in both groups, at about 1%, with one person in the vaccine group reporting severe myocarditis. The vaccine and placebo groups reported one death caused by respiratory failure and one sepsis caused by COVID-19 infection.

A clinical trial was further performed to evaluate the efficacy of NVX-CoV2373 in AIDS patients, in which the Beta variant infected most people. The results indicated that this vaccine showed 60.1% efficacy in HIV-negative participants, indicating that the NVX-CoV2373 vaccine was efficacious in preventing COVID-19. 112

Similar to the viral vector vaccines, mRNA vaccines, especially mRNA-1273, also induced Th1 biased CD4 + T-cell responses in clinical trials. 28 , 113 Moderna performed a Phase I clinical trial of mRNA-1273 (NCT04283461). In the first stage, 45 healthy adults aged 18–55 received two doses of 25, 100, and 250 μg mRNA-1273 at a ratio of 1:1:1. In the second stage, 40 subjects aged >56 years were injected with two doses of 25 and 100 μg vaccine at a ratio of 1:1. The interval between all injections was 28 days. There was no control group. PRNT 50 was used to detect the titers of serum neutralizing antibodies in different age groups 14 days after the second dose, and the titers were 1:343.8 (100 μg, 18–55 years old), 1:878 (100 μg, 56–70 years old), and 1:317 (100 μg, >70 years old). The vaccine induced potent neutralizing antibodies in different age groups, and the highest titer was induced in the 56–70 age group. After the first dose, 23 participants aged 18–55 (51.1%) reported systemic adverse reactions. All the adverse reactions were mild or moderate. After the second dose, three subjects reported serious adverse reactions. No serious adverse events occurred in the group aged over 56 years.

Moderna also performed a Phase III clinical trial of the mRNA-1273 vaccine. The number of participants was 30,420, aged over 18 years and had no history of SARS-CoV-2 infection. Subjects were injected with two doses of mRNA-1273 vaccine (100 μg) at a 28-day interval or with normal saline at a 1:1. 114 From the first day to November 25, 2020, 196 cases of COVID-19 were diagnosed by preliminary analysis, with 11 cases in the vaccine group and 185 cases in the placebo group, indicating a 94.1% effectiveness of mRNA-1273. After the first dose, adverse events occurred in 84.2% of the participants in the vaccine group, and 88.6% of the participants in the vaccine group reported adverse events after the second dose. The adverse events were mainly graded 1 or 2.

Furthermore, there were three deaths in the placebo group (one each from intraperitoneal perforation, cardiopulmonary arrest, and systemic inflammatory syndrome) and two deaths in the vaccine group (one from cardiopulmonary arrest and suicide). Although the death rate was low and unrelated to vaccination, the effects of nucleic acid vaccines on cardiopulmonary and other functions still need to be further studied. Phase IV clinical trials of the mRNA-1273 vaccine are currently underway (NCT04760132, NCT05060991, NCT04952402, NCT05030974, NCT05047718, NCT05075538, and NCT05075538) ( https://clinicaltrials.gov ).

The mRNA-1273 vaccine is still effective for the Alpha variant, but its neutralization effect on the Beta variant is reduced. The pseudovirus neutralization test showed that the antibody titers of mRNA-1273 against the Beta variant were 6.4 times lower than that of the D614G mutant. 115 McCallum et al. tested the neutralization efficacy of mRNA-1273 against the B.1.427/B.1.429 variant and found that the neutralizing antibody GMTs induced by the vaccine decreased by 2–3.5 times compared to the wild type. 116 Furthermore, more than 50% of mRNA-1273 recipients’ serum failed to neutralize the Omicron variant, with the GMTs reduced by about 43 times. 110 , 117

Phase I and III clinical trials of the BNT162b2 mRNA vaccine have also been performed (NCT04368728). 117 The Phase I clinical trial performed by Pfizer-BioNTech involved two candidate vaccines, BNT162b1 encoding RBD and BNT162b2 encoding the full-length of S protein. This trial included 185 healthy adults aged 18-55 and 65–85. With 15 individuals per group, they were divided into 13 groups (seven groups aged 18–55 and six groups aged 65–85) and inoculated with two doses of 10/20/30 μg BNT162b1 or BNT162b2, and an additional group aged 18–55 received a single dose of 100 μg BNT162b2. Twelve individuals in each group were vaccinated with BNT162b1/BNT162b2, and three were vaccinated with a placebo. The 50% neutralization titers were determined on the 14th day after the second dose, ranging from 1:33 to 1:437 (BNT162b1) and 1:81 to 1:292 (BNT162b2). BNT162b1 and BNT162b2 both induced high-level production of antibodies. The local adverse reactions caused by these two vaccines were similar, mainly pained at the injection site. However, the overall rate of adverse events of BNT162b2 was low, with less use of antipyretic analgesics and these findings indicated that BNT162b2 is safer.

The Phase III clinical trial involved 43,548 participants aged 16 years and over, who were injected with two doses of BNT162b2 (30 μg at an interval of 21 days) or placebo at a ratio of ~1:1. 118 At least 7 days after the second dose, eight cases of COVID-19 were observed in the vaccine group, while 162 cases of COVID-19 were observed in the placebo group, indicating the effectiveness of 94.6%. Mild-to-moderate pain at the injection site within 7 days of the first dose of BNT162b2 was the most common local adverse reaction. Less than 1% of all subjects reported severe pain, and none of the participants reported grade 4 local adverse reactions. Two BNT162b2 vaccinees died (one from arteriosclerosis and one from cardiac arrest), four placebo subjects died (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). None of the deaths was related to the vaccine or placebo. Like the mRNA-1273 vaccine, heart disease also occurred in the BNT162b2 vaccine injection group, indicating that the mRNA vaccine needs to be strictly evaluated. Phase IV clinical trials of the BNT162b2 vaccine are currently underway (NCT04760132, NCT05060991, NCT04961229, NCT04775069, NCT04878211, NCT04952766, NCT04969250, NCT05047718, NCT05057169, NCT05057182, and NCT05075538) ( https://clinicaltrials.gov ).

Collier et al. tested the neutralization efficacy of the sera of single-dose BNT162b2 vaccine subjects against the Alpha variant. 119 Ten of 23 samples showed a decrease in neutralization efficacy, with a maximum decrease of about six times. Supasa et al. showed that the neutralization activity of the BNT162b2 vaccine against the Alpha variant decreased by 3.3 times. 105 Subsequently, the researchers further tested the neutralization activity of BNT162b2 against the Beta variant and found that the GMTs of neutralizing antibodies decreased by 7.6 times. 106 In addition, the neutralization activity of the BNT162b2 vaccine against Kappa, Delta, B.1.427, and B.1.429 variants was reduced by at least two times (Kappa and Delta), 1.2 times (B.1.427), and 1.31 times (B.1.429). 120 Although the Delta variant has high infectivity and can cause immune escape, Liu et al. reported that BNT162b2 retained neutralizing activity against the delta variant. 121 In the study carried out by Cameroni E and colleagues, the neutralization activity of BNT162b2 booster-dose recipients’ serum significantly increased, but its neutralization capability against the Omicron variant still decreased by at least fourfold compared with the Wuhan-Hu-1 strain. 122

The effectiveness of COVID-19 vaccines in the real world

Although clinical trials can reflect the effectiveness of vaccines, the outcomes are partly dependent on the status of participants. Thus, the data were not very objective. The real-world study can help to establish clinical trial evidence and provide information for adjusting the vaccination strategy. Here, we summarize several current real-world studies to support these vaccines’ efficacy further. A study on the effectiveness of mRNA vaccine in American healthcare workers (HCW) showed that the overall efficacy of BNT162b2 and mRNA-1273 vaccines were 88.8 and 88.9%, respectively. 123 A study involving six locations in the United States, HCW, and the first responders also showed that after two doses of mRNA vaccine, the effective rate was about 90%. 124 In addition, the 2nd dose of BNT162b2 was shown to reduce 94% of COVID-19 cases in a 1.2 million person dataset. 125 A large-scale study in Scotland showed that the first BNT162b2 vaccination could achieve an efficacy of 91%, and the number of COVID-19 hospitalization decreased in 28–34 days after vaccination. The efficacy of AZD1222 in the same period was 88%, and these two vaccines showed a similar effect on preventing infection. 126 There are limited real-world data on inactivated vaccines. The effectiveness of the CoronaVac vaccine was evaluated in a St. Paul study and showed more than 50% efficacy. 127

These real-world studies showed that the approved COVID-19 vaccines effectively prevent SARS-CoV-2 infections, especially reducing the infection in susceptible people like healthcare workers.

Variants of Concern (VOC)

As mentioned earlier, the emergence of VOC poses great challenges to the efficacy of existing vaccines. WHO has designated five VOCs, including Alpha, Beta, Gamma, Delta, and Omicron (Fig. 5 ), among which Alpha and Delta variants had strong contagious activity, while Beta and Gamma variants gained powerful immune escape ability. However, the Omicron variant obtained high infectivity and can evade most COVID-19 vaccines simultaneously. Understanding the relationship between the mutations and pathogenic characteristics (like infectivity and immune escape ability) is useful to analyze the efficacy of vaccines better and adjust the vaccination strategy properly. Here, the origin of these VOCs has been systematically reviewed, and the influence of mutations on the pathogenic characteristics is illustrated (Fig. 7 ). Furthermore, the effectiveness of approved vaccines on the Omicron variant was also discussed, given that the Omicron variant has caused large-scale infections worldwide and aroused people’s worries.

A systemic illustration of the mutation in the S protein of VOCs. VOCs were designated by WHO because of the enhanced infectivity or immune escape ability (or with both), the specific mutations in the S protein of VOC Alpha to Omicron are displayed, and the mutations related to enhanced immune escape ability were marked in green color, while the mutation related to decreased immune escape ability was marked into orange color

B.1.1.7 is the first variant circulating worldwide, which was first detected in the southeast of the UK in September 2020 and became the dominant variant in the UK during the following 3 months. On December 18, 2020, B.1.1.7 was designated as Variants of Concern (VOC) and labeled Alpha by WHO ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). Compared with other variants at that time, the Alpha variant had a stronger transmission ability, with a higher reproduction number. 128 Interestingly, the variant lineage contained three subgroups initially, but the variant with Del69/70 in the S protein eventually occupied the mainstream, and 96.6% of all detected sequences of Alpha variants contained the mutation ( https://outbreak.info/ ), which indicated the existence of selective advantage in the transmission of SARS-CoV-2. 12 Apart from Del69/70, other mutations (like D614G in each VOC and E484K in Beta and Gamma) also proved the selective advantage. Variants with certain mutations gained stronger infectivity, fitness, or immune escape ability and are prone to survive and spread in the struggle between humans and COVID-19.

The analysis of these mutations with the selective advantage will further help to understand the pathogenic characteristics of these variants, such as infectivity, contagious ability, and immune escape ability. In addition to Del69/70, there are eight mutations in the S protein of Alpha variant: Del144 (contained in 95% of all detected sequences of Alpha variants), N501Y (97.6%), A570D (99.2%), D614G (99.3%), P681H (99%), T716I (98.7%), S982A (98.8%), and D1118H (99.2%) ( https://outbreak.info/ ). Among these mutations, Del69/70 and Del144 can significantly reduce the neutralization of NTD targeted antibodies, 105 because most of the immune epitopes of NTD antibodies are located in N3 (residues 141-156) and N5 (residues 246–260) loops, while Del144 can alter the N3 loop and cause the immune escape of such antibodies, 129 Del69/70 can enhance the infectivity. 130 The characteristic mutation N501Y can significantly increase the binding of S protein to ACE2, 131 and further enhance the infectivity. In addition, N501Y was also related to the immune escape, in which the epitope of class A antibodies was located. 129 This mutation was also in other VOCs like Beta, Gamma, and Omicron. Not only VOC, but almost all circulating variants also had a D614G mutation. Plante JA et al. found that D614G can alter the fitness and enhance the replication of SARS-CoV-2 in the lungs. However, D614G will reduce the immune escape ability of the virus and improve the sensitivity to neutralizing antibodies. 131 , 132 The above studies suggested that this mutation may be essential to maintaining the survival of SARS-CoV-2. Thereby, it can be retained continuously. The P681H mutation near the furin-cleavage site may enhance the cleavage of S1 and S2 subunits and increase the Alpha variant’s entry. The P681R in VOC Delta may improve fitness compared with P681H in the Alpha variant. 133

In general, the Del69/70, N501Y, D614G, and P681H of the Alpha variant were helpful to improve the infection, which can explain the high reproduction number of about 3.5–5.2 ( https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants ). However, Del144 and N501Y affected the neutralization of antibodies, the vaccines approved by WHO showed strong neutralization ability to VOC Alpha, shown in Table 3 .

B.1.351 (also known as 501Y.V2) was first detected in South Africa in May 2020 and firstly appeared after the first epidemic wave in Nelson Mandela Bay. This variant had different characteristics from the dominant variants B.1.154, B.1.1.56, and C.1 in the first wave of pandemic 134 and had spread rapidly in Eastern Cape, Western Cape, and KwaZulu-Natal provinces in just a few weeks, causing the second wave of epidemic in South Africa (October 2020). 135 On December 18, 2020, B.1.351 was designated as VOC by WHO and named Beta ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). Similar to the Alpha variant, B.1.351 lineage also included three subtypes 501Y.V2-1/-2/-3, and 501.Y.V2-1 occupied mainstream, then the 501Y.V2-2 with additional mutations of amino acid site 18 and 417 appeared, and finally Del241/243 mutation occurred in 501Y.V2-3. 136 Among all detected sequences of VOC Beta, 89.6 and 93% had K417N and Del241/243 mutations, indicating that 501Y.V2-3 was the dominant subgroup of VOC Beta ( https://outbreak.info/ ).

There were nine mutations in the S protein of Beta variant: L18F (found in 43.6% reported Beta variants), D80A (97.1%), D215G (94.6%), Del241/243 (89.6%), K417N (93%), E484K (86.5%), N501Y (87%), D614G (97.8%), and A701V (96.4%) ( https://outbreak.info ). The glycans of amino acid site 17, 174, 122, and 149 in the NTD region combined into seven targeted epitopes of NTD antibodies 137 and L18F may interfere with the binding between antibodies, and residue 17 affect the neutralization of antibody. The Del241/243 map to the same surface as the Del144 in the Alpha variant, 138 which may also interfere with the neutralization of antibodies. In addition, several studies have shown that K717N and E484K mutations (as well as the K417T in Gamma variant and E484A in Omicron variant) both contribute to the immune escape against group A-D antibodies, 129 , 136 , 139 , 140 and K417N can enhance the infectivity at the same time. 129 , 141

Overall, the L18F, Del241/243, K417N, E484K, and N501Y mutations all contribute to the immune escape ability of VOC Beta, while K417N, N501Y, and D614G can enhance the viral infection. Therefore, compared with the Alpha variant, the Beta variant has poor transmissibility, but a very strong immune escape ability and can reduce the neutralization efficacy of WHO-approved vaccines by more than 10 times.

P.1 was first detected in Brazil in November 2020 and caused the second wave of the epidemic in this country, causing more than 76% infection of the population, 142 and the average number of daily-confirmed COVID-19 patients in Manaus increased by 180 from January 1 to 19, which was about 30 times of the average increased cases in December. On January 11, 2021, P.1 was designated as VOC by WHO and labeled Gamma.

There were 12 mutations in the S protein of Gamma variant: L18F (found in 97.9% reported P.1 strains), T20N (97.9%), P26S (97.6%), D138Y (95.5%), R190S (93.6%), K417T (95.5%), E484K (95.2%), N501Y (95.3%), D614G (99%), H655Y (98.5%), T1027I (97.2%), V1176F (98.1%) ( https://outbreak.info ). Since most of the mutations of interest like K417T, E484K, N501Y, and D614G have been introduced in the Alpha and Beta variants mentioned above, they will not be repeated here.

Among these mutations, L18F, K417T, E484K, and N501Y help to enhance the immune escape ability, while K417T, N501Y, and D614G can enhance the viral infection. Therefore, VOC Gamma showed a similar immune escape ability to VOC Beta, but less than the Beta variant, which may be caused by mutations outside the RBD region, 143 the infectivity of both Beta and Gamma variants were less than the Alpha variant ( https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants ).

B.1.617.2 was first detected in Maharashtra, India, in October 2020 and spread rapidly in a few months due to the relaxation of prevention and control measures for COVID-19, causing the death of more than 400,000 people. 107 On May 11, 2021, this variant was designated as VOC by WHO and labeled Delta ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). VOC Delta was a worldwide circulating VOC after VOC Alpha and was detected by at least 169 countries ( https://outbreak.info ).

There were ten mutations in the S protein of Delta variant: T19R (found in 98.3% reported delta strains), T95I (38.3%), G142D (66.1%), E156G (92.1%), Del157/158 (92.2%), L452R (96.9%), T478K (97.2%), D614G (99.3%), P681R (99.2%), D950N (95.3%) ( https://outbreak.info ). G142D and E156G are located in the N3 loop, which NTD antibodies could target, 129 thus may affect the neutralization activity of NTD antibodies. The Del157/158 map to the same surface as the Del144 in the Alpha variant and the Del241/243 in the Beta variant, respectively, which may affect the neutralization of antibodies. 138 In addition, both L452R and T478K are located in immune epitopes targeted by group A-B antibodies, enhancing the immune escape ability of Delta variant, 129 , 138 , 144 and L452R is related to a higher infectivity. 145 The P681R mutation enhanced the infectivity of the virus and further improved the fitness compared with P681H, 138 which explained the higher infectivity of VOC Delta than VOC Alpha.

Although the mutations like L452R, T478K have not been reported in previous VOC Alpha, Beta, and Gamma, these mutations gave VOC Delta a stronger transmission ability (with a reproduction number of 3.2–8, mean of 5) and immune escape ability than VOC Alpha, which made Delta variant quickly become a dominant variant and reduce the efficacy of approved vaccines ( https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants ).

In November 2021, B.1.1.529 appeared in many countries. Since the S protein of this variant contains more than 30 mutation sites, and many of them coincide with the S protein mutations of previous VOCs, B.1.1.529 was designated as VOC by WHO on 26 November 2021 and labeled Omicron ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). Although the Omicron variant has more mutations, the severity of the Omicron infected patient was less than Delta. After infection with the Omicron variant, hamsters did not have progressive weight loss similar to that after infection with Alpha/Beta/Delta, and the number of virus copies in the lungs was lower, 146 indicating that Omicron has less effect on the lower respiratory tract. By evaluating Omicron infection on different cells, Thomas P. Peacock et al. found that the infection degree of Omicron on Calu-3 (a lung cell line, whoseTMPRSS2 expression is normal, but lack of CTSL expression, hindering the nuclear endosome pathway of virus entry) is weaker than Delta, indicating that Omicron entry is more dependent on the nuclear endosome mediated endocytosis pathway 147 rather than the membrane fusion pathway involved in TMPRSS2, and TMPRSS2 is mainly distributed in human lung epithelial cells. Therefore, Omicron has less infectivity to the lungs and causes mild symptoms, mainly causing upper respiratory tract infection.

The S protein of the Omicron variant contains 31 mutations: A67V, Del69/70, T95I, G142D, Del143/145, N211I, Del212-212, G339D, S371L, S373P, S375F, K417N, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F (since the proportion of mutations is constantly changing, it is not shown here) ( https://outbreak.info ). Cao Y and colleagues systematically analyzed the effect of these mutations on immune escape. Among them, 477/493/496/498/501/505 mutations affected the neutralization activity of group A antibodies, 477/478/484 mutations affected the neutralization activity of group B antibodies, while the neutralizing activity of group C/D/E antibodies was affected by 484, 440/446, and 346/440 mutations, respectively, Group F antibodies are disturbed by 373/375 mutations. 94 , 129 However, group E and F antibodies showed effective neutralization of the Omicron variant among these antibodies. These two groups of antibodies were rarely used in the clinic and formed lower immune pressure on the virus, reducing the viral mutation of these antibodies and maintaining the binding of antibodies to corresponding epitopes.

Although the Del69/70, K417N, N501Y, D614G, and P681H mutations can enhance the viral infection (with a reproduction number of 2.6–4.0) and Del143/145, K417N, T478K, E484A, and N501Y are related to the immune escape, the infection of Omicron variant has less impact on the lung and is unlikely to cause serious diseases compared with VOC Delta. In addition, many vaccines serum almost lost the neutralization effect on the Omicron variant, indicating that new strategies (such as booster vaccination, sequential vaccination, and the development of new platforms such as nanoparticle vaccine) should be considered.

Pajon et al. and Nemet et al. evaluated the enhanced protection of the third dose of mRNA-1273 and BNT162b2 against the Omicron variant, respectively. 148 , 149 Although a booster dose can enhance the response of memory cells and increase the antibody titers to produce stronger neutralization activity of 20 to100-fold, the enhanced immune response is still limited. An Israeli study showed that the fourth dose of the BNT162b2 or mRNA-1273 vaccine still could not prevent Omicron infection ( https://www.shebaonline.org/ ). In addition, Wang J and colleagues evaluated the protection of the fourth BBIBP-CorV against the Omicron variant. Although the additional inoculation successfully recalled memory cell response in the 6th month after the third dose, the production of antibodies targeting the RBD region was suppressed due to the enhanced immune pressure and decreased peak level 150 The suppression of RBD-targeted antibodies may induce the change of immune epitopes, and a vaccine inducing diverse epitopes antibodies (like a polyvalent vaccine) may decrease the immune pressure on certain epitopes and maintain the efficacy on different VOCs.

SCTV01E is a protein subunit vaccine under development that uses the S trimer of Alpha/ Beta/ Delta/ Omicron variants, and two clinical trials evaluating the safety and immunogenicity of SCTV01E are on the way (NCT05239806 and NCT05238441) ( https://clinicaltrials.gov ). In addition to the polyvalent vaccine, the mRNA vaccine used the VOC Beta sequence also showed better protection against Omicron in the hamster model than existing vaccines. 151

Relevant data of COVID-19 vaccines not yet approved by the WHO

According to the WHO data, as of March 28, 2022, 196 candidate vaccines are in the preclinical stage, and 153 candidate vaccines based on different vaccine platforms have been approved for clinical trials. Here, we present some data for each type of vaccine that the WHO has not approved.

Inactivated vaccines

As of March 28, 2022, 12 inactivated virus vaccines underwent Phase II/III and Phase IV clinical trials. Of these Phase III clinical trials, the QazCovid-in ® -COVID-19 inactivated vaccine developed by the Research Institute for Biological Safety Problems, Republic of Kazakhstan, showed superiority in many aspects, including good immunogenicity and high seroconversion ( https://clinicaltrials.gov/ct2/show/NCT04691908 ).

Live attenuated vaccine

As of March 28, 2022, only one live attenuated vaccine-COVI-VAC has entered a Phase III clinical trial (ISRCTN15779782). The vaccine was developed by the Codagenix and Serum Institute of India. The study starts in August 2021 and runs until September 2023 to objectively evaluate the benefit and risk of COVI-VAC as a candidate vaccine, and relevant data have not been released ( https://www.isrctn.com/ISRCTN15779782 ).

Viral vector vaccine

As of March 28, 2022, two replicating viral vector platform vaccines and eight non-replicating viral vector platform vaccines have been tested in Phase II/III and Phase IV clinical trials. The Gam-COVID-Vac aroused many concerns owing to its effectiveness of 91.6%. 152 A Phase III trial was conducted in Moscow on September 7, 2020 (NCT04530396). 21,977 adults were randomly assigned to the vaccine and placebo groups in this trial. The vaccine group received 0.5 mL Gam-COVID-Vac. Only 0.1% of recipients were infected with SARS-CoV-2, while the percentage of the placebo group was 1.3%. No severe adverse events related to the vaccine were reported.

Protein subunit vaccine

As of March 28, 2022, 22 candidate protein subunit vaccines were in Phase II/III and Phase IV clinical trials. The CpG 1018/Alum-adjuvanted SCB-2019 vaccine was developed by Clover Biopharmaceuticals Inc. and Dynavax. A Phase III clinical trial (NCT05012787), beginning on August 19, 2021, was conducted to evaluate the safety and immunogenicity of the investigational SCB-2019 in adult participants with stable chronic inflammatory immune-mediated diseases (IMDs) ( https://clinicaltrials.gov/ct2/show/NCT05012787 ). Moreover, an RBD-based subunit vaccine developed by the West China Hospital, Sichuan University, and WestVac Biopharma Co., Ltd, showed strong induction of potent functional antibodies, as well as CD4 + T-cell responses in the preclinical trial, 60 and the phase III clinical trial (NCT04887207) of this vaccine, has been completed ( https://clinicaltrials.gov/ct2/show/results/NCT04887207 ).

DNA and mRNA vaccines

As of March 28, 2022, nine RNA and four DNA vaccines have undergone Phase II/III and Phase IV clinical trials. An mRNA vaccine called mRNA ARCoV, developed by the Academy of Military Science, Walvax Biotechnology, and Suzhou Abogen Biosciences was conducted for a Phase III clinical trial of 28,000 subjects (NCT04847102). The subjects were inoculated with a vaccine or placebo in a 1:1 ratio with an interval of 28 days between two injections. It was reported that expected efficacy and good safety had been achieved. The effects of cross-injection will be assessed, including an immunogenic subgroup and a reactive subgroup, to evaluate the humoral immunity induced by the vaccine ( https://clinicaltrials.gov/ct2/show/NCT04847102 ).

Safety of vaccines

Vaccine-induced complications.

Although the currently approved COVID-19 vaccines were safe in clinical trials, the resulting adverse reactions are numerous, including fever, headache, fatigue, injection site pain, and nausea. 3 , 153 As the vaccination campaign progressed, complications occurred in some subjects, and several patients died of cardiovascular diseases, such as arteriosclerosis. Furthermore, cardiac arrest occurred in Phase III clinical trials of the mRNA-1273 and BNT162b2 vaccines. 114 , 118 The possible complications induced by COVID-19 vaccines mainly include the following categories: (1) coagulation dysfunction, such as thrombocytopenia; 52 , 154 (2) heart diseases, such as myocarditis; 74 , 75 (3) immune diseases, such as allergic reactions, 155 autoimmune hepatitis, 156 and autoimmune thyroid diseases; 157 (4) nervous system diseases, such as facial paralysis 158 , 159 and functional neurological disorders; 153 (5) lymphatic system diseases; 160 and (6) other diseases, such as Rowell’s syndrome, 161 macular rash, 162 and chilblain-like lesions 163 (Fig. 8 ). Although the incidence of these complications is low, the relationship between vaccines and these diseases needs to be explored. Here, we describe related COVID-19 vaccine complications and analyze the factors.

A summary of some possible complications induced by COVID-19 vaccines. The possible complications induced by COVID-19 vaccines mainly include the following categories: (1) coagulation dysfunction, such as thrombocytopenia; (2) heart diseases, such as myocarditis; (3) immune diseases, such as allergic reactions, autoimmune hepatitis, and autoimmune thyroid diseases; (4) nervous system diseases, such as facial paralysis and functional neurological disorders; (5) lymphatic system diseases; and (6) other diseases, such as Rowell’s syndrome, macular rash, and chilblain-like lesions

Blood coagulation dysfunction

Greinacher et al. and Lee et al. reported thrombocytopenia in an adenovirus vector vaccine and mRNA vaccine recipients. 154 , 164 A large number of platelet factor 4 (PF4) antibodies were presented in the patients, and the antibody heparin PF4 complex acted on platelet FC γ receptors, activating platelets and further producing procoagulant substances. 154 Adenoviruses can bind to platelets and activate them. 165 , 166 However, trace adenoviruses in vaccines injected one or two weeks before onset seem unlikely to cause platelet activation. Further analysis of PF4 structure revealed that PF4 antibodies from vaccine-induced immune thrombocytopenia patients induced heparin-induced thrombocytopenia by binding eight surface amino acids on PF4. 51 One study counted the cases of thrombosis sequelae voluntarily reported after vaccination, of which at least 169 cases of possible cerebral venous thrombosis and 53 cases of possible visceral venous thrombosis were reported among 34 million individuals vaccinated with ChAdOx1 nCoV-19 vaccine, and 35 cases of central nervous system thrombosis among 54 million individuals vaccinated with BioNTech mRNA vaccine. Among the 4 million subjects receiving the Moderna mRNA vaccine, cerebral venous sinus thrombosis may have developed in five cases. Among the more than 7 million subjects receiving Ad26.COV-2-S vaccine, cerebral venous thrombosis may have developed in six cases. 52 Although the relevant pathogenesis is unclear, a possible trigger factor for these PF4 antibodies is free RNA or DNA in the vaccine. 167

Moreover, platelet activation may also relate to the injury and inflammation induced by mast cell (MC) degranulation. Wu ML et al. found that SARS-CoV-2 can induce degranulation of MCs located in the mucosa, and a rapid MC degranulation could be recapitulated through the binding of RBD to ACE2, resulting in supra-alveolar dermatitis and lung injury. 168 In addition, in the case of inflammation induction and lung epithelial injury, many plasminogen activators may be released. 169 Thus, the increased D-dimer (one of the products formed when plasminase degrades fibrine) concentration was observed in many COVID-19 patients, with a decreased level of platelets. 169 These pathological characteristics of patients were very similar to the thrombotic thrombocytopenia caused by the COVID-19 vaccination. Combined with the above studies, this mechanism may be explained as follows: after the SARS-CoV-2 infection or mRNA vaccine vaccination, S protein stimulated lung epithelial cells and induced MC degranulation, increasing the level of inflammatory mediators. These mediators increased the destructive effect of monocyte macrophages on erythrocytes and led to abnormal platelet levels. In addition, the injury of epithelial cells activated platelets and released coagulation factors, finally forming fibrin and forming extensive micro thrombosis. In this process, the over-consumed platelets and coagulation factors lead to the reduction of coagulation activity, further imbalance of coagulation and anticoagulation, secondary hyperfibrinolysis, and the release of a large number of plasminogen activators, eventually leaded to disseminated intravascular coagulation (DIC), which appeared in most COVID-19 patients. 154 , 169 , 170 Compared with COVID-19 patients, fewer mRNA vaccine subjects reported DIC, which may be due to the lower amount of S protein produced after vaccination than natural infection, and the inflammation is also lower.

Relevant indexes (e.g., measuring prothrombin time, platelet count, and D-dimer concentrations of the receptors) should be tested within 2–3 days after vaccination to prevent the platelet abnormalities caused by COVID-19 vaccination. 169 For patients with abnormal index, preventive treatment (usually heparin or low molecular weight heparin transfusion, the latter is safer) should be taken as soon as possible. 169 In addition, degranulation inhibitors may also be a feasible means to inhibit the inflammatory response and prevent lung injury and platelet abnormalities. 168

Heart diseases

Myocarditis is a rare cardiac complication after COVID-19 vaccine injection. 74 , 75 Rosner et al. reported seven patients hospitalized for acute cardiomyoid disease after vaccination with Pfizer-BioNTech/AstraZeneca ( n  = 6) and Janssen ( n  = 1) vaccines. Larson et al. reported eight patients hospitalized for chest pain within 2–4 days of vaccination with the BNT162b2 or mRNA-1273 vaccine. The laboratory diagnostic cardiac magnetic resonance imaging analysis revealed that these patients have myocarditis. All the subjects had left ventricular ejection dysfunction. The median ejection blood percentage was 48–59%. 74 , 75 These two studies showed a significant temporal correlation between mRNA-based COVID-19 vaccines (including viral vector and mRNA vaccines) and myocarditis. Such systemic adverse events usually occur within 48 h after the second dose. 114 , 118 There may be two potential mechanisms for COVID-19 mRNA vaccines causing heart diseases, such as myocarditis. The first is the nonspecific innate inflammatory responses induced by mRNA. The second is the interaction of the S protein produced by mRNA after the translation within the heart or blood vessels, resulting in cardiovascular injury. 171 Since protein subunit vaccines like ZF2001 and NVX-CoV2373 have not been used widely, and the relevant data are still unreleased, it is not easy to judge whether the S protein causes myocarditis.

Immune diseases

Immune diseases caused by the injection of the COVID-19 vaccine mainly include allergic reactions and autoimmune diseases that include autoimmune hepatitis and autoimmune thyroid diseases. 155 , 156 , 157

Allergic reactions

From December 14 to 23, 2020, 175 of the first batch of 1,893,360 individuals vaccinated with BNT162b2 developed severe allergic reactions within 24 h. These cases were submitted to the vaccine adverse events reporting system (VAERS). 155 Finally, 21 cases were identified as allergic reactions based on the Brighton Collaboration definition criteria. 155 , 172 , 173 Between December 21, 2020, and January 10, 2021, ten of the 4,041,396 subjects vaccinated with the first batch of mRNA-1273 vaccine were identified as allergic reactions. 155 , 173 Risma et al. analyzed the causes of allergic reactions induced by the COVID-19 vaccine. The reasons included nucleic acid of COVID-19 vaccine activated contact system; complement system that was directly activated by the nano lipid plasmid (LNP) vector of the vaccine, resulting in complement-related pseudoanaphylaxis; 174 pre-existing antibodies to polyethylene glycol (PEG) that induced allergic reactions; 175 and direct activation of mast cells leads to degranulation. Allergic reaction mainly includes classical pathway and non-classical pathway. The classical pathway is activated by mast cells and cross-linked IgE, 176 which PEG IgE antibodies may activate in the inoculant. Non-classical pathways mainly involve complement antibody-dependent activation of mast cell activation. 177 To further understand the causes of allergic reactions to the mRNA vaccine, Troelnikov et al. evaluated the ability of PEG, polysorbate 80, BNT162b2 vaccine, and AZD1222 vaccine to activate basophils and mast cells in patients with a previous allergic history of PEG. The authors clarified that PEG covalently modified on vaccine LNP carriers was a potential factor that triggered allergic reactions. 178 For the allergic reaction caused by mRNA vaccines, molecules with better biocompatibility and lower immunogenicity should be considered vaccine carriers to reduce the rate of hypersensitivity reactions.

Autoimmune diseases

Vaccination can trigger a series of immune reactions and the production of neutralizing antibodies against antigens. An excessively strong immune response may simultaneously produce antibodies targeting normal organs or tissues, leading to autoimmune diseases like hepatitis and autoimmune thyroid diseases.

Lodato et al. 156 reported that two days after the second dose of the BNT162b1 vaccine, a 43-year-old woman developed jaundice. A liver biopsy revealed moderate portal inflammatory infiltration, accompanied by bile duct injury and hepatic lobular punctate necrosis. After eight weeks of corticosteroid treatment, the clinical indices of the liver returned to normal. Given the beneficial effect of steroid treatment and the overall period from vaccination to onset consistent with the progress of the immune response, the patient was diagnosed with autoimmune hepatitis. Furthermore, the causal relationship between vaccine injection and autoimmune hepatitis has not yet been fully determined.

In addition to autoimmune hepatitis, cases of immune hypothyroidism caused by vaccination have been reported. Two female medical staff members showed increased thyroid hormone secretion and elevated thyroid antibody levels three days after receiving the COVID-19 vaccine, indicating inhibited thyroid functions. 157

The relationship between autoimmune diseases and COVID-19 vaccines has not been clarified. However, the above cases emphasize the importance of regular follow-up and close observation of the physical condition of vaccines. While vaccination is an effective weapon in ending the COVID-19 epidemic, immune-related complications need to be considered.

Nervous system diseases

Facial paralysis.

Bell’s palsy, also known as acute peripheral facial paralysis of unknown cause, is usually characterized by sudden unilateral facial paralysis. 159 This type of nerve paralysis is typically temporary. Most patients recover within 6–9 months without drug or steroid treatment, 179 but a few patients may have facial dysfunction. Facial paralysis may occur after vaccination, such as the influenza vaccine, caused by viral reinfection. 180 In a clinical trial of the COVID-19 mRNA-1273 vaccine, three of 15,210 subjects developed facial paralysis. 114 , 118 Wan et al. used the reporting systems of medical institutions to evaluate the proportions of facial paralysis within 42 days after vaccination with BNT162b2 and CoronaVac vaccines and found that they were 66.9 cases/100,000 individuals/year in CoronaVac recipients and 42.8 cases/100,000 individuals/year in BNT162b2 recipients, respectively. A higher proportion of facial paralysis occurred in inactivated vaccine recipients, 159 indicating that this complication may be related to the vaccine adjuvant as the inactivated vaccine is unlikely to cause virus reinfection and does not contain active viral nucleic acid. Renoud et al. conducted a disproportionate data analysis based on the WHO pharmacovigilance database and found that 844 cases among 133,883 mRNA vaccination cases had facial paralysis-related events. 181 Although the COVID-19 vaccine may cause acute peripheral facial paralysis, the beneficial and protective effects outweigh the risk of this generally self-limiting adverse event. Adverse event monitoring and controlling should be improved and strengthened to ensure a timely treatment in case of complications.

Functional neurological disorder (FND)

FND is a nervous system disease that can produce neurological symptoms caused by biological, psychological, or environmental factors. 153 The predisposing factors for FND include head injury, surgery, and vaccination. Currently, at least one vaccinated individual has been diagnosed with FND. Kim et al. 153 described the potential relationship between FND and COVID-19 vaccination. Vaccine components are unlikely to be the main cause of FND because FND also occurs after normal saline injection.

Moreover, adverse events, such as local pain at the injection site or systemic muscle pain, may occur after vaccination, which may increase the sensitivity of the patient’s nerves. The reason for FND attacks caused by COVID-19 vaccines has not been determined. Close attention should be paid to the adverse events of vaccinated individuals. Improving the reporting of such events, the public’s confidence in the government and medical institutions will greatly reduce recipients’ psychological and mental pressure, reducing the incidence of FND.

Lymphatic diseases

Injection of the COVID-19 vaccine may lead to inhibition of thyroid function. Since the time window from vaccination to the disease is consistent with the immune process, such adverse reactions are classified as immune diseases, namely autoimmune diseases. In addition, lymphatic diseases, such as abnormal lymph nodes, 160 may also occur after receiving the COVID-19 vaccine. For example, three days after receiving the first dose of the AZD1222 vaccine, eosinophils were detected in the left axillary lymph nodes of a 75-year-old male using [18 F] Choline positron emission tomography/computed tomography (PET/CT), demonstrating the mild uptake ability of choline. The choline uptake occurred in his left arm 3 days after AZD1222 vaccination, indicating the AZD1222 vaccine-induced abnormal lymph node exists. Eifer et al. also described that a 72-year-old woman vaccinated with BNT162b2 subsequently displayed the same phenomenon of increased choline uptake by lymph nodes. 182 The vaccine recipients had tumors resected or treated by other means in both cases. [18 F] Choline PET/CT is an effective method to determine the location of tumor infiltration and the prognosis of tumor patients. Therefore, close follow-up of patients with tumors inoculated with the COVID-19 vaccine should be prudent to avoid incorrect interpretation of the imaging results and incorrect diagnoses of diseases.

Other diseases

In addition to the diseases mentioned above, some COVID-19 vaccines recipients may also have skin diseases, including Rowell syndrome, 161 macula, 162 and chilblain-like lesions. 163

Gambichler T et al. 161 found that a 74-year-old woman developed a severe rash one day after receiving the BNT162b2 vaccine. Clinical examinations showed that the patient had red cohesive spots and papules on the trunk and limbs but no mucosal infiltration. The patient was diagnosed with Rowell’s syndrome (RS), a relatively rare disease characterized by lupus erythematosus with pleomorphic erythematosus lesions and immunological manifestations through further skin biopsy. 183 Subsequently, the patient received steroid treatment, and the symptoms were relieved. In this case, the BNT162b2 vaccine was considered a possible cause of RS, but the patient took pantoprazole for a long-time treatment of chronic gastrointestinal ulcers. Combining this drug and the COVID-19 vaccine may lead to the onset of RS. Some studies have pointed out that omeprazole, a proton pump inhibitor, may cause RS. 184 Therefore, special vaccination groups, especially the elderly or patients with underlying diseases, should be paid attention to their post-vaccination status, and corresponding treatment should be given in time.

Jedlowski P et al. 185 have reported a measles-like rash and papules caused by the BNT162b2 vaccine. After the first dose of the vaccine, a 30-year-old male had adverse reactions such as fever and pain at the injection site, followed by a measles-like rash. After the second dose of the vaccine, he had a recurrent measles-like rash and flesh-colored papules, which had subsided after corticosteroid treatment. Similarly, a 55-year-old man suffered pain and pruritus erythema at the injection site after the first dose of the BNT162b2 vaccine, accompanied by impaired liver function. 162 Subsequently, the patient’s symptoms were significantly improved after corticosteroid therapy.

Piccolo et al. noted that a 41-year-old woman had chilblain-like lesions (CLL) on her fingers and was accompanied by severe pain after receiving the second dose of the BNT162b2 vaccine. 163 This symptom is most likely related to the strong activation of innate immunity and the production of potent antibodies. 186 Additionally, CLL was observed in another 41-year-old female vaccinee, accompanied by severe pain. 187 Although the reasons for CLL in the above cases have not been clarified, the occurrence of CLL after the COVID-19 mRNA vaccine proves the correlation of CLL with the vaccination. 186

In conclusion, although COVID-19 vaccination may be associated with diseases such as thrombosis, myocarditis, and allergy, the proportion of adverse events is low, and vaccination is still an effective means to control and block the epidemic.

Effect of COVID-19 vaccination in different populations

COVID-19 vaccine mainly functions by inducing neutralizing antibodies and memory cells. However, for patients with innate immune diseases, such as autoimmune rheumatism and a history of allergies or tumors, COVID-19 vaccination may cause adverse events. In addition, elderly and pregnant women are also of concern. Compared to adults, vaccine immunization of the elderly may not achieve the desired protective effect due to their weakened immune system functions. 188 , 189 , 190 For pregnant women, the COVID-19 vaccine may cause adverse events, such as abortion, premature birth, or fetal malformation. 191 , 192 Here, we summarize the effects of vaccination in different populations (Fig. 9 ).

Effect of vaccination in different populations. COVID-19 vaccines are still effective for pregnant women, patients with autoimmune diseases, and controlled HIV-infected patients, and the overall efficacy can maintain about 80–90%, while the 30% neutralization reduction occurs in older people. Moreover, the overall neutralizing activity of COVID-19 vaccines in solid organ transplant recipients, cancer patients, and uncontrolled AIDS patients is significantly reduced

Pregnant women

Previous studies have shown that complications including lung injury, diabetes, and cardiovascular diseases in pregnant women after SARS-CoV-2 infection are higher than that in non-pregnant women. 193 However, adverse events, such as abortion or fetal malformation, may occur after COVID-19 vaccination, 191 , 192 which have raised concerns. Shimabukuro et al. 192 evaluated the effects of COVID-19 vaccination on pregnant women and fetuses using the V-safe monitoring and VERS systems. The results indicated that adverse reactions were higher in pregnant women than in non-pregnant women. The most significant adverse event was pain at the injection site. After mRNA vaccination, pregnancy loss occurred in 13.9% of the pregnant women, 86.1% had a normal pregnancy, and 9.4% had a premature delivery. Although pregnancy loss and premature birth could occur, both are low-probability cases, and the benefits of vaccination far outweigh the risks. In addition, the proportion of local or systemic adverse reactions in elderly non-pregnant women was similar to that in pregnant women, 191 indicating that physiological changes during pregnancy did not significantly impact the occurrence of adverse events.

Two other studies analyzed the immunogenicity of COVID-19 in pregnant women and fetuses, and COVID-19 vaccines overall are approximately 90% effective for the vaccinated women. 194 , 195 R Collier et al. analyzed the immune condition of pregnant or lactating women and fetuses after COVID-19 vaccination. 194 Both pregnant and lactating women could produce binding, neutralizing, and functional non-neutralizing antibodies, accompanied by CD4 + and CD8 + T-cell responses. More importantly, binding and neutralizing antibodies were also detected in infant umbilical cord blood and breast milk. These results show that vaccinated pregnant women experience a personal protective effect and produce antibodies that can be delivered to the fetus through the umbilical cord or breast milk to provide immune protection.

Furthermore, a multicenter study conducted in Israel also showed that after vaccination with the BNT162b2 vaccine, IgG antibodies could be produced in the mother. These antibodies can pass through the fetal barrier, and newborns can detect antibody reactions. 195 These two studies showed that after the COVID-19 vaccination, the antibodies in pregnant women could be transferred into the fetus through efficient mother-to-child transmission, effectively protecting the fetus.

Although pregnant women are more likely to experience adverse events after vaccination than non-pregnant women, this proportion is still limited. Within the ideal range, the COVID-19 vaccine can simultaneously protect mothers and infants, reducing the probability of fetal infection with SARS-CoV-2 after birth to a certain extent. Therefore, pregnant women should be voluntarily vaccinated with the COVID-19 vaccine. Meanwhile, government and medical institutions should further improve the health monitoring of pregnant women in the trial to ensure the safety of pregnant women and fetuses.

Elderly individuals

Several studies have analyzed the related immunization levels in the elderly (> 80 years of age) after the COVID-19 vaccination. About 70% protection suggested that at least two vaccination doses should be given to these people. 189 , 190 Lisa et al. 190 compared the production of serum neutralizing antibodies between elderly (>80 years old) and young (<60 years old) vaccine recipients after vaccination with BNT162b2. The IgG antibody titer of the elderly subjects was generally lower than that of the young subjects. Although the antibody levels increased after secondary immunization, 31.3% of the elderly did not produce SARS-CoV-2 neutralizing antibodies, while the antibodies were not detected in only 2.2% of the young subjects after the second dose. Because virus variants, especially variants of concern (VOC), have stronger infectivity or immune escape ability and are prevalent globally. Collier et al. 189 evaluated the effect of serum neutralizing antibodies in elderly individuals on VOC strains Alpha, Beta, and Gamma after two doses of the BNT162b2 vaccine. Neutralizing antibodies against the VOC strain were detected in all age groups. Therefore, the COVID-19 vaccination can still protect the elderly. However, compared with young vaccinated individuals, the CD4 + T-cell response of elderly participants was poor and manifested as low levels of IFN-γ and IL-2. Consequently, government and medical institutions should conduct long-term monitoring of the elderly population and timely deliver “booster shot” vaccination or increase the vaccine dosage to maintain immune efficacy.

Although the COVID-19 vaccine is an effective method to control the pandemic, the current global vaccine resources are still relatively scarce, and complete immunization has not been achieved in most countries. Shrotri et al. 196 conducted a prospective cohort study to systematically analyze the protective effect of a single dose of AZD1222 or BNT162b2 vaccine in individuals aged ≥ 65. After the first dose of the vaccine, evident protection for the elderly lasted for at least 4 weeks, and SARS-CoV-2 transmission was reduced to a certain extent. Another study showed that a single dose of the COVID-19 vaccine could reduce the risk of hospitalization in elderly patients infected with SARS-CoV-2. 197

The collective findings support the view that the elderly should be actively vaccinated against COVID-19. If two doses of vaccine cannot be administered, they should be vaccinated with a single dose. The COVID-19 vaccine can reduce the risk of SARS-CoV-2 transmission to a certain extent, decrease the risk of hospitalization, and promote the safety of the elderly.

Organ transplant recipients

To reduce the immune system’s recognition and attack, patients with solid organ (e.g., kidney and heart) transplantation require long-term immunosuppressants, such as tacrolimus, corticosteroids, and mycophenolate organs. 198 Although immunosuppressive drugs can maintain transplanted organs, they may also affect the body’s antiviral immunity, making solid organ transplant patients more susceptible to SARS-CoV-2 infection and increased mortality risk. 198

Effective immunization of this population is necessary to reduce the infection and death caused by SARS-CoV-2. Several studies have reported that the efficiency of COVID-19 vaccines in solid organ transplant patients after single-dose/two-dose vaccination and enhanced immunization (third dose) was only 20–50%. 199 , 200 , 201 Boyarsky et al. evaluated the effect of a single dose of BNT162b2 or mRNA-1273 vaccine in organ transplant patients. 199 Only 76 (17%) of the 436 subjects elicited neutralizing antibodies, and the titer of these antibodies in elderly patients was lower than that in young individuals. Individuals vaccinated with mRNA-1273 produced higher levels of antibodies. These results showed that a single dose of the COVID-19 vaccine could not effectively prevent SARS-CoV-2 infection in organ transplant patients. Subsequently, this group analyzed two vaccine doses in 658 organ transplant patients. 200 15% of the subjects produced neutralizing antibodies after the first dose of vaccine, whereas 54% after the second dose, indicating that complete vaccination should be fully deployed for organ transplant patients and that these individuals should be closely monitored after vaccination to prevent SARS-CoV-2 infection. Another study carried out by Benotmane I et al. showed that after the third dose of the mRNA-1273 vaccine, neutralizing antibodies were detected in the serum of 49% of renal transplant patients. 201 However, some patients still did not produce neutralizing antibodies, especially those receiving triple immunosuppressive therapy with tacrolimus, corticosteroids, and mycophenolate mofetil after vaccination. In addition to the mRNA vaccine, the protective effect of an inactivated vaccine—the CoronaVac vaccine on organ transplant patients was also evaluated 31 days after two doses. 198 Sixteen of the 85 renal transplant patients had neutralizing antibody reactions.

Furthermore, this result may be related to some participants’ small sample size and impaired renal function. Monitoring neutralizing antibody levels in organ transplant patients should be strengthened, and a booster shot should be administered in time. Mazzola et al. 202 assessed antibody levels in other organ transplant patients after two doses of the BNT162b2 vaccine. In liver, kidney, and heart transplant patients, serum conversion rates were 37.5, 16.6, and 34.8%, respectively. The lower neutralization level in kidney transplant patients was consistent with the study by Sadioğlu et al. 198

The collective findings support the view that for solid organ transplant patients who take immunosuppressants, timely vaccination is important, and clinicians should closely monitor their appropriate antibody levels. Based on the actual situation of this population, immunosuppressive programs and vaccination countermeasures should be formulated to reduce SARS-CoV-2 infection rates.

Cancer patients

Besides organ transplant patients, cancer patients are also a COVID-19 high-susceptible population. Anti-tumor treatments, including radiotherapy and chemotherapy, may lead to systemic hypoimmunity. 203 Several studies have indicated that vaccination can protect about 50–60% of cancer patients from the SARS-CoV-2 infection; thus, they should receive COVID-19 vaccines as soon as possible and complete at least two doses of injection. 204 , 205 , 206

Monin et al. 204 evaluated the safety and immunogenicity of a single dose and two doses of the BNT162b2 vaccine in cancer patients. Twenty-one days after the first dose of the vaccine, 21 of the 56 patients with solid tumors and eight of the 44 patients with blood cancer displayed an anti-S protein immune response. These findings showed that a single dose of the COVID-19 vaccine could not effectively prevent cancer patients, especially those with blood cancer, from the infection with SARS-CoV-2. In contrast, 18 patients with solid cancer and three patients with blood cancer were seroconverted after the second dose of the vaccine. In addition, the BNT162b2 vaccine was safe for patients with breast and lung cancer, and no death caused by vaccination was reported during the trial.

Similarly, Palich et al. evaluated the neutralization activity of the BNT162b2 vaccine in patients with cancer. 206 The seroconversion rate after vaccination was only 55%. Terpos et al. 207 and Maneikis et al. 208 studied the effectiveness of the BNT162b2 vaccine in elderly patients with multiple myeloma and hematological malignancies, respectively. After the first dose of the vaccine, low levels of neutralizing antibodies were detected in the serum of the myeloma patients, which may be due to the inhibition of B-cell proliferation and antibody production by myeloma cells. Patients with hematological malignancies who received two doses of the BNT162b2 vaccine could display serious SARS-CoV-2 breakthrough infections since malignant hematological tumors can destroy immune homeostasis, and the immunosuppressive drug used in the treatment can also affect the production of neutralizing antibodies.

The above studies demonstrate that patients with malignant tumors are susceptible to COVID-19 and should receive timely vaccinations. The vaccination schedule should be based on the patient’s antibody titers to appropriately shorten the interval between the two vaccine injections 205 and ensure a strong immune response. Moreover, patients with malignant tumors should be closely monitored after receiving the COVID-19 vaccine to prevent serious breakthrough infections.

Human immunodeficiency virus (HIV) infected persons and patients with autoimmune diseases

Organ transplant patients and tumor patients may be affected by immunosuppressive drugs and systemic hypoimmunity. 198 , 207 In addition, HIV-infected and autoimmune disease patients are also susceptible to SARS-CoV-2 infection due to their impaired immune system function and immunosuppressants. Several studies have shown that the overall efficacy of the COVID-19 vaccine in controlled HIV-infected people and people with autoimmune disease was about 80%, while the vaccination could not prevent the breakthrough infection in patients with progressive AIDS. 209 , 210

In one study, the AZD1222 vaccine induced strong neutralization reactions in HIV-negative individuals and AIDS patients with well-controlled infections after receiving antiretroviral therapy (ART). 27 Fourteen days after the second dose of the AZD1222 vaccine, HIV-negative individuals and HIV-positive patients treated with ART showed similar neutralizing antibody levels, and antibodies were detected in 87% (13/15) of HIV-infected persons. The results indicate that for HIV patients receiving ART, COVID-19 vaccination can produce an immune response similar to HIV-negative individuals. In contrast, for HIV patients whose condition is not effectively controlled, especially those with progressive AIDS, two doses of the vaccine may not prevent breakthrough infection. 209

In addition to individuals infected with HIV, patients with autoimmune diseases (e.g., autoimmune rheumatism) may also get impaired immunity from the COVID-19 vaccine because of their medication with immunosuppressants, such as mycophenolate mofetil and corticosteroids. 210 In one study, after two doses of the BNT162b2 vaccine, 86% of patients with autoimmune rheumatism experienced serum transformation, but the levels of S1/S2 neutralizing antibodies were significantly lower than that in healthy individuals. Some patients with enteritis who received immunosuppressive treatment also showed reduced immunogenicity following the BNT162b2 and AZD1222 vaccines. 211 These findings highlight that immunization should be completed promptly for individuals receiving the immune drug and that the drug dosage should be adjusted appropriately during vaccine injection to ensure the production of neutralizing antibodies.

Antibody-dependent enhancement (ADE) of vaccines

ADE is a phenomenon in which the pathogenic effect of some viral infections is strengthened in sub-neutralizing antibodies or non-neutralizing antibodies. 212 , 213 , 214 In other words, after natural immunization or vaccination, when contacting the relevant virus again, the antibody produced before might enhance the infection ability of the virus and eventually aggravate the disease. Currently, there is no definitive mechanism to explain the causes of this phenomenon. 215 The ADE simulated in vitro attributes to the pathogenic mechanism as follows: (1) The entry of virus-mediated by the Fcγ receptor (Fcγ R) increases viral infection as well as replication; 216 , 217 (2) Excessive antibody Fc-mediated effector functions or immunocomplex formation enhances inflammation and immunopathology. 214 , 215

Previous studies have shown that HIV, Ebola, influenza, and flaviviruses may induce ADE. 215 And it was reported that respiratory syncytial virus and dengue virus vaccines could also cause ADE, so it is necessary to evaluate the ADE risk of COVID-19 vaccines. 218 Although no serious ADE event caused by the COVID-19 vaccine has been released, 217 the data obtained from other coronaviruses like SARS-CoV and MERS-CoV vaccines can provide experience. 215

Pathogen-specific antibodies that can promote the incidence of pathological ADE should be considered during the development of COVID-19 vaccines. In vitro studies of antibodies against viral infection have identified factors associated with ADE, such as insufficient concentration or low-affinity antibodies. 18 However, protective antibodies may also induce ADE. For instance, the antibody against feline infectious peritonitis virus also enhances infection of monocytes, 214 and data from SARS-CoV or other respiratory virus studies suggest that SARS-CoV-2 antibodies may exacerbate COVID-19. 217 Clinical studies have shown that SARS-CoV-2 antibodies can bind to mast cells, which may be related to the multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) after COVID-19. 219 The binding of SARS-CoV-2 antibodies to Fc receptors on macrophages and mast cells may represent two different mechanisms of ADE in patients. The above findings indicate the possibility of ADE induced by COVID-19 vaccines, to which more attention should be paid to. 220

The preclinical results suggest that vaccination with formalin-inactivated SARS-CoV virions, MVA vaccine expressing SARS-CoV S protein, and S-derived peptide-based vaccine may induce lung disorders in the NHP model. 214 When macaques were inoculated with inactivated SARS-CoV vaccine, they showed ADE after viral infection, manifesting as extensive macrophage and lymphocyte infiltration in the lungs and edema in the alveolar cavity. Mice and hamsters inoculated with trimeric S protein vaccine were not infected with SARS-CoV, but the serum produced could promote the entry of ACE2-independent pseudovirus. 221 Rhesus monkeys inoculated with a high dose of COVID-19 vaccine had elevated body temperature within 1 day, increased respiratory rate, and decreased appetite within 9–16 days. 216 Monkeys euthanized on days 3 and 21 displayed multifocal lung injury, alveolar septum thickening due to edema and fibrin, the slight appearance of type II lung cells, and perivascular lymphocyte proliferation. 214

These models and data emphasize the importance of developing a safe anti-antibody-independent COVID-19 vaccine. At the same time, it is necessary to pay close attention to ADE caused by vaccination against COVID-19. Some studies have shown that antibodies with low affinity and poor neutralization ability may aggravate this disease, while current clinical markers cannot distinguish between severe infection and enhanced antibody dependence. 214 , 218 Therefore, data and mitigation methods from SARS-CoV and MERS-CoV are referential to analyze the ADE phenomenon caused by COVID-19 vaccination. It is important to develop better COVID-19 vaccines and immunotherapy, overcome the identified mutants, and reduce possible ADE pathology.

Improvement of COVID-19 vaccines

Although COVID-19 vaccines can reduce the risk of infection and the mortality of patients, problems with the vaccines at present include declining neutralization activity of variants and vaccination-related adverse events. 14 , 153 , 222 Adopting mix-and-match vaccines 223 and developing new vaccines, such as VLPs and nanoparticle vaccines, 224 improving existing vaccine adjuvants, 225 and changing the vaccination route 226 might enhance the efficacy of vaccines and reduce the occurrence of adverse events to some degree (Fig. 1 ).

Mixed inoculation

In the absence of available vaccine resources, the second injection of an allogeneic vaccine may effectively advance the immunization process. However, vaccination with non-homologous vaccines may raise concerns about safety and effectiveness. Borobia et al. assessed the immunogenicity after inoculating a heterogeneous COVID-19 vaccine and indicated that the heterogeneous vaccine might provide greater immune protection. An initial dose of AZD1222, followed by the BNT162b2 vaccine, can induce strong immune responses and is safe. 227 The research of Hillus et al. 228 reached a similar conclusion. Compared with two doses of AZD1222 administered 10–12 weeks apart and BNT162b2 administered 2–3 weeks apart, the AZD1222 and BNT162b2 vaccines administered at an interval of 10–12 weeks were more effective, with better tolerance and immunogenicity. Heterologous vaccination can complement the advantages of different vaccines, 229 as vaccination with BNT162b2 can elicit strong B-cell immunity and induce high levels of neutralizing antibodies, whereas the AZD1222 vaccine can induce strong T-cell responses. Therefore, this scheme is suitable for individuals with decreased immune function (e.g., organ transplants and cancer patients). Several studies evaluated the neutralization activity of the Omicron variant by the booster dose of homologous or heterologous inoculation. 230 , 231 Both homologous and heterologous enhancers could increase the neutralization activity of subjects’ serum against the Omicron variant, but the neutralization efficiency of an additional heterologous vaccine was higher, supporting the sequential vaccination with heterologous vaccines.

In addition, several studies have shown that individuals previously infected with SARS-CoV-2 have a stronger immune response after the vaccination. 138 , 232 , 233 , 234 Planas et al. tested the serum and antibody levels of 21 medical staff infected with SARS-CoV-2 12 months before vaccinating with a single dose of COVID-19 vaccine (vaccinated 7–81 days before sampling). 138 The serum effectively neutralized Alpha, Beta, and Delta variants, and similar results were obtained by Mazzoni et al. 232 After a single dose of the vaccine, the cellular and humoral immunity levels of patients who had rehabilitated from COVID-19 were further strengthened, 233 and memory B-cell responses were significantly enhanced. These findings explain the significant increase in antibody levels after the first vaccination of rehabilitation patients. 24 Havervall et al. showed that a single dose of COVID-19 vaccine could be used as an effective immune enhancer within at least 11 months after being infected with SARS-CoV-2. 234 Liu and colleagues evaluated the efficiency of the BNT162b2 booster dose against B.1.1.529 (Omicron) variant and found that the serum neutralizing antibody levels from previous-infected recipients with booster dose is higher than naive-uninfected counterparts. 235

The collective findings support the view that vaccination should be actively carried out, regardless of whether the individuals have been infected with SARS-CoV-2 or not. Although previously infected individuals are better protected after a single dose of vaccine, the possibility of breakthrough infection still exists as this immune enhancement may be related to the body’s level of memory B cells. 24 However, there may be individual differences in the level of memory B cells. Therefore, regular antibody testing should be performed for rehabilitated persons who have received a single dose of vaccine to ensure lasting immunity. In addition, it is also a feasible method to implement heterologous vaccination in case of a vaccine shortage. The mixed-vaccination results of CoronaVac and ZF2001 vaccines also supported this view, as the former is much safer while the latter has better immunogenicity. 236 In addition, Zhu et al. found that the mix-vaccination of CoronaVac and Ad5-nCoV can induce higher neutralizing antibodies and provide more effective protection than homologous vaccination. 237

Nanoparticle vaccines

New vaccine platforms, such as mRNA vaccines, provide more powerful immune protection than traditional vaccines. However, these vaccines have lower neutralizing activity against variants, especially the Beta and Delta. 14 , 222 Nanoparticle vaccines may have better neutralizing activity than mRNA vaccines, 224 , 238 , 239 providing a new direction for vaccine development.

Ko et al. 224 designed a nanoparticle vaccine consisting of 24 polymer SARS-CoV-2 RBD nanoparticles and a ferritin skeleton. The vaccine caused cross-neutralizing antibody reactions to bat coronavirus, SARS-CoV, and SARS-CoV-2, including Alpha, Beta, and Gamma variants. The DH1041-DH1045 potent neutralizing antibody induced by the vaccine had neutralizing activity against various mutations, including K417N, E484K, and N501Y. Walls et al. designed a self-assembled protein nanoparticle immunogen composed of 60 SARS-CoV-2 S protein RBDs. The immunogen can target different immune epitopes and still induce high levels of neutralizing antibody expression at low doses. 239 Moreover, compared with traditional vaccines, nanoparticles can exist in B-cell follicles for a long time, producing a sustained germinal center reaction to ensure the high-level production of antibodies. 238 In addition, according to the self-assembly function of ferritin, S protein RBD, 224 hemagglutinin, 240 , and other important viral proteins can be inserted and act as the physiologically relevant trimeric viral spike form to further improve the vaccine efficacy. 238 Therefore, by optimizing the packaging of antigens and producing a stronger, longer-lasting immune response, nanoparticle vaccines are likely to play an important role in future COVID-19 vaccines.

Improvement of immune adjuvants

An adjuvant is a vaccine component to enhance the immune response, playing a very important role in improving the efficacy of vaccines and reducing adverse events to ensure safety. 225 , 241 In the past two decades, a series of new adjuvants have been used in licensed vaccines, including Aluminum hydroxide, MF59, AS03, CpG 1018, and CoVaccine HT, 241 among which the Aluminum hydroxide can reduce the immune-related pathological reactions while other adjuvants can trigger specific cell receptors and induce an innate immune response in the injection site as well as the draining lymph nodes, further promoting the production of antibodies. 225 , 242 Therefore, appropriate adjuvants are critical for maintaining vaccines’ durability and effectiveness. Here, some brief information on existing adjuvants used in COVID-19 vaccines is provided in Table 4 .

Alum is the most widely used adjuvant in global vaccine development, which can induce the antibody response and different CD4 + cell responses (low level). 225 , 241 Relevant mechanisms can be explained as enhancing anti-phagocytosis and activating the proinflammatory NLRP3 pathway. 242 In addition, Aluminum adjuvants can reduce immune-related pathological reactions and improve safety, explaining the excellent safety of BBIBP-CorV and CoronaVac (both of the vaccines used Aluminum hydroxide as adjuvants). 221 , 243 However, the immunogenicity of aluminum adjuvant is poor. The chemical modification of alum with short peptide antigens composed of repeated serine phosphate residues can significantly enhance GC cell and antibody responses. 244

MF59 is a squalene oil-in-water emulsion adjuvant approved for use in influenza vaccines in more than 38 countries, and it is biodegradable and biocompatible. 245 MF59 showed good tolerance and safety, and the inoculation of vaccines that use this adjuvant can motivate the activation of macrophages and the production of chemokines. These chemokines will recruit neutrophils, eosinophils, and monocytes to the lymph nodes, further form a cascade amplification reaction, and activate B cells and T cells. 225 In addition, MF59 can stimulate IL-4 and STAT6 signal pathways and induce the antibody response. It is worth noting that the above response does not depend on type 1 interferon or inflammatory pathway. 246 Thereby, MF59 has been selected as the adjuvant of COVID-19 vaccines.

AS03 is similar to MF59 but has an additional immune-enhanced component α- tocopherol (vitamin E). Thus, it can induce the expression of proinflammatory cytokines and chemokines independently (not depending on the type I interferon). 242 In addition, AS03 can trigger a transient innate immune response, the injection of AS03 induces the transient production of cytokines in the mice model, and vitamin E can further enhance the expression of some chemokines and cytokines like CCL2, CCL3, and IL-6. 225 AS03 is evaluated as the adjuvant of several recombinant S protein vaccines in the clinical trial, the add of AS03 further improve Th2-unbiased cell responses and the production of IFN-γ, which may enhance the efficacy of COVID-19 vaccines. 247

CoVaccine HT is also an oil-in-water (O/W) emulsion, while CpG is a synthetic DNA sequence containing an unmethylated CpG sequence. 242 , 248 Compared with the aluminum hydroxide adjuvant, AMP-CpG and CoVaccine HT showed better immunogenicity. 249 Using AMP-CpG as an adjuvant, persistent antibody and T-cell reactions were still induced in elderly mice at low-dose S protein levels. Reducing the dose of S protein may decrease the occurrence of adverse events and improve vaccine safety. Compared to aluminum hydroxide, CoVaccine HT can promote the production and maturation of neutralizing antibodies to a greater extent, thereby quickly inducing an immune response to SARS-CoV-2. 248

The use of aluminum adjuvants may reduce the adverse events of related vaccines and improve vaccine safety. However, the immunogenicity of aluminum adjuvants is poor. Therefore, the common use of different adjuvants may improve immunogenicity while ensuring subjects’ safety.

Change of inoculation route

In addition to sequential immunization (mixed-vaccination), development of new vaccines (such as nanoparticle vaccine), and adjuvant improvement, changing the vaccination route is also a feasible measure to improve the protection and efficacy of existing COVID-19 vaccines. 3 , 250 All WHO-approved vaccines adopt the intramuscular route (i.m route), and most of them can only protect the lower respiratory tract except for Ad26.COV-2.S, which can both protect the upper and lower respiratory tract. 48 However, the new VOC Omicron has stronger infectivity of the upper respiratory tract and mainly causes symptoms of the upper respiratory tract, so the existing vaccine is difficult to protect effectively. 122 , 235 , 251 Mucosal immunity plays an important role in preventing pathogen invasion. The intranasal administration(inhalation route, i.n route) of vaccines may achieve a better protection effect on preventing SARS-CoV-2 infection (especially Omicron variant). 3 , 250 , 252 , 253 Compared with the traditional i.m route, the i.n route can effectively induce a local immune response. Vaccine antigen enters the respiratory tract and passes through the mucus layer through inhalation to induce the production of local IgA and provide protection at the pathogen’s entry site. 253 In addition, the i.n route can induce the production of higher levels of mucosal antibodies. Although some IgG can be detected on the mucosal surface after the intramuscular injection, the lack of mucosal IgA still makes the respiratory tract vulnerable to infection. 3 In addition, the i.n route has better compliance than the i.m route, and the administration is more convenient. However, the i.n route still has some disadvantages: the systemic immune response induced by this administration method is often lower than that of the i.m route because the titer of the virus may decrease when it is made into aerosol; the i.n route may cause antigen or vaccine adjuvant to enter the central nervous system and cause an adverse reaction; and i.n route usually needs auxiliary drug delivery devices (such as pressure device, atomizer), and the cost is higher, which limits the application of this approach.

Among the currently approved inactivated vaccine, viral vector vaccine, protein subunit vaccine, and mRNA vaccine, only viral vector vaccine has the potential to apply intranasal administration because inactivated vaccine, protein subunit vaccine, and mRNA vaccine antigens cannot actively enter cells, so it is difficult to stimulate mucosa effectively, and they remain difficult to commercialize. 250 Van Doremalen N and colleagues evaluated the efficacy of AZD1222 in macaques and hamsters via intranasal administration. They found that the viral load in the nasal cavity of the experimental group decreased significantly after enhanced intranasal inoculation. No virus particle or RNA was detected in the lung tissue, indicating that intranasal administration is a prospect route for COVID-19 vaccines. 254 Wu S et al. evaluated the safety, tolerability, and immunogenicity of the aerosolized Ad5-nCoV. The inhalation group(2 doses via i.n route on days 0 and 28) reported fewer adverse events compared with the injection group(2 doses of Ad5-nCOV via i.m route on days 0 and 28) and the mixed group(1 dose via i.m route on day 0 and the second dose via i.n route on day 28). The mixed group showed the highest induced-immune level, but the antibodies produced by the inhalation group were less than those of the injection group, suggesting that the inhalation route of Ad5-nCoV is an effective measure to boost immunity. 226

The above study shows that the i.n route can protect the upper respiratory tract and inhibit virus infection more effectively than the i.m route, and relevant adverse events are fewer. However, the immune response induced by the i.n route alone is lower than that induced by the i.m route. Thus i.n route is more suitable for strengthening immunity. Through the mix route (i.m route at first and then i.n route), higher levels of antibodies can be induced compared with the repeat i.m route and provide stronger protection. As more and more vaccines are approved for clinical trials, the i.n route will be used more widely.

Prospects and perspectives

More than 153 candidate vaccines have entered human clinical trials. New vaccine platforms will undoubtedly be evaluated, such as nanoparticle and VLP vaccines.

After vaccination against COVID-19, T-cell immunity (such as the Th1 cell response), B-cell immunity (such as the germinal center response), and other immune responses may be produced. 19 , 21 Differentiated Th cells can enhance the immune response in the body by promoting the activation of CD8 + T cells and secreting IFN-γ. 31 With the aid of Th cells, activated B cells proliferate and divide in lymphatic follicles to form germinal centers, eventually form plasma cells, and memory B cells secret high-affinity antibodies. In addition, COVID-19 vaccines can produce memory B cells and memory T cells. 24 The antiviral immune barrier in the host body can be constructed through the combined action of the humoral immune response, cellular immune response, and memory cells.

Although the COVID-19 vaccines have achieved exciting results in both animal studies and clinical trials, 3 and seven vaccines have been authorized for emergency use by the WHO, adverse events that include pain at the injection site and fever, 114 , 118 as well as complications such as coagulation dysfunction, 154 myocarditis, 74 immune diseases, 155 nervous system diseases 159 and lymphatic system diseases 160 caused by vaccination, have raised concerns about vaccine safety. Given the low proportion of overall incidence of adverse events of vaccines and the fact that some complications occur mainly in patients with underlying diseases (e.g., cardiovascular diseases and tumors). Governments and relevant agencies are recommended to accelerate the vaccine immunization process. Simultaneously, special attention should be paid to the health status of the recipients, timely treatment of complications, vaccine development, and ensuring the lives and health of patients. In addition, considering the characteristics of some individuals (e.g., the elderly, pregnant women, organ transplant patients, cancer patients, and patients infected with HIV), relevant agencies should closely monitor adverse events and detect antibody titers after immunization. 190 For organ transplant and cancer patients, the COVID-19 vaccine showed approximately 50% overall protective efficacy due to the continuous use of immunosuppressive drugs, which is unsatisfactory. 201 , 206 Those populations are susceptible to SARS-CoV-2 infection, and timely immunization-enhanced measures should be performed to reduce breakthrough infections. For HIV-infected individuals, the viral level in the body should be effectively controlled during vaccination. Otherwise, breakthrough infections may still occur. 27 , 209

New SARS-CoV-2 variants like Omicron often have high infectivity and high immune escape ability in the post epidemic era. The existing vaccine strategies are difficult to effectively prevent infections caused by the Omicron variant, which is not only due to the accumulation of more mutation sites in the S protein, but also because the Omicron variant mainly causes upper respiratory tract infection, while the protective antibodies induced by i.m route are often directed at the lower respiratory tract (lung). In this case, changing or adjusting vaccination strategies is very significant to control the infections and alleviate public health pressure. We believe that the following points deserve attention: (1) Although a booster dose can enhance the response of memory cells and increase the antibody titers to produce a stronger protective effect, the fourth dose injection might not effectively Omicron variant infection. 150 (2) The optimization of COVID-19 vaccines, such as changing the administration route (use the inhaled vaccine and induced mucosal immunity to protect the upper respiratory tract further), developing new vaccines (for inactivated vaccines, the combined use of seed strain of VOCs like Beta + Delta may induce antibodies with multi-epitopes, as well as the use of VOC sequence for mRNA or viral vector vaccines, 151 ) and adopting sequential immunization (the use of vaccines developed in different routes like inactivated + viral vector vaccine/mRNA vaccine) will provide better protection than existing vaccination strategies. (3) Although the adoption of inhalable and sequential immunization can improve the efficacy of COVID-19 vaccines, the incidence of adverse reactions of additional Ad5-nCoV was higher than the additional inoculation with homologous inactivated vaccine. 226 In addition, the inoculation with viral vector vaccines or mRNA vaccines may lead to the complications mentioned above (such as myocarditis and thrombosis). The vaccine’s safety and effectiveness should be balanced. Although the new vaccine platform (such as the mRNA vaccine) may provide more effective protection, its safety is lower than the inactivated vaccine. Suppose multivalent inactivated vaccines like Beta + Delta inactivated vaccine strategies are adopted. In that case, the development can only be carried out after the emergence of a new variant, and the developing speed is lower than the mRNA vaccine uses new variants’ sequences. (4) The emergence of the Omicron variant may indicate the change of the main infection site of SARS-CoV-2 (other VOC usually cause the lung infection except for Omicron), and the symptoms of Omicron infected people are lighter, the hospitalization rate is lower than Delta, infected patients. 255 In this case, there are many asymptomatic Omicron infected people. Convenient and effective COVID-19 antiviral drugs (especially oral-taken drugs) will greatly alleviate the severe epidemic situation and contribute to the early end of the COVID-19 pandemic. 256 In addition, Omicron might not be the last VOC, a new recombinant variant Delta 21 J/AY.4-Omicron 21 K/BA.1, also called “Deltamicron”, has appeared in many countries like France and America, and the NTD of Delta combined with the RBD of Omicron may lead to optimization of viral binding to host cell membranes. 257 Although the detected sequence of Deltacron was lower than Omicron, and the main symptom is mild upper respiratory tract infection, surveillance should be enhanced for this emerging variant.

Furthermore, previously SARS-CoV-2-infected individuals produced high-level antibody responses after a single dose of the COVID-19 vaccine, which may be associated with the strong memory cell response. 24 For those who have not been infected with SARS-CoV-2, nanoparticle vaccines may be a better choice to bestow immunity to infections by mutant strains. Compared with traditional vaccines, nanoparticles can remain in germinal center B cells and ensure the production of high-level antibodies by generating a sustained germinal center reaction. 238 In addition to developing new vaccines, adjuvants with better immunogenicity or combined adjuvants may reduce adverse events and improve the vaccine’s protective efficacy. 248

With the launch of new vaccines and the approval of oral antiviral drugs, such as molnupiravir, the stalemate between humans and SARS-CoV-2 will be broken. 256 , 258 A study conducted by Swadling et al. of 58 medical staff with high exposure risk but had not been infected with SARS-CoV-2 found a higher anti-replication transcription complex (RTC) T-cell reaction. 258 These findings may provide new ideas for vaccine design by targeting RTC and inducing similar T-cell responses. And a nasal-delivery IgY antibody based on SARS-CoV-2 RBD showed multi-protection against Beta, Delta, and Omicron variants in the animal model, which promised to be an additional measure of pre-exposure prophylaxis of SARS-CoV-2 infection. 259 These new achievements in the pharmaceutical field will undoubtedly become powerful weapons against COVID-19 and help end the pandemic.

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Acknowledgements

We thank Fuxing Lou, Ruolan Hu (Beijing University of Chemical Technology, China), and Prof. Chunfu Zheng (University of Calgary, Canada) for language and grammar editing.

H.F. declares grants from the National Key Research and Development Program of China (Grant No. 2022YFC0867500, BWS21J025, 20SWAQK22 and 2020YFA0712102), National Natural Science Foundation of China (Grant No. 82151224), Key Project of Beijing University of Chemical Technology (Grant No. XK1803-06, XK2020-02), Fundamental Research Funds for Central Universities (Grant No. BUCTZY2022), and H&H Global Research and Technology Center (Grant No. H2021028).

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College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China

Maochen Li, Lili Tian, Zehan Pang, Tianqi Huang, Lihua Song, Yigang Tong & Huahao Fan

Laboratory for Clinical Immunology, Harbin Children’s Hospital, Harbin, China

College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, China

Qingkun Yang

Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China

Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, China

Yigang Tong

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H.F., Y.T., and L.S. designed the research; M.L., H.W., Z.P., and L.T. read and analyzed the papers; Q.Y., T.H., and J.F. participated in the discussion; M.L. and H.F. wrote and revised the manuscript. All authors have read and approved the article.

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Correspondence to Lihua Song , Yigang Tong or Huahao Fan .

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Li, M., Wang, H., Tian, L. et al. COVID-19 vaccine development: milestones, lessons and prospects. Sig Transduct Target Ther 7 , 146 (2022). https://doi.org/10.1038/s41392-022-00996-y

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COVID-19 vaccine: A 2021 analysis of perceptions on vaccine safety and promise in a U.S. sample

Roles Conceptualization, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Global Health, Indiana University School of Medicine, Indianapolis, Indiana, United States of America

Roles Investigation, Methodology, Project administration, Validation, Visualization, Writing – review & editing

Affiliation Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, United States of America

Roles Investigation, Methodology, Validation, Visualization, Writing – review & editing

Affiliation Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America

Roles Data curation, Formal analysis, Software, Visualization, Writing – review & editing

Affiliation Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, United States of America

Roles Data curation, Funding acquisition, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – review & editing

Affiliation Department of Global Health, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, United States of America

• Vitalis C. Osuji, 
• Eric M. Galante, 
• David Mischoulon, 
• James E. Slaven, 
• Gerardo Maupome

• Published: May 19, 2022
• https://doi.org/10.1371/journal.pone.0268784
• Reader Comments

Despite reliable evidence-based research supporting the COVID-19 vaccines, population-wide confidence and trust remain limited. We sought to expand prior knowledge about COVID-19 vaccine perceptions, while determining which population groups are at greatest risk for not getting a vaccine.

Study participants in the U.S. (79% female, median age group 46–60 years) were recruited through an online Qualtrics survey distributed as a Facebook advertisement from 3/19/21–4/30/21. We assumed that every participant is at risk of COVID-19 infection and should be able to get the vaccine with proper access. Bivariate and multivariable models were performed. Collinearity between variables was assessed.

A total of 2,626 responses were generated and 2,259 were included in data analysis. According to our multivariate model analysis, vaccines were perceived as safe by those who had or planned to obtain full vaccination (adjusted odds ratio (aOR) (95% confidence interval) = 40.0 (19.0, 84.2); p< 0.0001) and those who indicated trust in science (aOR = 10.5 (5.1, 21.8); p< 0.0001); vaccines were perceived as not safe by those who self-identified as Republicans vs. self-identified Democrats (aOR = 0.2 (0.1, 0.5); p = 0.0020) and those with high school or lower education (aOR = 0.2 (0.1, 0.4); p = 0.0007). Similarly, according to our multivariate model analysis, the following groups were most likely to reject vaccination based on belief in vaccinations: those with lower income (aOR = 0.8 (0.6, 0.9); p = 0.0106), those who do not know anyone who had been vaccinated (aOR = 0.1 (0.1, 0.4); p< 0.0001), those who are unwilling to get vaccinated even if family and friends had done so (aOR = 0.1 (<0.1, 0.2); p< 0.0001), those who did not trust science (aOR < 0.1 (<0.1, 0.1); p< 0.0001), those who believe that vaccination was unnecessary if others had already been vaccinated (aOR = 2.8 (1.5, 5.1); p = 0.0007), and those who indicate refusal to vaccinate to help others (aOR = 0.1 (0.1, 0.2); p< 0.0001). An alpha of p<0.05 was used for all tests.

Level of education and partisanship, but not race/ethnicity, were the most likely factors associated with vaccine hesitancy or likelihood to vaccinate. Also, low vaccination rates among underrepresented minorities may be due to distrust for healthcare industries. Population sub-groups less likely to be vaccinated and/or receptive to vaccines should be targeted for vaccine education and incentives.

Citation: Osuji VC, Galante EM, Mischoulon D, Slaven JE, Maupome G (2022) COVID-19 vaccine: A 2021 analysis of perceptions on vaccine safety and promise in a U.S. sample. PLoS ONE 17(5): e0268784. https://doi.org/10.1371/journal.pone.0268784

Editor: Weijing He, University of Texas Health Science Center at San Antonio, UNITED STATES

Received: July 26, 2021; Accepted: May 8, 2022; Published: May 19, 2022

Copyright: © 2022 Osuji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

In early 2020, the SARS-CoV-2 (COVID-19) pandemic unmasked the many flaws that healthcare systems faced worldwide. While some of these issues were difficult to predict, such as the feasibility of pandemic response protocols or federal government regulations to be activated [ 1 ], other healthcare issues were to be expected, especially in the United States. For example, disparities in healthcare treatment and outcomes derived from different socioeconomic factors. Studies published in 2020 showed that the pandemic had much higher infection rates in minority populations such as Black and Hispanic/Latinx compared to their white counterparts; American Indians/ Alaska Natives (AI/ ANs), Black and Hispanic/Latinx communities also experienced significantly higher mortality rates [ 2 , 3 ]. The Centers for Disease Control and Prevention (CDC) released information relating social determinants of health to poorer COVID-19 outcomes, stating that “factors such as discrimination, neighborhood and physical environment, housing, occupation, education, income, and wealth gaps put some racial and ethnic minority groups at increased risk of severe illness from COVID-19, including death” [ 4 ]. Many factors play a role in disparities relevant to the COVID-19 pandemic. These include limited access to health services, education, and transportation, which tend to affect more severely communities of color and people of low socioeconomic status [ 5 ].

Just under one year after the first identification of COVID-19 in China [ 6 , 7 ], the PfizerBioNTech and Moderna COVID-19 vaccines were approved by the US Food and Drug Administration (FDA) under Emergency Use Authorization [ 8 , 9 ]. Ultimately, the Pfizer vaccine was fully approved as of August 23 rd , 2021. These vaccines represented a major milestone in vaccine production history, as no other vaccine had ever been created so rapidly with such positive results [ 10 ]. Although mistrust of vaccines is not uncommon in American culture, hesitation regarding the COVID-19 vaccines may be among the strongest yet [ 11 ]. Despite substantial evidence-based research supporting the vaccines’ safety and efficacy, there are lay public concerns regarding the vaccine rollout. For instance, an analysis [ 12 ] from March 2021 in individuals getting vaccines showed that white Americans were receiving vaccinations at a rate two times that of Black Americans, and the gap for Hispanic/Latinx was even larger. The rationale behind these gaps between racial/ethnic groups remains uncertain and highlights the importance of characterizing the factors and mechanisms underlying potential associations amongst demographic and socioeconomic groups.

With the current vaccines showing 95% efficacy, the estimated percentage of Americans needing vaccination to reach herd immunity ranges from 60 to 72% [ 13 ]. However, according to a November 2020 survey [ 14 ], 40% of Americans said that they will “definitely not” or “probably not” get the COVID-19 vaccine when it becomes available to them. Therefore, more needs to be done to bolster interest and trust in the vaccines. While companies and governmental organizations attempt to convey the necessary strategies to ease vaccine uncertainty and hesitation, a large segment of the lay public remains skeptical. As of May 2021, there were state-level COVID-19 vaccine incentives developed to increase vaccination rates across the United States. Irrespective of these incentives, only 48.6% of the US population was fully vaccinated as of July 2021, while 56% had received at least one dose [ 15 ]. Given these data, reasons surrounding vaccination hesitancy needed to be further explored. We aimed to expand current knowledge about COVID-19 vaccine perceptions through a characterization of sociocultural, socioeconomic, and demographic features in the context of opinions about receiving a COVID-19 vaccine. The objectives of the present survey were to establish:

• What segments of the population believe the COVID-19 vaccines to be safe?
• What are the perceived barriers to obtaining the COVID-19 vaccine—for self and others?
• Is there an association between individual sociocultural characteristics and either acceptance or rejection of the vaccine?
• Is there an association between individual demographic characteristics and either acceptance or rejection of the vaccine?

Materials and methods

This research project was granted IRB approval by Indiana University (protocol #10670).

Data collection was done using an online survey distributed to the general public, and our methodology followed criteria from the CHERRIES checklist [ 16 ]. The survey was created using Qualtrics and piloted with 15 respondents. Based on responses and feedback from our iterative process to pilot the survey, questions were added, rephrased, or deleted. The final survey had 37 questions, with 1–6 questions per page. Question format included 28 multiple choices, with the remainder as yes/no questions. Both English and Spanish versions of the survey were available. A description of the ethical approval, anonymity, and data utilization was provided and acknowledged at the beginning of the survey. Personal information was not required, and participants were offered the option to enter an email address if they wished to participate in an optional raffle draw for five $20 Walmart gift cards. All data were stored in a secure password protected website, to which only study investigators had access. A completeness check prior to submission was not implemented, but a forced response feature on Qualtrics was used for all questions except those involving zip code and email address, to ensure that no significant questions were left unanswered. A link to the final version of the survey was posted to a Facebook page created for the study, and Facebook advertisements were used to promote the study. The survey was made available on March 19 th , 2021 and was closed on April 30 th , 2021. The final data collection survey is available as an attachment ( S1 File ).

This was a survey open to every Facebook user in the United States, based on the assumption that every adult was at risk of COVID-19 infection and should theoretically be able to get the vaccine. We limited responses to people stating they were at least 18-years old and able to read, understand, and agree to the terms of the online survey. Bivariate associations were evaluated using Mantel-Haenszel chi-square tests for questions where one or both variables had ordered categorical responses, and Pearson chi-square tests if both variables had nominal categories. Multivariable models were also performed, using an a priori p-value cut point of 0.20 for inclusion in the model. Collinearity between variables was assessed, leading to the exclusion of several variables from each multivariable model, retaining those based on statistical analysis and the team’s clinical experience. For ease of analysis, race was grouped into 2 categories: white and underrepresented minority. Low income was categorized based on respondents who indicated making less than $40,000 in annual income. The final level of significance for these multivariable models was set at p < 0.05.

All analytic assumptions were verified, and the analyses were performed using SAS/STAT software ® v9.4 [ 17 ].

A total of 2,626 responses were obtained. Based on a total of 3,743 potential participants who clicked our survey link on Facebook, our completion rate was 70.2%. Following data cleaning and exclusion of incomplete responses, a total of 2,259 responses were evaluable.

As outlined in Table 1 , most participants were under 60 years of age (61.5%; median age in the 46–60 years group), female (79.2%) and white (89.6%). Most had never been employed in the healthcare field (63.4%), some were employed full time (44.5%), many had at least some college education (93.1%), about half were affiliated with the Democratic party (54.7%), and many lived within family households (75.7%).

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https://doi.org/10.1371/journal.pone.0268784.t001

To determine what groups perceived the vaccine as safe, bivariate and multivariable models were created. Table 2 shows that subjects who perceived the vaccination as being safe were more likely to have already obtained their second dose or planned on getting it (we allowed for single shot vaccines in our analyses) (97% vs. 12%; p< 0.0001), did not have a prior health condition (98% vs. 86%; p< 0.0001), trusted science (97.1% vs. 21%; p< 0.0001)/vaccines (97% vs. 17%; p< 0.0001)/doctors (97% vs. 21%; p< 0.0001), believed in the effectiveness of hand washing (94% vs. 88%; p = 0.0056)/social distancing (96% vs. 59%; p< 0.0001)/wearing a mask (95% vs. 43%; p< 0.0001), were female (88% vs. 66%; p = 0.0005), were white (90% vs. 82%; p = 0.0063), had higher levels of education (94% vs. 79%; p< 0.0001), and identified as Democrats (58% vs. 7%; p< 0.0001). In the multivariate model, subjects who were still independently associated with the perception of the vaccines being safe were those more likely to have received their second dose (or planned on it) (p< 0.0001), who trusted science (p< 0.0001), had higher levels of education (p = 0.0007), or were Democrats (p = 0.0020).

https://doi.org/10.1371/journal.pone.0268784.t002

To determine what groups were likely to perceive the most barriers to vaccination, bivariate and multivariable models were created ( Table 3 ). By analyzing subjects who were actively seeking vaccination versus those who were not, we found the former were more likely to have had their second dose (or were likely to get it) (92% vs. 20%; p< 0.0001), did not have a prior health condition (94% vs. 85%; p = 0.0283), trusted science (96% vs. 34%; p< 0.0001)/vaccines (95% vs. 31%; p< 0.0001)/doctors (93% vs. 35%; p< 0.0001), believed in the effectiveness of social distancing (91% vs. 68%; p< 0.0001)/wearing a mask (97% vs. 52%; p< 0.0001), were younger (p< 0.0001), were not male (72% vs. 68%; p = 0.0326), were an under-represented minority (40% vs. 23%; p = 0.0043), had a higher median income ($56,000 vs. $49,000; p = 0.0053), or were Democrats (48% vs. 12%; p< 0.0001). In the multivariate model, subjects that were still independently associated with actively seeking a vaccination were those with their second dose already received (or planned on it) (p< 0.0001) and who trusted in science (p = 0.0006).

https://doi.org/10.1371/journal.pone.0268784.t003

Data for the final two objectives were aggregated and analyzed together ( Table 4 ). For those who “do not believe in vaccines”, the variables more likely associated with such outcome included not having a high-risk medical condition (42% vs. 53%; p = 0.0111), not knowing someone who is vaccinated (87% vs. 98%; p< 0.0001), not trusting vaccines (21% vs. 97%; p< 0.0001)/science (26% vs. 97%; p< 0.0001)/doctors (28% vs. 97%; p< 0.0001), not believing in the effectiveness of hand washing (90% vs. 94%; p = 0.0410)/ social distancing (65% vs. 96%; p< 0.0001)/wearing a mask (51% vs. 94%; p< 0.0001), not receiving an annual flu shot (21% vs. 83%; p< 0.0001), thinking there is no need if others have been vaccinated (58% vs. 8%; p< 0.0001), and not wanting to get vaccinated to help others (27% vs. 96%; p< 0.0001). In the multivariate model, subjects that were still independently associated with not believing in vaccines did not know someone who was vaccinated (p< 0.0001), did not trust science (p< 0.0001), believed vaccination is unnecessary if others were vaccinated (p = 0.0007), and would not get vaccinated to help others (p< 0.0001).

https://doi.org/10.1371/journal.pone.0268784.t004

Additionally, the variables associated with subjects who “do not believe in vaccines” included not getting vaccinated even if friends and family had been vaccinated (26% vs. 89%; p< 0.0001), being male (30% vs. 19%; p = 0.0053), being an underrepresented minority (25% vs. 9%; p< 0.0001), not being employed full time (65% vs. 55%; p = 0.0260), having a lower median income ($ 49, 000 vs. $51, 000; p = 0.0020), having lower levels of educational attainment (21% vs. 6%; p< 0.0001), and not being a Democrat (89% vs. 43%; p< 0.0001). In the multivariate model, subjects who were still independently associated with not believing in vaccines were those not getting vaccinated even if friends and family had done so (p< 0.0001), and having a lower median income (p = 0.0106).

Our study is not the first to examine the relationship between various demographics and vaccine hesitancy. Kini and colleagues explored 39 studies regarding demographics of vaccine acceptance and hesitation. Their systematic review suggests that vaccine acceptance increases with age and is higher for males and white individuals [ 18 ]. While our study reports different significant findings (see below), this is likely attributed to the context and sample of the studies, along with possible confounding variables as discussed later. Our results pertain to the time when data were collected: given the long and haphazard evolution of the pandemic and associated perceptions, the relevance of our results must be contextualized to the time and the stage of the pandemic. Our data show some disparities in perception and opinions regarding the COVID-19 vaccines based on the following key variables: age, race, income, educational level, underlying health conditions, and political partisanship. Participants who had received the first of two doses of the COVID-19 vaccine at the time of our study may already have been convinced of the safety of the vaccines. Additionally, during the early stages of vaccine promotion, there was emphasis from the CDC on possible worsening of underlying pulmonary, cardiac, and other health conditions, such as chronic obstructive pulmonary disease, heart failure, and asthma [ 19 ]. This could explain why individuals with underlying health conditions were likely to regard the vaccines as protective and safe.

Our results also showed that those who identifies as white, compared to members of underrepresented minorities, were more likely to consider the vaccine as safe. Based on an assumption of a positive correlation between perceiving the vaccine as safe and actually getting the vaccine, the CDC has shown that as of July 4 th , 2021, of those who had received at least one dose of the vaccine, 59% were white, 9% were black, 16% were Hispanic/Latinx, and 6% were Asian Americans [ 20 ]. However, it is unclear whether such disparity is affected by the communities in which vaccines are most readily available, or if such disparity in fact represents an individual decision due to distrust that might exist between underrepresented minorities and the healthcare industry. As such, it is vital to review past literature as it pertains to recent findings during the pandemic. Regarding vaccine hesitancy of underrepresented minorities, there has been clear evidence of disparities in healthcare treatment for Black and white patients. Davidio et al reviewed multiple papers that describe physician perceptions and treatment of Black vs. white patients with clear significance regarding the negative handling of Black patients [ 21 ]. Armstrong et al point out that experience of discrimination was strongly associated with healthcare system distrust (HCSD) in their study comparing African American and white survey respondents [ 22 ]. Additionally, Balasuriya et al explored factors associated with COVID-19 acceptance and access among Black and Latinx communities, and identified the pervasive mistreatment of Black and Latinx communities, rooted in structural racism, to be a key influence on vaccine acceptance [ 23 ]. Results such as this provide a strong basis to argue why underrepresented minorities may have been less eager to seek out vaccinations. Regarding vaccine hesitancy and political affiliation, other studies corroborate these results. In one study, it was found that US Republican counties consistently had lower general vaccination rates than Democratic counties [ 24 ]. In a polling done by Kaiser Family Foundation in May 2020, it was found that Republicans were less likely to report wearing masks, social distancing or getting vaccinated against COVID-19 [ 25 ].

Level of education has a strong effect on willingness to receive a COVID-19 vaccine: having a college degree has been associated with a 43% increase in likelihood of getting the vaccine [ 26 ]. Assuming the likelihood of obtaining the COVID-19 vaccine is positively correlated with perception that the vaccine is safe, it is worthwhile posing the question whether level of education outweighs other effects of race, gender, political affiliation, and underlying health conditions. Delay in COVID-19 vaccination notwithstanding (earlier in 2021 when our data were collected), the CDC has pointed to a divide in communities based on political party affiliation. To ultimately determine the prime factors in safety perception, we conducted a multivariable analysis and found that the following groups were most likely to perceive vaccines as being safe: 99.3% Democrats (vs. 86.0% Republicans, specifically) and 93.1% with higher educational attainment (vs. 6.8% with high school level specifically). It is important to correlate these results with previous studies that examined similar topics. Regarding results about education impacting vaccine rates, previous studies would support this. Suryadevara and colleagues collaborated with their county health department to educate high-risk, resource-poor families regarding vaccination concerns. Their results showed a drastic increase for general vaccine completion and annual influenza vaccine rates [ 27 ]. Another study showed that when providing low-literacy educational materials to resource-poor families regarding the pneumococcal vaccine, the test group was four times more likely to discuss the vaccination in appointments and five times more likely to receive the vaccine than control group [ 28 ]. Even more recent studies with COVID-19 support our findings. For instance, a recent study indicated that lack of high school education positively correlates with increased vaccine hesitancy and decreased vaccination levels [ 29 ].

Our multivariable model outcome also suggests that race and ethnicity are not necessarily the primary determinants of vaccine hesitancy and likelihood of vaccination, because low vaccination rates among underrepresented populations may be explained by the historical distrust within some members of underrepresented minorities toward health care organizations and providers, as well as suspicion about clinical research studies, in view of past atrocities such as the Tuskegee Syphilis experiment [ 30 ], or similar experiments with STD infections in Guatemala [ 31 ]. Our multivariable results support this possibility by indicating those being potential factors in rejecting the COVID-19 vaccine. Specifically, after adjusting for variables, one of the groups found to be independently associated and most likely to reject vaccination according to socioeconomic and demographic factors were individuals with lower income. Considering that low-income populations usually consist of groups that identify as underrepresented minorities [ 32 ], slow rates of vaccination in these groups might reflect individual distrust of health care providers. However, this finding does not rule out the possibility of low distributions in low-income locations (e.g., rural), which could be a barrier by itself for vaccination opportunities. As pointed out by DeMaria-Ghalili and colleagues, “health inequalities are most acute among those living in rural and low resourced areas of the state, and among underrepresented populations (particularly Black/African American and Latino), who lack access to health care, experience digital divide, and face persistent local healthcare workforce shortages.” The report further discusses that people in areas of lower socio-economic status or fewer resources (usually rural areas) have a more difficult time scheduling and going to appointments for vaccinations, noting “pharmacy deserts” to be an issue in having access to appropriate healthcare resources such as vaccines [ 33 ]. Economic precarity and poor technological advancements may be obstacles to both registering for and getting the vaccine, possibly associated with sparse information among low-income populations [ 34 ]. Therefore, to bolster vaccination, efforts should be made to target groups who are most likely to encounter barriers to COVID-19 vaccination, through governmental incentives, including free childcare and rides to vaccination sites, lottery tickets or cash vouchers, complimentary food and drinks at the vaccination sites, and tax credit [ 35 ], rather than privately offered incentives that may vary greatly throughout the country.

Our successful recruitment for this survey was helped by the ever-increasing prevalence of social media in peoples’ lives. This highlights the need for proper, scientific-based information regarding the pandemic to reach the lay public before opinions appear on social media newsfeeds. On the other hand, only 2.1% of our sample thought that social media sites were reliable sources for vaccine information. While this would appear to suggest limited influence of social media with regard to COVID vaccines, we have to interpret this with caution in view of a small, self-selected sample that may not reflect the U.S. population as a whole. While some individuals may have legitimate reasons for declining vaccination, e.g. allergies to some ingredients in the preparation or other medical contraindications, misperceptions about vaccines as presented by some members of the media can lead to vaccine refusal for inappropriate reasons [ 36 ]. Therefore, it is important to disseminate the scientific basis for vaccines whenever possible. Negative press about variant viruses and the possibility of ineffective vaccines lead to further public distrust of the otherwise monumental feat of creating and distributing the COVID-19 vaccines [ 37 ]. Education of the public is essential for the continued success of vaccination efforts in general. As an example, in one study [ 38 ], Human Papilloma Virus (HPV) vaccine education sessions were held for parents, healthcare and school staff who had little knowledge regarding HPV vaccines. After the sessions, results showed that over 90% of respondents felt vaccine education was important and 85–97% were supportive of school-based vaccine clinics. In another study on flu vaccination during pregnancy [ 39 ], pregnant women refused flu vaccines due to likely susceptibility to influenza and concerns for vaccine safety. The study intervention was a brief educational video by the CDC, which addressed vaccination health beliefs in a clear and easy to understand format. The primary outcome was receipt of the flu vaccine on the next prenatal visit, and suggested that appropriate education and reassurance were influential in vaccination. We must do the same for the COVID-19 vaccine, seeing that our findings suggest that educational attainment is one of the two most important factors that determine the likelihood that one will perceive the vaccine as safe and be likely to accept vaccination. Given that an overwhelming majority of our respondents indicated that they considered doctors, nurses, and other healthcare workers as reliable sources of vaccination information, it is imperative to begin incorporating COVID-19 vaccine questions and education during health care visits. Moreover, training healthcare professionals in cultural competency, defined as “the ability of individuals and systems to work or respond effectively across cultures in a way that acknowledges and respects the culture of the person or organization being served” [ 40 ] would help them navigate this conversation with knowledge and transparency to promote mutual trust and possibly increased likelihood of vaccination [ 41 , 42 ]. Unfortunately, cultural competency training is still limited in medical schools and residency programs [ 43 ], and broader implementation is needed. This will be critical for engaging minority/underrepresented groups, though we acknowledge that these groups may have general difficulties accessing any medical care and this in turn may contribute to lower vaccination rates. Some respondents chose “no access” as a reason for not receiving the vaccine. The term “no access” is admittedly broad and could have included decreased vaccination distribution to impoverished neighborhoods, or it could mean that individuals do not know where to go to get their vaccine. We kept our questionnaire concise so as not to overburden respondents, and consequently could not necessarily qualify the specific reasons for perception about no or limited access. Further investigation is needed to characterize the specific obstacles experienced by people seeking the vaccination. As health literacy regarding the still relatively new COVID-19 pandemic remains a challenge [ 44 ], our present survey can hopefully act as a compass to inform providers on the underlying rationale that their patients have for being skeptical about vaccines or medical advice.

In addition, we need steps to encourage the population to get vaccinated irrespective of political affiliation. Per our findings, those who identify as Democrats are more likely to perceive the vaccine as being safe. Partisanship and vaccination status continue to play a role in both U.S. vaccination efforts and the government’s response to the pandemic in general. Other studies have shown similar results [ 45 ], where 65% of Democrats and 51% of vaccinated adults say that the surge in COVID cases makes them angry at people who have not gotten a vaccine, while 59% of Republicans and 56% of unvaccinated adults say that the federal government should be blamed. Our study shows that Republicans less likely to become vaccinated trust information that comes directly from their health care team, more than information that originates from the government. Therefore, ensuring that all personnel on the health care team are culturally competent to facilitate conversations brought on by patients regarding the COVID-19 vaccine will be instrumental in ensuring vaccination acceptance across spectra. Finally, incentives must be focused on core groups that we believe are more likely to reject the vaccine. These include underrepresented minorities, people with lower educational level, those who identify as young, males, and those with high risk underlying medical conditions.

Our study has limitations, especially regarding data collection. Given the current pandemic and difficulty with in-person survey distribution, it was decided that an online distribution would be preferable, based on the assumption that every individual is at risk of contracting the virus and becoming affected by the pandemic. We used Facebook due to its wide reach. However, we recognize that not everyone has access to computers or Facebook, so this survey may favor those of higher socioeconomic status. Likewise, we did not seek parity since the sample was largely one of convenience, based on who responded to the questionnaire. Although forced responses were used for our survey to ensure completion and prevent answers, we could not determine other potential factors that may have caused incomplete responses in cases where respondents were allowed to select up to three options, e.g. for trusted sources of information. Obstacles to completion might have included feeling pressed for time, concerns about privacy in view of the open nature of social media, or rejection based on personally held political views. This could result in a self-selection bias due to differences between respondents and non-respondents, therefore skewing the findings. For example, many participants were white, female, and/or Democrat voters, which is not representative of the U.S. population per se and could bias the results in favor of opting for vaccination, perhaps due to stronger belief in vaccines. Obviously, given the enormous number of Facebook users in the U.S., and the fact that users are allowed to protect their privacy by restricting access to personal data (including by omitting it in their profiles), it would be difficult to assess the “typical” Facebook user in the context of these factors. Along those lines, about 87% of respondents were already vaccinated, which suggests that most considered the benefits greater than the risks. This may therefore result in under-reporting and under-characterizing negative views of the vaccine that we sought to capture in the survey. Another limitation of this study is that it only represents a snapshot in time of opinions of COVID-19 vaccine perceptions, which can be fluid. Because the vaccine data are rapidly changing and information provided to the public may evolve as days progress, our results can only be applicable to this specific point in time. Ideally, the present study should be repeated in the future to ascertain trends over time. From a methodological standpoint, future studies should focus on obtaining a wider and more diverse set of respondents, including individuals that do not have access to computers or Facebook. One feasible alternative could be the distribution of both online and paper surveys to the same group of respondents during the same wave of data collection, thus allowing for estimation of changes across strategies for survey contact.

While our findings are in line with some existing perspectives in the field, as they relate to the role of socioeconomic factors [ 26 , 32 ], educational influence [ 38 , 39 ], and partisanship [ 45 ], we have contributed a more robust and elaborate perception of the U.S population on COVID vaccines, while identifying specific groups at risk for not getting a vaccine. In conclusion, level of education and partisanship, but not race/ethnicity, were the most likely factors associated with vaccine hesitancy or likelihood to vaccinate. This suggests that improved education, not just about vaccines per se, but with regard to formal schooling in general, may be at the heart of promoting greater acceptability of vaccination. Likewise, low vaccination rates among underrepresented minorities may be due to distrust for healthcare industries, but further research is needed to fully characterize the relative contributions of low access vs. distrust. Many white people and many with a Republican party affiliation also expressed reluctance about vaccination, suggesting that mistrust of the healthcare industry, vaccinations in general, and/or the government is not limited to minorities and/or economically challenged populations. Regardless, population sub-groups less likely to be vaccinated and/or receptive to vaccines should be targeted for vaccine education and incentives, and outcomes of these interventions need to be closely studied for determination of efficacy.

Supporting information

S1 file. qualtrics survey questionnaire..

https://doi.org/10.1371/journal.pone.0268784.s001

S1 Data. Inclusion criteria.

https://doi.org/10.1371/journal.pone.0268784.s002

Acknowledgments

The authors would like to thank our collaborators at Qualtrics and Facebook for helping facilitate the successful completion of this study.

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• 30. Ada McVean. McGill. 40 Years of Human Experimentation in America : The Tuskegee Study . https://www.mcgill.ca/oss/article/history/40-years-human-experimentation-america-tuskegee-study Accessed on 19th January, 2022.
• 31. Amy Gutmann. Presidential Commission for the Study of Bioethical Issues. “Ethically Impossible” STD Research in Guatemala from 1946 to 1948. https://bioethicsarchive.georgetown.edu/pcsbi/node/654.html Accessed on 19 th January, 2022.
• 32. Simms, M. The Urban Institute. Racial and Ethnic Disparities among low-income Families . https://www.urban.org/sites/default/files/publication/32976/411936-racial-and-ethnic-disparities-among-low-income-families.pdf Accessed on 18th October, 2021
• 33. DiMaria-Ghalili, R., Foreshaw Rouse, A., Coates, M., Hathaway, Z., Hirsch, J., Wetzel, S., et al. Disrupting Disparities in Pennsylvania: Retooling for Geographic, Racial and Ethnic Growth [White paper]. https://aarp-states.brightspotcdn.com/6f/b6/de161f3a4a63a23e811693d90b68/aarp-drexel-pennsylvania-disrupting-disparities-design-0421-final.pdf Accessed on 19th January, 2022.
• 35. Devon Delfino. Incentives for CoVID-19 Vaccination : Food , Cash , & Other Perks . https://www.goodrx.com/health-topic/vaccines/covid-19-vaccination-incentives Accessed on 20th, January, 2022.
• 37. The Atlantic. 5 Pandemic Mistakes We Keep Repeating . https://www.theatlantic.com/ideas/archive/2021/02/how-public-health-messaging-backfired/618147/ Accessed on 26 th , February 2021.

COVID-19 vaccines: Get the facts

A s the coronavirus disease 2019 (COVID-19) continues to cause illness, you might have questions about COVID-19 vaccines. Find out about the different types of COVID-19 vaccines, how they work, the possible side effects, and the benefits for you and your family.

What are the benefits of getting a COVID-19 vaccine?

Staying up to date with a COVID-19 vaccine can:

• Help prevent serious illness and death due to COVID-19 for both children and adults.
• Help prevent you from needing to go to the hospital due to COVID-19.
• Boost your body's protection, also called immunity, against catching the virus that causes COVID-19.
• Be a safer way to protect yourself compared to getting sick with the virus that causes COVID-19.

How much protection a COVID-19 vaccine gives depends on different factors. Factors that can affect how much you're protected with a vaccine can include your age, if you've had COVID-19 before or if you have medical conditions such as cancer.

How well a COVID-19 vaccine protects you also depends on how the virus that causes COVID-19 changes and what variants the vaccine protects against. Your level of protection also depends on timing, such as when you got the shot.

Talk to your healthcare team about how you can stay up to date with COVID-19 vaccines.

Should I get the COVID-19 vaccine even if I've already had COVID-19?

Yes. After you've had COVID-19, getting vaccinated can boost your body's protection against catching the virus that causes COVID-19 another time.

Getting COVID-19 or getting a COVID-19 vaccination gives you protection, also called immunity, from being infected again with the virus that causes COVID-19. But over time, that protection seems to fade. Getting COVID-19 again may cause serious illness or medical complications, especially for people with risk factors for severe COVID-19.

Researchers continue to study what happens when someone has COVID-19 a second time. Reinfections are generally milder than the first infection. But severe illness can still happen. Some people may see their risk of having to go to the hospital and having medical problems such as diabetes go up with each COVID-19 infection.

Research has found that people who have had COVID-19 and then have had all of the suggested COVID-19 vaccinations are less likely to be treated in the hospital due to COVID-19 than people who are not vaccinated or who haven't had all the suggested shots. This protection wears off in the months after getting the vaccine.

Also, because the virus that causes COVID-19 can change, also called mutate, a vaccination with the latest strain, or variant, that is spreading or expected to spread can help keep you from getting sick again.

What COVID-19 vaccines have been authorized or approved?

The COVID-19 vaccines available in the United States are:

• 2023-2024 Pfizer-BioNTech COVID-19 vaccine, available for people age 6 months and older.
• 2023-2024 Moderna COVID-19 vaccine, available for people age 6 months and older.
• 2023-2024 Novavax COVID-19 vaccine, available for people age 12 years and older.

In general, people age 5 and older with typical immune systems can get any vaccine that is approved or authorized for their age. They usually don't need to get the same vaccine each time.

Some people should get all their vaccine doses from the same vaccine maker, including:

• Children ages 6 months to 4 years.
• People age 5 years and older with weakened immune systems.
• People age 12 and older who have had one shot of the Novavax vaccine should get the second Novavax shot in the two-dose series.

Talk to your healthcare professional if you have any questions about the vaccines for you or your child. Your healthcare team can help you if:

• The vaccine you or your child got earlier isn't available.
• You don't know which vaccine you or your child received.
• You or your child started a vaccine series but couldn't finish it due to side effects.

At the start of the COVID-19 pandemic, COVID-19 vaccines were needed right away. But the U.S. Food and Drug Administration's (FDA's) vaccine approval process can take years.

To provide vaccines sooner, the FDA gave emergency use authorization to COVID-19 vaccines based on less data than is typically required. But the data still has to show that the vaccines are safe and effective.

In August 2022, the FDA authorized an update to the Moderna and the Pfizer-BioNTech COVID-19 vaccines. Both included the original and omicron variants of the virus that causes COVID-19.

In June 2023, the FDA directed vaccine makers to update COVID-19 vaccines. The vaccines were changed to target a strain of the virus that causes COVID-19 called XBB.1.5.

In September and October 2023, the FDA authorized the use of the updated 2023-2024 COVID-19 vaccines made by Novavax, Moderna and Pfizer-BioNTech.

Vaccines with FDA emergency use authorization or approval include:

2023-2024 Pfizer-BioNTech COVID-19 vaccine. This vaccine was first tested against the original strain of the COVID-19 virus. That strain began spreading at the end of 2019. In December 2020, the Pfizer-BioNTech COVID-19 vaccine two-dose series was found to be both safe and 91% to 95% effective in preventing COVID-19 infection in people age 18 and older. This data helped predict how well the vaccines would work for younger people. The effectiveness varied by age.

The Pfizer-BioNTech vaccine is approved under the name Comirnaty for people age 12 and older. It is authorized for people age 6 months to 11 years. The number of shots in this vaccination series varies based on a person's age and COVID-19 vaccination history.

2023-2024 Moderna COVID-19 vaccine. This vaccine also was first tested against the original strain of the virus that causes COVID-19. In December 2020, the Moderna COVID-19 vaccine was found to be both safe and about 93% effective in preventing infection among study volunteers, all age 18 or older.

Based on the comparison between people who got COVID-19 in the placebo group, the Moderna COVID-19 vaccine was 98% effective at preventing serious COVID-19 illness. Vaccine effect was predicted for younger people based on that clinical trial data as well.

The vaccine is approved under the name Spikevax for people age 12 and older. The vaccine is authorized for use in people age 6 months to 11 years. The number of shots needed varies based on a person's age and COVID-19 vaccination history.

• 2023-2024 Novavax COVID-19 vaccine, adjuvanted. This vaccine is available under an emergency use authorization for people age 12 and older. It requires two shots, given 3 to 8 weeks apart. Research done before the spread of the delta and omicron variants has shown that the vaccine is 90% effective at preventing mild, moderate and severe disease with COVID-19. For people age 65 and older, the vaccine is 79% effective.

How do the COVID-19 vaccines work?

Both the Pfizer-BioNTech and the Moderna COVID-19 vaccines use genetically engineered messenger RNA (mRNA). Coronaviruses have a spikelike structure on their surface called an S protein. COVID-19 mRNA vaccines give your cells instructions for how to make a harmless piece of an S protein.

After vaccination, your muscle cells begin making the S protein pieces and displaying them on cell surfaces. The immune system recognizes the protein and begins building an immune response and making antibodies. After delivering instructions, the mRNA is immediately broken down. It never enters the nucleus of your cells, where your DNA is kept.

The Novavax COVID-19, adjuvanted vaccine is a protein subunit vaccine. These vaccines include only the parts (proteins) of a virus that best stimulate your immune system. The Novavax COVID-19 vaccine contains harmless S proteins. It also has an ingredient called an adjuvant that helps with your immune system response.

Once your immune system recognizes the S proteins, this vaccine creates antibodies and defensive white blood cells. If you later become infected with the COVID-19 virus, the antibodies will fight the virus.

Protein subunit COVID-19 vaccines don't use any live virus and can't cause you to become infected with the COVID-19 virus. The protein pieces also don't enter the nucleus of your cells, where your DNA is kept.

Can a COVID-19 vaccine give you COVID-19?

No. The COVID-19 vaccines currently being developed and used in the U.S. don't use the live virus that causes COVID-19. Because of this, the COVID-19 vaccines can't cause you to become sick with COVID-19 or shed any vaccine parts.

It can take a few weeks for your body to build immunity after getting a COVID-19 vaccination. As a result, it's possible that you could become infected with the virus that causes COVID-19 just before or after being vaccinated.

What are the possible general side effects of a COVID-19 vaccine?

Many people have no side effects from the COVID-19 vaccine. For those who get them, most side effects go away in a few days. A COVID-19 vaccine can cause mild side effects after the first or second dose, including:

• Pain, redness or swelling where the shot was given.
• Muscle pain.
• Joint pain.
• Nausea and vomiting.
• Feeling unwell.
• Swollen lymph nodes.

Babies ages 6 months through 3 years old also might cry, feel sleepy or lose their appetite after vaccination. Children in this age group also may have the common side effects seen in adults. These include pain, redness or swelling where the shot was given, fever, or swollen lymph nodes.

A healthcare team watches you for 15 minutes after getting a COVID-19 vaccine to see if you have an allergic reaction.

If the redness or tenderness where the shot was given gets worse after 24 hours or you're worried about any side effects, contact your healthcare professional.

Are there any long-term side effects of the COVID-19 vaccines?

The vaccines that help protect against COVID-19 are safe and effective. The vaccines were tested in clinical trials. People continue to be watched for rare side effects, even after more than 650 million doses have been given in the United States.

Side effects that don't go away after a few days are thought of as long term. Vaccines rarely cause any long-term side effects.

If you're concerned about side effects, safety data on COVID-19 vaccines is reported to a national program called the Vaccine Adverse Event Reporting System in the U.S. This data is available to the public. The CDC also has created v-safe, a smartphone-based tool that allows users to report COVID-19 vaccine side effects.

If you have other questions or concerns about your symptoms, talk to your healthcare professional.

Can COVID-19 vaccines affect the heart?

In some people, COVID-19 vaccines can lead to heart complications called myocarditis and pericarditis. Myocarditis is the swelling, also called inflammation, of the heart muscle. Pericarditis is the swelling, also called inflammation, of the lining outside the heart.

The risk of myocarditis or pericarditis after a COVID-19 vaccine is rare. These conditions have been reported after a COVID-19 vaccination with any of the three available vaccines. Most cases have been reported in males ages 12 to 39.

If you or your child develops myocarditis or pericarditis after getting a COVID-19 vaccine, talk to a healthcare professional before getting another dose of the vaccine.

Of the cases reported, the problem happened more often after the second dose of the COVID-19 vaccine and typically within one week of COVID-19 vaccination. Most of the people who got care felt better after receiving medicine and resting.

Symptoms to watch for include:

• Chest pain.
• Shortness of breath.
• Feelings of having a fast-beating, fluttering or pounding heart.

If you or your child has any of these symptoms within a week of getting a COVID-19 vaccine, seek medical care.

Are COVID-19 vaccines free?

In the U.S., COVID-19 vaccines may be offered at no cost through insurance coverage. For people whose vaccines aren't covered or for those who don't have health insurance, options are available. Anyone younger than 18 years old can get no-cost vaccines through the Vaccines for Children program. Adults can get no-cost COVID-19 vaccines through the temporary Bridges to Access program, which is scheduled to end in December 2024.

Can I get a COVID-19 vaccine if I have an existing health condition?

Yes, COVID-19 vaccines are safe for people who have existing health conditions, including conditions that have a higher risk of getting serious illness with COVID-19.

Your healthcare team may suggest you get added doses of a COVID-19 vaccine if you have a moderately or severely weakened immune system. Talk to your healthcare team if you have any questions about when to get a COVID-19 vaccine.

Is it OK to take an over-the-counter pain medicine before or after getting a COVID-19 vaccine?

Don't take medicine before getting a COVID-19 vaccine to prevent possible discomfort. It's not clear how these medicines might impact the effectiveness of the vaccines. However, it's OK to take this kind of medicine after getting a COVID-19 vaccine, as long as you have no other medical reason that would prevent you from taking it.

What are the signs of an allergic reaction to a COVID-19 vaccine?

You might be having an immediate allergic reaction to a COVID-19 vaccine if you experience these symptoms within four hours of getting vaccinated:

• Swelling of the lips, eyes or tongue.

If you have any signs of an allergic reaction, get help right away. Tell your healthcare professional about your reaction, even if it went away on its own or you didn't get emergency care. This reaction might mean you are allergic to the vaccine. You might not be able to get a second dose of the same vaccine. However, you might be able to get a different vaccine for your second dose.

Can I get a COVID-19 vaccine if I have a history of allergic reactions?

If you have a history of severe allergic reactions not related to vaccines or injectable medicines, you may still get a COVID-19 vaccine. You're typically monitored for 30 minutes after getting the vaccine.

If you've had an immediate allergic reaction to other vaccines or injectable medicines, ask your healthcare professional about getting a COVID-19 vaccine. If you've ever had an immediate or severe allergic reaction to any ingredient in a COVID-19 vaccine, the CDC recommends not getting that specific vaccine.

If you have an immediate or severe allergic reaction after getting the first dose of a COVID-19 vaccine, don't get the second dose. But you might be able to get a different vaccine for your second dose.

Can pregnant or breastfeeding women get the COVID-19 vaccine?

If you are pregnant or breastfeeding, the CDC recommends that you get a COVID-19 vaccine. Getting a COVID-19 vaccine can protect you from severe illness due to COVID-19. Vaccination also can help pregnant women build antibodies that might protect their babies.

COVID-19 vaccines don't cause infection with the virus that causes COVID-19, including in pregnant women or their babies. None of the COVID-19 vaccines contains the live virus that causes COVID-19.

If children don't often experience severe illness with COVID-19, why do they need a COVID-19 vaccine?

While rare, some children can become seriously ill with COVID-19 after getting the virus that causes COVID-19.

A COVID-19 vaccine might prevent your child from getting the virus that causes COVID-19. It also may prevent your child from becoming seriously ill or having to stay in the hospital due to the COVID-19 virus.

Can I stop taking safety precautions after getting a COVID-19 vaccine?

You are considered up to date with your vaccines if you have gotten all recommended COVID-19 vaccine shots when you become eligible.

After getting vaccinated, you can more safely return to doing activities that you might not have been able to do because of high numbers of people with COVID-19 in your area. However, if you're in an area with a high number of people with COVID-19 in the hospital, the CDC recommends wearing a well-fitted mask indoors in public, whether or not you're vaccinated.

If you have a weakened immune system or have a higher risk of serious illness, wear a mask that provides you with the most protection possible when you're in an area with a high number of people with COVID-19 in the hospital. Check with your healthcare professional to see if you should wear a mask at other times.

The CDC recommends that you wear a mask on planes, buses, trains and other public transportation traveling to, within or out of the U.S., as well as in places such as airports and train stations.

If you've gotten all recommended vaccine doses and you've had close contact with someone who has the COVID-19 virus, get tested at least five days after the contact happens.

Can I still get COVID-19 after I'm vaccinated?

COVID-19 vaccination will protect most people from getting sick with COVID-19. But some people who are up to date with their vaccines may still get COVID-19. These are called vaccine breakthrough infections.

People with vaccine breakthrough infections can spread COVID-19 to others. However, people who are up to date with their vaccines but who have a breakthrough infection are less likely to have serious illness with COVID-19 than those who are not vaccinated. Even when people who are vaccinated develop symptoms, they tend to be less severe than those experienced by unvaccinated people.

©2024 Mayo Foundation for Medical Education and Research (MRMER). All rights reserved.

SYSTEMATIC REVIEW article

How has research on the effectiveness and safety of covid-19 vaccination been evaluated: a scope review with emphasis on coronavac.

• 1 Grupo de Epidemiología, Universidad de Antioquia, Medellín, Colombia
• 2 Grupo de Enfermedades Tropicales y Resistencia Bacteriana, Universidad del Sinú, Montería, Colombia
• 3 Grupo de investigación EMAP - Estadística y Matemáticas Aplicadas, Pontificia Universidad Javeriana, Cali, Colombia
• 4 Grupo de Investigación, Secretaría de Salud Distrital, Cali, Colombia
• 5 Grupo de Investigación Clínica - PECET (GIC-PECET), Universidad de Antioquia, Medellín, Colombia
• 6 Grupo de Investigación en Economía, Gestión y Salud, ECGESA. Pontificia Universidad Javeriana, Cali, Colombia
• 7 Departamento de Salud pública y Epidemiología, Pontificia Universidad Javeriana, Cali, Colombia

Introduction: The control of the COVID-19 epidemic has been focused on the development of vaccines against SARS-CoV-2. All developed vaccines have reported safety and efficacy results in preventing infection and its consequences, although the quality of evidence varies depending on the vaccine considered. Different methodological designs have been used for their evaluation, which can influence our understanding of the effects of these interventions. CoronaVac is an inactivated vaccine, and it has been assessed in various studies, including clinical trials and observational studies. Given these differences, our objective was to explore the published information to answer the question: how has the efficacy/effectiveness and safety of CoronaVac been evaluated in different studies? This is to identify potential gaps and challenges to be addressed in understanding its effect.

Methods: A scoping review was carried out following the methodology proposed by the Joanna Briggs Institute, which included studies carried out in humans as of 2020, corresponding to systematic reviews, clinical trials, analytical or descriptive observational studies, in which the effectiveness and/or safety of vaccines for COVID19 were evaluated or described. There were no age restrictions for the study participants.

Results: The efficacy/effectiveness and safety of this vaccine was assessed through 113 studies. Nineteen corresponded to experimental studies, 7 of Phase II, 5 of Phase IV, and 4 were clinical trials with random assignment. Although some clinical trials with random assignment have been carried out, these have limitations in terms of feasibility, follow-up times, and with this, the possibility of evaluating safety outcomes that occur with low frequencies. Not all studies have used homogeneous methods of analysis. Both the prevention of infection, and the prevention of outcomes such as hospitalization or death, have been valued through similar outcomes, but some through multivariate analysis of dependencies, and others through analysis that try to infer causally through different control methods of confounding.

Conclusion: Published information on the evaluation of the efficacy/effectiveness and safety of the CoronaVac is abundant. However, there are differences in terms of vaccine application schedules, population definition, outcomes evaluated, follow-up times, and safety assessment, as well as non-standardization in the reporting of results, which may hinder the generalizability of the findings. It is important to generate meetings and consensus strategies for the methods and reporting of this type of studies, which will allow to reduce the heterogeneity in their presentation and a better understanding of the effect of these vaccines.

1 Introduction

Starting from the first reports coming from China and from countries in Europe and Asia, about the infection produced by SARS-CoV-2, its high contagion, and lethality of up to 14% in older adults, and the subsequent declaration of a COVID-19 pandemic, and together with the measures established by the healthcare authorities to manage the disease, efforts began to develop effective and safe vaccines that would contribute to speeding up the control of this health condition, through the reduction of infections, complications, and deaths associated with this disease ( 1 ).

For this reason, pandemic control efforts have focused on developing vaccines against SARS-CoV-2 that are capable of acting against infection, disease, or transmission, and thus contribute to disease control ( 2 ). In this context, different research groups have developed vaccines using different platforms, including mRNA, viral vectors, and inactivated viruses ( 3 ).

Unlike most drugs, whose benefits are limited to the individual taking them, vaccines have the potential to produce far-reaching effects on general public health and well-being, cognitive development, and, ultimately, economic productivity ( 4 ). However, the global advances in vaccination coverage achieved during the first years of the 21st century have been threatened by the emergence of anti-vaccination groups that have questioned vaccine efficacy to create public distrust of vaccines and immunization programs. This requires an adequate and conscious evaluation of both the efficacy/effectiveness and the different aspects that can affect the safety of the people who receive them ( 5 ).

In general, vaccines that have gained approval for human use have been effective in preventing COVID-19, particularly in preventing severe disease and death. However, reports on their implementation are mainly based on follow-up studies of the adult population ( 6 ). Additionally, if the vaccination prevents symptoms from developing and asymptomatic infections are less likely to be discovered than symptomatic ones, it is feasible that the effectiveness against any infection has been overstated. A competitive tendency toward underestimate arises when estimates are based on tests with inadequate specificity, particularly when testing are conducted more frequently than has been estimated for various COVID-19 vaccinations ( 7 ).

All vaccines seem to be safe and efficacious against all variations of interest in preventing hospitalization, death, and severe COVID-19; however, the quality of the data differs significantly between the vaccines under consideration ( 8 ).

Different methodological designs have been used to evaluate the effectiveness and safety of vaccines for COVID-19. Most clinical trials were carried out before the appearance of variants of concern, and the duration, subgroups evaluated, and analysis methods were not homogeneous between vaccines, creating uncertainty about some effects and comparisons ( 9 ).

CoronaVac is an inactivated whole-virus vaccine against COVID-19 adjuvanted with aluminum hydroxide created from African green monkey kidney cells (Vero cells) inoculated with SARS-CoV-2 (strain CN02). The Chinese company Sinovac Biotech developed the vaccine, and on June 1, 2021, the World Health Organization (WHO) approved the vaccine for emergency use ( 10 ). Using two 3 μg doses of CoronaVac, the overall efficacy for avoiding symptomatic COVID-19 (before the emergence of concerning variations) has been assessed at 67.7% (95%CI: 35.9 to 83.7%) ( 10 ). Compared to COVID-19 prevention, its impact in preventing hospital stays, ICU admissions, and fatalities has been much stronger. Three-dose regimens have also been shown to raise seroconversion levels of neutralizing antibodies, even against variants like Omicron. Few serious vaccine-related adverse reactions have been reported ( 10 ).

However, given the differences that may exist in the methods used to assess the efficacy, effectiveness, and safety of vaccines against COVID-19, our objective was to explore the published research on COVID-19 vaccines, focusing on CoronaVac, in order to answer the question: How has the efficacy/effectiveness and safety of CoronaVac been assessed in different designs and study phases of the vaccines used to control COVID-19?

A scoping review was carried out under a protocol registered in the Open Science Framework (OSF; osf.io/aeut4), and following the methodology proposed by the Joanna Briggs Institute ( 11 ), which included studies carried out in humans as of 2020, corresponding to systematic reviews, clinical trials, and analytical or descriptive observational studies in which the effectiveness and/or safety of vaccines for COVID19 were evaluated or described. There were no age restrictions on the study participants.

Abstracts from congresses were not evaluated because they had not been subjected to systematic peer evaluation at the time, nor were studies published in languages other than English or Spanish.

2.1 Search methods for study identification

To identify potentially relevant articles for review, the following databases were searched, starting from 2020: MEDLINE, EMBASE, LILACS, Scopus, and Cochrane.

The following valid strategy was used for MEDLINE through PubMed and then adapted to other databases:

(((SARS-CoV-2[MeSH Terms]) OR (COVID-19[MeSH Terms])) OR (Coronavirus[MeSH Terms])) AND ((COVID-19 Vaccines[MeSH Terms]) OR (Coronavirus vaccines[Title/Abstract])).

The full search strategy is presented in the Supplementary material .

2.2 Study selection

The initial screening of the studies was independently performed by two reviewers in pairs (PA-AG and PR-SR). The RIS files of each database were uploaded to Rayyan software ( 12 ). Disagreements were resolved by a third author (JA).

Both reviewers assessed all titles and abstracts and excluded those considered irrelevant for the review, those not meeting the inclusion criteria, or because they were duplicates. Subsequently, 15 reviewers independently (JA, PA, DA, AC, AG, LL, LM, DO, GQ, SR, CR, PR, MS, CT, MA) evaluated the full text of the studies to verify the eligibility criteria. A cross-review was carried out for studies evaluating CoronaVac by four reviewers (PA, AG, PR, and SR).

2.3 Variable

Of the definitively selected studies, the following variables were extracted in a paired form: (i) type of study, (ii) population studied, (iii) intervention (vaccine) evaluated, (iv) control, (v) follow-up time, (vi) efficacy and/or effectiveness outcomes, and (vii) safety outcomes.

2.4 Data synthesis

For each outcome, a description of the results was made following the description in the document and/or Supplementary material of the article.

3.1 Study selection

The search identified 42,813 titles for the initial evaluation, of which 40,372 were excluded after a review of the title, abstract, and possible duplication. A total of 2,441 full texts were reviewed to verify the eligibility criteria, of which 1,685 were included in the synthesis ( Figure 1 ; Supplementary material ).

Figure 1 . Flow diagram of the literature review process.

3.2 Synthesis of the results

One hundred vaccines were evaluated through randomized clinical trials (RCT). The other studies corresponded to observational studies, 705 (43.9%) analytical studies, and mainly cohort studies (467; 29.1%). Three hundred and seventy-seven patients (23.5%) were series or case reports.

One hundred twenty-six studies (7.8%) did not specify the vaccine evaluated. Other studies have evaluated one or more specific vaccines. Seven hundred thirty-two studies did not include a vaccine or a control group. Two hundred and thirty-eight evaluated several types of vaccines, and 160 compared a vaccine against a placebo. The number of patients or vaccine doses evaluated in each study went from one (case report) to 306,473,169 doses of applied vaccines ( 13 ).

Regarding the population assessed, 44.4% of the studies evaluated the effects of vaccines on adults. 3.4% in adults and adolescents, 2% in adolescents, 1.2% in immunosuppressed individuals, 1.2% in children, 0.9% in pregnant women, and 0.25% in people living with HIV. The overall monitoring time ranged from hours to 6 months; this difference occurred between studies that evaluated immunological outcomes, which could occur within hours or days, and those that evaluated clinical outcomes.

A total of 15.1% of the studies evaluated the effectiveness or efficacy of vaccines by evaluating their effects on preventing infection, hospitalization, or death from infection. 59.1% of the studies corresponded to the description of safety events. The events were described heterogeneously. In some studies, they are only recorded as “mild adverse events” or “mild systemic events.” Few studies reported specific events such as myocarditis, and hepatic or allergic alterations. Of the studies, 25.8% described immunological outcomes, 368 studies through the measurement of antibodies, and 64 through the effects mediated by cellular immunity.

3.2.1 CoronaVac

The efficacy, effectiveness, and safety of this vaccine have been assessed in 113 studies. Nineteen corresponded to experimental studies, seven of Phase II, five of Phase IV, and four were clinical trials with random assignment, carried out in adults in Chile, Indonesia, and Turkey ( 14 – 17 ), comparing the effect of the vaccine versus placebo. The other studies were observational studies, most of which were case reports, case series, or descriptions of cohorts. Of these, 45.1% were conducted in Asia, 23% in Latin America, and 22.1% in Europe, mainly in Turkey (of 27/29 European studies).

As for the population, 87.6% of the studies were conducted in adults, while the representation of studies in pregnant women, children, immunosuppressed people, or people living with HIV ranged between 0.9 and 3.5% of the studies.

Sixty studies (53.1%) evaluated the effect of CoronaVac in a control group. The others were case reports or descriptions of cohorts without comparison. Of these, 42 (70%) described events in patients who received CoronaVac and another vaccine, without performing an effectiveness or efficacy analysis. Other studies evaluated the efficacy and effectiveness by measuring the effect of preventing hospitalization, death, or COVID. Of the total, 34 studies evaluated CoronaVac (30.1%) and described some immune outcomes.

Although the objective of the review was not to assess the effectiveness of the vaccine, but rather how it has been evaluated, the results of some of the identified studies are shown below in order to present relevant information about the methods used and possible differences between them, which lead to discussing the effect that this can have on the analysis and use of CoronaVac and other vaccines. More details on the results of the identified studies can be found in the Supplementary material section.

3.2.2 Efficacy/effectiveness of CoronaVac

3.2.2.1 prevention of covid-19.

Cheng et al. ( 18 ) evaluated the effectiveness of BNT162B2 and CoronaVac in patients with chronic kidney disease in Hong Kong. 28,374 people were not vaccinated, 27,129 received two doses of BNT162b2, and 47,640 received two doses of CoronaVac in this retrospective cohort analysis. Following inverse probability of treatment weighting with 1% extreme values, a cohort that was well-balanced and had a standardized mean difference of less than 0.1 was generated.

The effectiveness of CoronaVac on Turkish healthcare professionals was assessed by Can et al. ( 19 ). 4,067 medical personnel worked at a University Hospital in Istanbul, where this retrospective cohort study was carried out. In the fully vaccinated group, the follow-up period was defined as beginning 14 days following the second dose. If PCR test findings were positive or the trial came to an end, healthcare personnel were excluded. Healthcare personnel who were not vaccinated were prohibited from participating in any COVID-19 vaccination. The vaccine’s unadjusted and adjusted effectiveness were calculated using the incidence rate ratio and Cox regression. 29% of the healthcare staff had not received any vaccinations, whereas 71% had received all recommended doses.

Jara et al. ( 20 ) conducted an evaluation of a prospective, observational, national-level cohort of individuals (≥ 16 years) associated with the Fondo Nacional de Salud insurance program in Chile. They used individual-level data to assess the efficacy of booster vaccines, namely BNT162B2 (Pfizer-Biontech), AZD1222 (Oxford-AstraZeneca), and CoronaVac (Syovac Biotech), in individuals who had completed a primary immunization schedule with CoronaVac, in comparison to those who had not received any vaccinations. The hazard ratios were estimated using inverse probability-weighted and stratified survival regression models that took into account the time-varying vaccination status and adjusted for pertinent clinical, socioeconomic, and demographic confounders. An estimate was made of the change in risk associated with the primary immunization series and booster shot from being unvaccinated to vaccinated. 11,174,257 persons in total fulfilled the trial’s eligibility conditions; of these, 4,127,546 finished the two doses of the CoronaVac primary immunization regimen and got a booster dose during the study period. 2,019,260 (48.9%) individuals received a BNT162b2 booster, 186,946 (4.5%) received a homologous booster with CoronaVac, and 1,921,340 (46–5%) participants received an AZD1222 booster. The weighted stratified Cox model was utilized to compute the modified vaccination efficacy in preventing COVID-19.

Utilizing hospitalization, vaccination, and National COVID-19 notification data, Cerqueira-Silva et al. ( 21 ) conducted a case–control study in Brazil to evaluate the efficacy of four vaccines (CoronaVac [synovac], ChAdOx1 nCoV-19 [AstraZeneca], Ad26.COV2.S [Janssen], and BNT162b2 [Pfizer-Bionntech]) in individuals with laboratory-confirmed prior SARS-COV-2 infection. The probabilities of test positivity and the likelihood of hospitalization or death from COVID-19 were compared based on vaccination status and the amount of time that had passed from the first or second dose of vaccinations using multivariable conditional logistic regression.

The same authors conducted a similar study in Brazil ( 22 ), using linked national Brazilian databases to conduct a negative-test design study with nearly 14 million participants (~ 16 million tests) to estimate the effectiveness of the CoronaVac vaccine over time and the BNT162B2 booster vaccination against severe COVID-19 outcomes (hospitalization or death) and severe acute respiratory syndrome, as confirmed by RT-PCR (SARS-COV-2).

To evaluate the effectiveness of homologous and heterologous boosters against COVID-19 in the context of OMICRON, Ranzani et al. ( 23 ) conducted a nationwide case–control study (with negative PCR results) to assess homologous and heterologous (BNT162B2) booster doses in adults who received two doses of CoronaVac in Brazil in the OMICRON context.

A case–control research was carried out in Thailand by Sritipsukho et al. ( 24 ) to assess the efficacy of various vaccination regimens in preventing COVID-19 during the time when the delta variant was the predominant causing virus (≥ 95%). By correcting for individual demographic and clinical factors, the efficacy of vaccines was assessed.

3.2.2.2 Prevention of hospitalization and death

Cheng et al. ( 18 ) found that both vaccines reduced hospitalization and death related to COVID-19, which was the opposite of the outcome of preventing COVID-19 infection. The vaccination efficacy for BNT162b2 users was 64% (95% CI: 57–69%) for hospitalization associated to COVID-19 and 86% (95% CI: 80–90%) for COVID-19-related death. Regarding hospitalization and death associated to COVID-19, the vaccine efficacy for CoronaVac was 44% (95% CI: 37–49%) and 70% (95% CI: 64–75%), respectively.

In the Jara et al. ( 20 ) study, the adjusted effectiveness of the vaccine against hospitalization due to COVID-19, ICU admission, and death was 86.3% (83.7–88.5), 92.2% (88.7–94.6), and 86.7% (80.5–91.0) for a CoronaVac homolog booster; 96.1% (95.3–96.9), 96, 2% (94.6–97.3), and 96.8% (93.9–98.3) for a BNT162b2 booster; and 97.7% (97.3–98.0), 98.9% (98.5–99.2), and 98.1% (97.3–98.6) for an AZD1222 booster, respectively.

In Brazil ( 21 ), the effectiveness against hospitalization or death 14 or more days after the completion of the vaccination schedule was 81.3% (75.3–85.8) for CoronaVac, 89.9% (83.5–93.8) for ChAdOx1 nCoV-19, and 57.7% (−2.6–82.5) for Ad26.COV2.S, and 89.7% (54.3–97.7) for BNT162b2.

3.2.2.3 Immunological outcomes

Bueno et al. ( 14 ), conducting a randomized placebo-controlled clinical trial in Chile, assessed the effectiveness of CoronaVac by assigning participants to either a placebo or two doses of CoronaVac spaced 2 weeks apart. Enrollments totaled 434, with 397 individuals in the 18–59 age range and 37 in the 60+ age range. 81 subjects had hemoral assessments. 2 and 4 weeks after the second dosage, respectively, the seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22 and 84.44% in the 18–59 years age group and 62, 69 and 70.37% in the ≥60 years age group. A notable rise in the amount of neutralizing antibodies in circulation was noted two and 4 weeks following the second dosage. 47 participants had their cells evaluated. After stimulation with Mega Pools of SARS-CoV-2 peptides, a notable increase in T cell responses was seen, as evidenced by the release of interferon-γ (IFN-γ).

According to Zeng et al. ( 25 ) the following were the findings of two single-center, double-blind, randomized, placebo-controlled phase II clinical trials: adults from Jiangsu, China, aged 18 to 59 years were first assigned (1:1) into two vaccination schedule cohorts: one for the days 0 and 14 of vaccination (cohort 1), and another for the days 0 and 28 of vaccination (cohort 2). Each cohort was then randomly assigned (2:2:1) to either a placebo group or a 3 μg or 6 μg dose of CoronaVac. A third dose was given to half of the participants in each cohort 6 months after the second dose, and an additional dose was given to the other half of the individuals 28 days following the second dose, as a result of a protocol revision. In a separate phase II experiment carried out in Hebei, China, individuals who met the eligibility criteria of 60 years or above were randomized to receive three injections of 1.5, 3, or 6 μg of vaccine or a placebo. The first two doses of the vaccine were given 28 days apart, while the second and third doses were given 6 months apart. For the per-protocol population (those who finished their allotted third dose), the primary research outcomes were geometric mean titers (GMTs), geometric mean increments (GMIs), and seropositivity of neutralizing antibodies to SARS-CoV-2. Out of the 600 participants, who were between the ages of 18 and59, 540 (90%) were qualified for a third dose. Of these, 269 (50%) received the third primary dose (cohorts 1a-14d-2 m and 2a-28d-2 m) 2 months after the second dose, and 271 (50%) received a booster dose 8 months later (cohorts 1b-14d-8 m and 2b-28d-8 m). For the 1b-14d-8 m cohort ( n  = 53; GMT 3.9 [95% CI 3.1–5.0]) and 2b-28d-8 m cohort ( n  = 49; GMT 6.8 [95% CI 5.2–8.8]), neutralizing antibody titers elicited by the first two treatments in the 3 μg group declined after 6 months to close or below the seropositive cut-off point (GMT of 8). The GMTs measured 14 days later increased to 137.9 (95% CI: 99.9–190.4) for the 1b-14d-8 m cohort and to 143.1 (110.8–184.7) 28 days later for the 2b-28d-8 m cohort when a booster dose was administered 8 months following a second dose. After the principal third dosage, GMTs increased somewhat in cohorts 1a-14d-2 m (n = 54) and 2a-28d-2 m ( n  = 53). In cohort 1a, GMTs increased from 21.8 (95% CI: 17.3–27.6) on day 28 after the second dose to 45.8 (35.7–58.9) on day 28 after the third dose. Six months following the third dose, GMTs had dropped to almost the positive threshold: in the 1a-14d-2 m group, they were 9.2 (95% CI 7.1–12.0), while in the 2a-28d-2 m cohort, they were 10.0 (7.3–13.7). Similarly, 6 months following the initial two-dose series, neutralizing antibody titers dropped to almost or below the seropositive threshold among people 60 years of age or older who received booster doses (303 [87%] of 350 participants were eligible for a third dosage). Eight months following the second treatment, which markedly raised neutralizing antibody concentrations, a third dose was administered: After the second dose on day 28, GMTs climbed to 42.9 (95% CI: 31.0–59.4), and after the third dose on day 28 ( n  = 29), GMTs increased to 158.5 (96.6–259.2).

Chantasrisawad et al. ( 26 ) assessed healthy children aged 5 to 11 who were given two intramuscular doses of either Covilo or CoronaVac and 10 μg of BNT162b2. Neutralizing antibodies against the Omicron version were assessed using a pseudovirus neutralization test (pVNT, ID50) and a surrogate viral neutralization test (sVNT, % inhibition) 14–21 days following the booster. The antibody responses were contrasted with those of a concurrent cohort of kids who got two BNT162b2 doses separated by 3 weeks. A total of 59 children, consisting of 20 CoronaVac recipients and 39 Covilo recipients, were registered between April and May 2022, with a mean age (SD) of 8.5 years (1.7). The primary series’ median interval was 49 days, with an interquartile range of 33–51. Following the booster, the geometric means (MG) of pVNT and sVNT were 499 (95%CI: 399–624) and 72.2% inhibition (95%CI: 67.2–77.6), respectively. From zero to 72 %, the percentage of kids with sVNT against Omicron strain ≥68% inhibition rose. In comparison to the parallel cohort, the geometric mean ratios (GMR) of sVNT and pVNT were 4.3 and 12.2, respectively. In comparison to children who received a booster dosage between 4 and 6 weeks, the GMR of sVNT and pVNT among those who received it at a time interval of more than 6 weeks was 1.2 (95% CI: 1.1–1.3) and 1.8 (95% CI 1.2–2.7).

In Turkey, ( 27 ) et al. assessed the variables influencing the antibody response in 235 adults over 65 years of age following two doses of the inactivated SARS-CoV-2 vaccination (CoronaVac). Four weeks following the first and second vaccination doses, the mean levels of anti-SARS-CoV-2 IgG antibodies were 37.70 ± 57.08 IU/mL and 194.61 ± 174.88 IU/mL, respectively. Additionally, 4 weeks following the first vaccination dose, 134 out of 235 participants (57.02%) had an antibody level of less than 25.6 IU/mL (negative); 4 weeks following the second vaccination dose, this percentage was 11.48% ( n  = 27). Eight participants (29.6%) had no comorbidities, while 19 (70.4%) with an antibody level less than 25.6 IU/mL 4 weeks after the first dose of the vaccination had at least one comorbid condition, including diabetes mellitus ( F  = 2.352, p  = 0.006). Individuals with comorbidities and those 65 years of age or older showed lower antibody response rates.

Demirbakan et al. ( 28 ) examined the presence of immunoglobulin G antibodies in the receptor-binding region of the S1 subunit of the SARS-CoV-2 spike protein in 1072 healthcare workers following immunization in a descriptive observational research. 28 days, 21 days, and 3 months following the first, second, and second dosages, respectively, were the times at which blood samples were taken. Anti-spike antibodies were found in 834/1072 (77.8%) subjects 4 weeks following the initial vaccination dose. Between 18 and 34 years of age, seropositivity was observed to be greater in both men and women (84.6%) compared to 70.6% ( p  < 0.001) in the former group. In 1008 of 1,012 (99.6%) cases, anti-spike antibodies were found 21 days after the second dose, and in 803 of 836 (96.1%) cases, anti-spike antibodies were found 3 months later.

3.2.2.4 Safety

According to Bueno et al. ( 14 ) in their placebo-controlled clinical trial, pain at the injection site was the primary adverse reaction in 434 volunteers, and it occurred more frequently in the vaccine arm than in the placebo arm. The majority of the negative effects that were seen were modest and limited. No significant negative events were noted.

The frequency of adverse reactions was reported by Zeng et al. ( 25 ) without providing any additional effect measurements. In every immunization group, all adverse responses that were reported within 28 days after the third dose were classified as either grade 1 or 2. In the 1a-14d-2 m cohort, 150 participants reported three serious adverse events (2%); in the 1b-14d-8 m cohort, 150 participants reported four (3%); in the 2a-28d-2 m and 2b-28d-8 m cohorts, 150 participants reported one (1%); overall 349 people reported 24 (7%) serious adverse events.

Cheng et al. ( 18 ) observed an incidence rate of any adverse events of special interest following the first vaccination dose of 34.28 (95% CI: 29.81–39.23) and 38.39 (95% CI: 34.81–42.23) per 10,000 doses of BNT162b2 and CoronaVac, respectively, in their retrospective cohort of patients with chronic kidney disease. BNT162b2 (incidence rate ratio [95% CI]: first dose: 0.86 [0.69–1.08]; second dose: 0.96 [0.76–1.22]; third dose: 0.60 [0.33–1.10]) and CoronaVac (incidence rate ratio [95% CI]: first dose: 0.76 [0.64–0.91]; second dose: 0.86 [0.71–1.05]; third dose: 0.74 [0.36–1.54]) did not show an increased risk of overall adverse event of special interest when compared to the baseline period.

4 Discussion

The COVID-19 pandemic has affected the world’s population with a high morbidity and mortality rate. Recent reports have described persistent symptoms that extend beyond the initial period of the disease. It has been observed that adverse consequences, in addition to respiratory effects, are produced at different levels: cardiovascular, neurological, or immunological; cutaneous, gastrointestinal, or kidney manifestations, as well as in mental health, both as a result of acute infection and by the so-called post-COVID-19 syndrome ( 29 ). In this context, developing effective and safe vaccines was the determining control measure for pandemic management since, in addition to reducing the transmission of infections and allowing the control of the disease, vaccines had a determining role in reducing severe and fatal complications associated with infection ( 30 ). In addition to the above, the time in which the vaccine candidates were available, where it took less than a year for developers to complete the design, manufacturing, efficacy and safety testing and evaluation and approval for use, is an immeasurable scientific and public health learning, as well as an example of cooperation between healthcare authorities, the scientific community and private sector ( 31 ).

This review presents an analysis of the methods, populations, and scope of the studies that have evaluated the efficacy/effectiveness and safety of the vaccines available for COVID-19, emphasizing CoronaVac. Differences were found in terms of the proportion of populations evaluated, follow-up times, and times of the studies regarding the appearance of variants of concern.

Although some clinical trials with random assignment have been carried out to assess efficiency and safety outcomes with CoronaVac, these have limitations in terms of feasibility, follow-up times, and with this, the possibility of evaluating safety outcomes that occur with low frequencies ( 32 ). In this sense, it is important to carry out observational data analysis. However, not all studies have used homogeneous methods of analysis. Both the prevention of infection, and the prevention of outcomes such as hospitalization or death, have been valued through similar outcomes, but some through multivariate analysis of dependencies, and others through analysis that try to infer causally through different control methods of confounding. Studies have compared the evaluation of the same outcome through different methods, including multivariable logistic regression, propensity matching, propensity adjustment, and propensity-base weighting. However, researchers described that the estimates are very sensitive to the explicit or implicit weighting system in an adjustment technique, so it must be clear for which population a global treatment estimate is most appropriate ( 33 ).

It is important to recognize that there are common challenges in the collection, notification, and use of epidemiological data, such as the exhaustiveness and representativeness of the results and their comparability in time, among others. Therefore, it is necessary to identify the strongest analytical designs (among them the interrupted temporal series and comparative longitudinal studies), accompanied by sensitivity analysis of the results and being explicit, starting from the design, in the type of biases and problems that can be found in the data analysis that is available ( 34 ).

Concerning the evaluation of the immune response to the different types of vaccines, it has been oriented both to the antibody-mediated response and that mediated by cellular immunity. Among the antibody-mediated response, the reference standard has been established with the specific neutralizing antibody response against spike proteins of the virus, and a proxy to this response assessing neutralizing capacity has been measured in other studies by immunoglobulin G (IgG) antibody levels against the SARS-CoV-2 receptor binding domain (RBD) ( 35 ).

In the different studies, the decrease in the response levels to specific neutralizing antibodies was assumed to indicate the vaccine protection level when the levels of specific neutralizing antibodies fell between 4 and 6 months. The statistical methods used for their measurement are not homogeneous among all studies which has been used to recommend the application of boosters with vaccines produced in homologous or heterologous platforms of those received in established vaccination schemes ( 36 , 37 ).

To assess the duration of vaccine protection in the real world, it is also important to consider the difficulties in assessing the cellular memory immune response. The measurement of the CD4+ and CD8+ T lymphocytes response expressed in the production of different activation markers is heterogeneous, depending on antigenic stimuli such as peptides from circulating virus variants, cells from infected individuals, or peptides from different vaccines, in addition to diversity in the host response, which does not allow to have precise indicators to define optimal vaccination schedules ( 38 , 39 ).

In this context, inactivated whole virus vaccines, such as CoronaVac, by preserving epitopes of the virus, could respond in a broader spectrum to the different variants of circulating viruses or to new mutations, which could lead to the optimization of global vaccination schedules ( 10 ).

The main strength of our study lies in its systematic development, which reduces the possibility of biases in study selection. The use of different databases, including Latin American ones, allows for a broader search, although it is acknowledged that due to the magnitude of research on this topic, there may still be unreported or unfound studies, behaving as gray literature. The review results enabled us to achieve our objective, which was to describe how the efficacy/effectiveness of COVID-19 vaccines has been evaluated, with emphasis on CoronaVac. This allowed for the identification of some differences in these methods and some persisting gaps in defining more homogeneous methods for evaluation, regardless of whether these studies had high or low certainty in their evidence, which should be revisited if the objective is to evaluate the effectiveness and/or safety in the population of these interventions. However, the findings presented could be assessed and discussed with broader groups of experts in the field, which would help generate more accurate recommendations regarding their significance and potential implications.

In addition to the mentioned limitations, it is important to acknowledge that this type of review, having less precise question definitions compared to systematic reviews of effectiveness and safety (with their PICO structure), may result in some gaps in the application of search terms that could affect the results. Additionally, the vast amount of information, as was the case in our review, can create difficulties in synthesis and analysis, so it is crucial, as mentioned, to continue the discussion in groups with increasingly greater expertise in the subject ( 40 ). Lastly, while it is tempting to provide quantitative results regarding the synthesis conducted, the most important aspect is to address the original question regarding the gaps in the evaluation of these vaccines.

5 Conclusion

Published information on the evaluation of the efficacy/effectiveness and safety of the different vaccines against COVID-19 is abundant. However, there are differences in terms of vaccine application schedules, population definition, outcomes evaluated, follow-up times, and safety assessment, as well as non-standardization in the reporting of results, which may hinder the generalizability of the findings. It is important to define the relevance of the analysis methods in advance, considering these differences and the heterogeneity that can be produced in the analysis and meta-analysis of this information. It is important to generate meetings and consensus strategies for the methods and reporting of this type of studies, which will allow to reduce the heterogeneity in their presentation and a better understanding of the effect of these vaccines.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author.

Author contributions

JA-Á: Conceptualization, Methodology, Writing – original draft, Writing – review & editing, Investigation. PA-V: Writing – original draft, Writing – review & editing, Investigation. DA-L: Writing – original draft, Writing – review & editing, Investigation. AC-E: Writing – original draft, Writing – review & editing, Investigation. AG-H: Writing – original draft, Writing – review & editing, Investigation. LL-C: Writing – original draft, Writing – review & editing, Investigation. IM: Writing – original draft, Writing – review & editing, Investigation. DO-L: Writing – original draft, Writing – review & editing, Investigation. GQ: Writing – original draft, Writing – review & editing, Investigation. SR-B: Writing – original draft, Writing – review & editing, Investigation. CR-B: Funding acquisition, Writing – original draft, Writing – review & editing, Investigation. PR: Writing – original draft, Writing – review & editing, Investigation. MS-O: Writing – original draft, Writing – review & editing, Investigation. CT-A: Writing – original draft, Writing – review & editing, Investigation. MA-M: Funding acquisition, Project administration, Writing – original draft, Writing – review & editing, Investigation, Project Administration.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. CDC-China COVEP Fund Project #211-CO-04 (Submission 03/06/2022). The funders had no role in the design and development of the study, collection, management, analysis, interpretation of the data, writing the report, and the decision to submit the manuscript for publication.

Acknowledgments

We would like to thank Doracelly Hincapié-Palacio and María Teresa Rugeles-López, professors and researchers at the University of Antioquia, for their contributions and suggestions in the discussion of the results.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh.2024.1321327/full#supplementary-material

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Keywords: COVID-19, SARS-CoV-2, vaccines, CoronaVac, review

Citation: Alzate-Ángel JC, Avilés-Vergara PA, Arango-Londoño D, Concha-Eastman A, Garcés-Hurtado A, López-Carvajal L, Minotta IL, Ortega-Lenis D, Quintero G, Reina-Bolaños S, Reina-Bolaños CA, Roa P, Sánchez-Orozco M, Tovar-Acero C and Arbeláez-Montoya MP (2024) How has research on the effectiveness and safety of COVID-19 vaccination been evaluated: a scope review with emphasis on CoronaVac. Front. Public Health . 12:1321327. doi: 10.3389/fpubh.2024.1321327

Received: 13 October 2023; Accepted: 25 March 2024; Published: 10 April 2024.

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Copyright © 2024 Alzate-Ángel, Avilés-Vergara, Arango-Londoño, Concha-Eastman, Garcés-Hurtado, López-Carvajal, Minotta, Ortega-Lenis, Quintero, Reina-Bolaños, Reina-Bolaños, Roa, Sánchez-Orozco, Tovar-Acero and Arbeláez-Montoya. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Juan C. Alzate-Ángel, [email protected]

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Economic Evaluation of COVID-19 Immunization Strategies: A Systematic Review and Narrative Synthesis

• Systematic Review
• Published: 10 April 2024

Cite this article

• Enxue Chang 1   na1 ,
• Haofei Li 1   na1 ,
• Wanji Zheng 1   na1 ,
• Lan Zhou 1 ,
• Yanni Jia 1 ,
• Yiyin Cao 1 ,
• Xiaoying Zhu 2 , 3 ,
• Juan Xu 4 ,
• Mao You 6 ,
• Kejun Liu 6 ,
• Mingsi Wang 1 &
• Weidong Huang   ORCID: orcid.org/0009-0008-9580-6862 1  

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This study aimed to systematically assess global economic evaluation studies on COVID-19 vaccination, offer valuable insights for future economic evaluations, and assist policymakers in making evidence-based decisions regarding the implementation of COVID-19 vaccination.

Searches were performed from January 2020 to September 2023 across seven English databases (PubMed, Web of Science, MEDLINE, EBSCO, KCL-Korean Journal Dataset, SciELO Citation Index, and Derwent Innovations Index) and three Chinese databases (Wanfang Data, China Science and Technology Journal, and CNKI). Rigorous inclusion and exclusion criteria were applied. Data were extracted from eligible studies using a standardized data collection form, with the reporting quality of these studies assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022).

Of the 40 studies included in the final review, the overall reporting quality was good, evidenced by a mean score of 22.6 (ranging from 10.5 to 28). Given the significant heterogeneity in fundamental aspects among the studies reviewed, a narrative synthesis was conducted. Most of these studies adopted a health system or societal perspective. They predominantly utilized a composite model, merging dynamic and static methods, within short to medium-term time horizons to simulate various vaccination strategies. The research strategies varied among studies, investigating different doses, dosages, brands, mechanisms, efficacies, vaccination coverage rates, deployment speeds, and priority target groups. Three pivotal parameters notably influenced the evaluation results: the vaccine's effectiveness, its cost, and the basic reproductive number ( R 0 ). Despite variations in model structures, baseline parameters, and assumptions utilized, all studies identified a general trend that COVID-19 vaccination is cost-effective compared to no vaccination or intervention.

Conclusions

The current review confirmed that COVID-19 vaccination is a cost-effective alternative in preventing and controlling COVID-19. In addition, it highlights the profound impact of variables such as dose size, target population, vaccine efficacy, speed of vaccination, and diversity of vaccine brands and mechanisms on cost effectiveness, and also proposes practical and effective strategies for improving COVID-19 vaccination campaigns from the perspective of economic evaluation.

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Enxue Chang, Haofei Li and Wanji Zheng have contributed equally to this work and share first authorship.

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School of Health Management, Harbin Medical University, Harbin, China

Enxue Chang, Haofei Li, Wanji Zheng, Lan Zhou, Yanni Jia, Wen Gu, Yiyin Cao, Mingsi Wang & Weidong Huang

School of Elderly Care Services and Management, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

Xiaoying Zhu

Nossal Institute for Global Health, School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia

Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, Shenzhen, China

Shenzhen Health Capacity Building and Continuing Education Center, Shenzhen, China

National Health Development Research Center, Beijing, 100191, China

Mao You & Kejun Liu

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Correspondence to Xiaoying Zhu , Kejun Liu , Mingsi Wang or Weidong Huang .

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Enxue Chang, Weidong Huang, Mao You, Kejun Liu, and Mingsi Wang contributed to the study conception and design. Enxue Chang, Haofei Li, and Wanji Zheng performed screening, full text selection, and data extraction. Enxue Chang, Haofei Li, Wanji Zheng, Lan Zhou, and Yanni Jia conducted the quality appraisal of the studies. Mingsi Wang, Wen Gu, Yiyin Cao, Juan Xu, and Bo Liu contributed to the data interpretation. The first draft of the manuscript was written by Enxue Chang, Weidong Huang, and Xiaoying Zhu, and all authors contributed to the critical revision of the manuscript for intellectual content and approved the final draft submitted for publication.

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Chang, E., Li, H., Zheng, W. et al. Economic Evaluation of COVID-19 Immunization Strategies: A Systematic Review and Narrative Synthesis. Appl Health Econ Health Policy (2024). https://doi.org/10.1007/s40258-024-00880-6

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DOI : https://doi.org/10.1007/s40258-024-00880-6

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A CROSS-SECTIONAL STUDY ON COVID-19 VACCINATION HESITATION AMONG UNIVERSITY STUDENTS

Affiliations.

• 1 1Naturopathy Registration Board Under the aegis of National Institute of Naturopathy, Pune, India.
• 2 2Oral Pathology and Microbiology, Bharati Vidyapeeth (Deemed to be university) Dental College and Hospital, Pune, Maharashtra, India.
• 3 3Department of Yoga, Alva's College of Naturopathy and Yogic Sciences, Moodbidri, India.
• 4 4Government of Nature Cure and Yoga Medical College and Teaching Hospital, Mysore, India.
• 5 5Department of Clinical Naturopathy & Department of Research Methodology and Recent Advances; Govt Nature Cure and Yoga Medical College and Hospital Mysore, Karnataka, India.
• 6 6Government Nature Cure and Yoga Medical College, Mysore, India.
• PMID: 38609107

Students serve as ambassadors, conveying effective messages to encourage the adoption of promotes healthy behaviors. Recognizing their consciousness about corona illness 2019 (COVID-19), desires to utilize the COVID-19 vaccines, and other associated variables will aid in developing viable vaccination promotion tactics for the present COVID-19 pandemic. A transverse-segment internet poll of university students in the healthcare and non-healthcare industries was conducted to analyze their motivations to be vaccinated against the coronavirus. To recruit research participants, a random snowball sampling approach was utilized using digital media sites and mails. The contestants were chosen from throughout India, including several main geographic areas, between Nov-2020 and Jan-2021, prior to the release of the COVID-19 vaccination. There were descriptive metrics utilized to illustrate the research participants' socio-demographics and vaccine-related behaviors. Using logistic regression modeling, key characteristics that are expected to influence vaccination uptake among students were modeled. p 0.06 was judged substantial in each study. 656 students participated in the study, with 48.4% coming from the healthcare sector & 51.5% from other fields. Of these 655 students, 43.6 and 22.4% came from India's northern and eastern areas. Graduate students accounted for 41.1% of the total population, and graduates for around 43.2%. The age range of 56.0% of the students was 18 to 25. Women made up 62% of the population, and 69.5% of them were unmarried. Seventy-eight percent of the students were from the medium socioeconomic level. Concerns about side effects and safety, distrust of government officials, and questions about the vaccine's efficacy were among the reasons given by students in this study for their reluctance to get vaccinated. It is essential to remember that these investigations were carried out at various times and in various nations; thus, the conclusions may not apply to all college students throughout the globe. According to the findings of this research, Indian university students showed rather a great deal of motivating desire to acquire COVID-19 immunizations. The people were either doubtful or reluctant to get the vaccination, which suggests possible vaccine aversion. There is a need for information campaigns and other actions to lessen vaccine hesitancy in order to promote the usage of COVID-19 vaccines.

CDC Redacted Study on Myocarditis After COVID-19 Vaccination?

The redacted document, released as part of a foia request, was not a study., anna rascouët-paz, published april 8, 2024.

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In April 2024, a rumor circulated claiming that the U.S. Centers for Disease Control and Prevention had released a 148-page, completely redacted study the previous month on myocarditis following COVID-19 mRNA vaccination. One user shared the claim without context on X (formerly Twitter), garnering more than 18,000 views:

Another X user  linked to a YouTube video of "The Jimmy Dore Show," posted at the end of March 2024, which discussed the topic at length and had received 13,000 likes and 124,000 views:

This YouTube channel had 1.34 million subscribers at the time of this writing.

The document had been the subject of discussions during a hearing of the Novel Coronavirus Southwestern Intergovernmental Committee on March 15, 2024, which was  livestreamed . 

"One hundred and forty eight pages," said Arizona state Sen. Janae Shamp as she held up blank pages during the hearing. "The entire thing is redacted. What good does a study do if there's nothing there?"

Peter McCullough, a cardiologist who contributed to the spread of misinformation during the COVID-19 pandemic, also was at the hearing. "We're witnessing an active cover-up of a colossal consumer safety debacle that is basically affecting the entire world," he said. He then accused the CDC and the FDA, as well as the U.K., European and Australian medicine regulation agencies, of being complicit in this alleged cover-up. 

As we will demonstrate below, the redacted document was not in any sense a "study."

A clip of the intergovernmental committee's hearing was shared on X  ( archived ) on March 18, 2024, and was viewed 4 million times and amplified more than 20,000 times.

The CDC's Redacted Pages

The CDC did release 148 redacted pages following a Freedom of Information Act request by The Epoch Times concerning "MOVING" (Myocarditis outcomes after mRNA COVID-19 vaccination) surveys. These pages, however, were not a study. Zachary Stieber, the Epoch Times reporter who made the FOIA request, posted on X that he had noticed "confusion" about the document: 

The post ( archived ) to which he replied included the 148 blank pages. Clicking on the linked document and zooming in, a small inscription appears in the upper left corner of the first page: 

The inscription (b)(5), seen above, is repeated on every page of the document. This refers to information that is exempted from FOIA requests. According to the U.S. Justice Department :

Exemption 5 of the FOIA protects "inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than an agency in litigation with the agency."

This detail confirms that the 148 redacted pages did not constitute a study, but were instead communications within the CDC or between the CDC and other agencies. We contacted the CDC asking for more details on the reason for the redaction and will update this story if we receive an answer.

Stieber, in his post, added that the CDC team in charge of studying myocarditis outcomes following COVID-19 vaccinations has already shared several studies on the topic. He links to one of them, published in 2022 in The Lancet, which concludes :

After at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination, most individuals in our cohort were considered recovered by health-care providers, and quality of life measures were comparable to those in pre-pandemic and early pandemic populations of a similar age. 

The paper also recommends further study into the topic.

More Studies on Myocarditis Outcomes After COVID-19 mRNA Vaccine

The CDC and other research institutions have indeed released several studies on the link between the COVID-19 vaccine and both myocarditis, which is an inflammation of the heart muscle, and pericarditis, which is an inflammation of the thin tissue that lines the heart. The CDC website links to 10 studies on myocarditis after the vaccine carried out between 2021 and 2022. As Stieber indicated in his post, the MOVING team told him it plans to publish another study with updated findings.

Several studies found that while myocarditis and pericarditis can follow mRNA vaccination, the data show vaccination protects against complications. For example, a study from Germany showed that the risk of dying from myocarditis from a COVID-19 infection is much higher than the risk of dying from myocarditis not caused by COVID-19. 

Bemtgen, Xavier, et al. 'Myocarditis Mortality with and without COVID-19: Insights from a National Registry'. Clinical Research in Cardiology , vol. 113, no. 2, 2024, pp. 216–22. PubMed Central , https://doi.org/10.1007/s00392-022-02141-9.

Kracalik, Ian, et al. ' Ian Kracalik, PhD   • Matthew E Oster, MD • Karen R Broder, MD • Margaret M Cortese, MD • Maleeka Glover, ScD • Karen Shields, BS • et al. Show All Authors Published:September 21, 2022•DOI:Https://Doi.Org/10.1016/S2352-4642(22)00244-9• PlumX Metrics'. The Lancet , vol. 6, no. 11, Nov. 2022, pp. 788–99, https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00244-9/fulltext.

Office of Information Policy | FOIA Guide, 2004 Edition: Exemption 5 . 23 July 2014, https://www.justice.gov/archives/oip/foia-guide-2004-edition-exemption-5.

Vaccine Safety Publications | Research | Vaccine Safety | CDC . 27 Feb. 2024, https://www.cdc.gov/vaccinesafety/research/publications/index.html.

Video Player . https://www.azleg.gov/videoplayer/?clientID=6361162879&eventID=2024031052. Accessed 22 Mar. 2024.

By Anna Rascouët-Paz

Anna Rascouët-Paz is based in Brooklyn, fluent in numerous languages and specializes in science and economic topics.

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