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

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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 .

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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 ).

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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 。

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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 。

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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)

  • Open access
  • Published: 21 February 2024

Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis

  • Xiaodi Wu 1   na1 ,
  • Ke Xu 1   na1 ,
  • Ping Zhan 2 ,
  • Hongbing Liu 2 ,
  • Fang Zhang 2 ,
  • Yong Song 1 , 2 &
  • Tangfeng Lv 1 , 2  

BMC Infectious Diseases volume  24 , Article number:  234 ( 2024 ) Cite this article

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Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis.

We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized controlled trials (RCTs) from their inception to September 30, 2023. Two investigators independently selected articles, extracted data, and assessed the risk of bias. Outcomes included efficacy in preventing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of serious adverse events (SAEs) according to vaccine type and individual vaccines in adults and elderly individuals. The risk ratio and mean differences were calculated with 95% confidence intervals using a Bayesian network meta-analysis.

A total of 25 RCTs involving 22 vaccines were included in the study. None of vaccines had a higher incidence of SAEs than the placebo. Inactivated virus vaccines might be the safest, with a surface under the cumulative ranking curve (SUCRA) value of 0.16. BIV1-CovIran showed the highest safety index (SUCRA value: 0.13), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. There were no significant differences among the various types of vaccines regarding the efficacy in preventing symptomatic SARS-CoV-2 infection, although there was a trend toward higher efficacy of the mRNA vaccines (SUCRA value: 0.09). BNT162b2 showed the highest efficacy (SUCRA value: 0.02) among the individual vaccines, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. BNT162b2 had the highest efficacy (SUCRA value: 0.08) in the elderly population, whereas CVnCoV, CoVLP + AS03, and CoronaVac were not significantly different from the placebo.

Conclusions

None of the different types of vaccines were significantly superior in terms of efficacy, while mRNA vaccines were significantly inferior in safety to other types. BNT162b2 had the highest efficacy in preventing symptomatic SARS-CoV-2 infection in adults and the elderly, whereas BIV1-CovIran had the lowest incidence of SAEs in adults.

Peer Review reports

Introduction

There have been over 600 million confirmed cases of coronavirus disease (COVID-19) and over 6 million worldwide deaths by the end of 2022 since the onset of the COVID-19 pandemic [ 1 ]. The pandemic has significantly impacted healthcare and socio-economic development worldwide. The most prevalent clinical features of COVID-19 include fever, cough, and dyspnea [ 2 ]. While most cases are mild, the elderly and those with underlying diseases are at high risk of severe COVID-19. Moreover, some people also experience long-term effects after recovery. Novel oral antivirals such as molnupiravir, fluvoxamine, and paxlovid [ 3 ] are still under development, and heteropathy is believed to be the main clinical treatment. Therefore, vaccination is the first and most important step in stopping the spread of COVID-19 and reducing the social burden.

Vaccines can be divided into five categories according to their principles of antigen generation and production processes: inactivated virus vaccines, mRNA vaccines, DNA vaccines, viral vector vaccines, and protein subunit vaccines. Each type has certain advantages. Inactivated viral vaccines containing intact spike proteins and other proteins protect against viral variants by inducing a broader immune response [ 4 ]. mRNA and DNA vaccines are rapid and cost-effective platforms that can simulate natural infections by synthesizing endogenous proteins to induce a strong immune response [ 5 ]. Viral vector vaccines are characterized by robust immunogenicity, the absence of adjuvants, and long-term storage without freezing [ 6 ]. Protein subunits vaccines can produce robust and durable antibody responses and are expected to be safer because they do not utilize genetic materials [ 7 ].

Vaccine efficacy (VE) data are primarily obtained from phase III randomized controlled trials (RCTs). Previous studies have compared the efficacy and safety of vaccines using multiple post-hoc pairwise comparisons in meta-analyses [ 8 , 9 , 10 ]. In June 2021, a meta-analysis was conducted for eight Phase III RCTs encompassing four vaccine types [ 8 ]. The study indicated that all vaccine types exhibited good preventive effects against COVID-19, accompanied by an elevated risk of overall adverse events in the vaccinated groups. However, these studies did not compare multiple vaccines administered under identical conditions [ 8 ]. A network meta-analysis (NMA) provides a methodological approach to simultaneously compare vaccines through a common comparator (placebo) since there are no head-to-head clinical studies directly comparing the relative efficacy and safety of COVID-19 vaccines. In April 2021, the first published NMA of four Phase III RCTs showed that the vaccine exhibited different efficacies to prevent COVID-19: BNT162b2 ≥ mRNA-1273 > Gam-COVID-Vac > AZD1222 [ 11 ]. Subsequently, Rotshild et al. reported no statistical differences among vaccines in the preventive effect against severe COVID-19 of the elderly [ 12 ]. The latest NMA evaluation of the efficacy of 16 vaccines (October 2022) revealed that BNT126b2 conferred the highest protection against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [ 13 ].

This study aimed to integrate the latest published data from Phase III RCTs to compare the efficacy and safety of COVID-19 vaccines in adult populations. The efficacy of COVID‑19 vaccines was also conducted to prevent symptomatic disease among the elderly. This manuscript was written following the PRISMA-NMA checklist [ 14 ].

Search strategy and selection criteria

A systematic search was performed in PubMed, EMBASE, the Cochrane Library, medRxiv, and SSRN from their inception to Sep 30, 2023 for COVID-19 vaccine studies. The search included the following keywords and subject terms: “COVID-19,” “SARS-CoV-2,” “vaccines,” “efficacy,” “safety” and “clinical trial”. Details regarding the search strings for the different databases are provided in Table S1 .

The PICOS design approach was used to formulate the study eligibility criteria:

Subjects who participated in clinical trials related to COVID-19 vaccines, aged > 18 years, and without a prior history of SARS-CoV-2 infection or COVID-19 vaccination.

Intervention

The intervention was to complete the COVID-19 vaccination according to the design plan. We selected the optimal administration regimen approved by the relevant agencies as the only intervention when a vaccine contained multiple regimens.

Placebo or COVID-19 vaccines.

The efficacy outcomes included the incidence of laboratory-confirmed (RT-PCR-positive) symptomatic SARS-CoV-2 infection. Safety outcomes included serious adverse events (SAEs).

Study design

Phase III RCTs with full-text publications were included.

Data extraction and quality assessment

Two investigators (XDW and KX) independently selected the articles and extracted data according to the title, abstract, full reports, and supplementary materials. All discrepancies were resolved by consensus between two other authors of the study (HBL and PZ). Data were extracted in three parts: study characteristics (date of publication, author, phase, sample size, trial country, and study design), baseline demographic characteristics (sex ratio and age range), vaccine characteristics (vaccine type, company, adjuvant, injection interval, and concentration), and outcomes (definition, and follow-up time). The quality of individual studies was evaluated using RoB2 (version 2 of the Cochrane tool for assessing the risk of bias in randomized trials) [ 15 ]. The five assessed sources of risk of bias were randomization process, deviations from intended intervention, missing outcome data, measurement of the outcome, and selection of the reported result.

The primary outcomes included type-specific efficacy and safety of COVID-19 vaccines in adults. Vaccines were divided into five categories: inactivated viral vaccines, mRNA vaccines, DNA vaccines, viral vector vaccines, and protein subunit vaccines. The secondary outcomes included the efficacy and safety of individual vaccines in adults, type-specific efficacy of COVID-19 vaccines in the elderly, and the efficacy of individual vaccines in the elderly.

VE was evaluated by comparing the difference in the number of laboratory-confirmed (RT-PCR-positive) symptomatic SARS-CoV-2 infection cases commencing 7–28 days after the last dose of the investigational product between the experimental and control groups.

Safety outcomes were evaluated as the number of participants that reported SAEs throughout the study period. Analysis of SAEs included all participants who received at least one dose. SAEs were defined in accordance with the ICH-GCP as any untoward medical contingency that resulted in death, was life-threatening, requiring hospitalization, or resulted in persistent or significant disability or incapacity at any dose, regardless of whether they were considered as associated with vaccination [ 16 ]. Safety analysis of the vaccines was limited to adults only, as no clinical research provided SAE data for the elderly.

Data synthesis and statistical analysis

An NMA only including indirect comparisons was conducted to compare and rank the COVID-19 vaccines in terms of efficacy and safety in the absence of trials directly comparing the two COVID-19 vaccines. Heterogeneity was initially assessed using the Cochrane Q test and I² statistics were calculated. A random-effects model was used when I² was greater than 50% and a fixed-effects model was used when I² was below 50%. Possible causes of heterogeneity were explored through sensitivity analysis. The transitivity underlying NMA was subjectively evaluated by comparing key clinical features. Inconsistency was not evaluated since no study directly compared the two vaccines. The risk ratio (RR) was chosen for the outcomes with a corresponding 95% confidence interval (95% CI) to determine the effect size. The model was run based on simulations of 20,000 iterations in the framework of the Bayesian theory with each of the four chains after a burn-in of 5,000 using Markov chain Monte Carlo (MCMC) techniques with Gibbs sampling. Model fit was ensured using trace plots, density plots with bandwidth, and Brooks-Gelman-Rubin diagnostic plots. Network diagrams were used to present the networks for the models, and the outcomes of pairwise comparisons were presented in the corresponding tables. The surface under the cumulative ranking curve (SUCRA) was calculated to summarize probability values and rank the interventions measured on a scale of 0 (best) to 1 (worst) [ 17 ]. Potential publication bias of the included studies was evaluated using a funnel plot and Egger’s test. All analyses were conducted using the “gemtc” package and “rjags” package that interfaces with JAGS 4.3.0 in R x64 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) [ 18 , 19 , 20 ].

A total of 5606 records were identified by the search, with 24 published and one unpublished Phase III RCT [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] involving 22 vaccines eventually included in the NMA (Fig.  1 ). Two of the search results included a small number of individuals under the age of 18 years [ 29 , 31 ], and another study included Phase I/II/III RCTs of AZD1222 vaccines [ 34 ]. These three studies were included in the NMA to ensure a sufficient number of samples. None of the included studies directly compared two different vaccines. In total, 915,370 participants were included, and more than 50% were randomly assigned for vaccination. Study characteristics and raw data are summarized in Table  1 and S2 . A comparison of basic features, including outcome definition and participant characteristics (age, sex, and race) is presented in Table S3 and Figure S1 . There was no evidence of violation of the transitivity assumption. Among these articles, studies with some concerns accounted for 36%, but there were no serious risks of bias according to the RoB2 (Figure S2 ).

figure 1

Flowchart of study selection

Comparative efficacy and safety of different types of vaccines in adults

We explored the differences in efficacy and safety between different types of vaccines using NMA. Vaccines were divided into five categories: inactivated viral vaccines, mRNA vaccines, DNA vaccines, viral vector vaccines, and protein subunit vaccines. Star-shaped network diagrams of the primary outcomes are shown in Fig.  2 (A) and S3 .

figure 2

Network diagram ( A ) Network diagram of type-specific efficacy for adults. ( B ) Network diagram of individual vaccine efficacy for adults. The thickness of the lines is proportional to the number of trials comparing every pair of treatments

The inactivated viral, mRNA, viral vector, and protein subunit vaccines were predictably more effective than the placebo in terms of efficacy (25 RCTs involving 22 vaccines), with RRs ranging between 0.13 (95% CI [0.05, 0.31]) for mRNA vaccines and 0.28 [0.16, 0.49] for inactivated viral vaccines (Fig.  3 (A)). The DNA vaccines (0.32 [0.07, 1.5]) were not statistically significant compared with the placebo. There were no significant differences between the various types of vaccines in the indirect pairwise comparisons (Table S4 ), although there was a trend in the mRNA vaccines for the lowest risk of symptomatic disease, with the lowest SUCRA value of 0.09 (Table S5 ).

figure 3

Forest plot of intervention compared to the placebo in the network meta-analysis. RR, risk ratio; CI, confidence interval. ( A ) Forest plot of the efficacy of different vaccine types in adults. ( B ) Forest plot of the safety of different vaccine types in adults. ( C ) Forest plot of individual vaccine efficacy for adults. ( D ) Forest plot of individual vaccine safety for adults. ( E ) Forest plot of efficacy of different vaccine types in the elderly. ( F ) Forest plot of individual vaccine efficacy for the elderly

In terms of safety (21 RCTs involving 19 vaccines), none of vaccines had a higher incidence of SAEs than the placebo (Fig.  3 (B)). The inactivated virus vaccine ranked first, with a SUCRA value of 0.04, whereas the mRNA vaccine ranked last, with a SUCRA value of 0.98 (Table S6 ). There was a significant difference in the side effect rates between mRNA vaccines and other vaccine types in the indirect pairwise comparisons (Table S7 ). Funnel plots and Egger’s tests revealed asymmetry in VE and no asymmetry in vaccine safety (Figure S4 ).

Comparative efficacy and safety of individual vaccines in adults

Network diagrams are shown in Fig.  2 (B) and S5 . In terms of efficacy (25 RCTs involving 22 vaccines), all 22 vaccines were more effective than the placebo, with RRs ranging between 0.05 [0.02, 0.09] for BNT162b2 and 0.64 [0.52, 0.79] for SpikoGen (Fig.  3 (C)). According to the outcome of pairwise comparisons (Table S8 ) and SUCRA value (Table S9 ), BNT162b2 had the highest efficacy (SUCRA value: 0.02), followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. The efficacy of SpikoGen was the lowest, with a SUCRA of 0.94.

In terms of safety (21 RCTs involving 19 vaccines), none of the vaccines had a higher incidence of SAEs than the placebo (Fig.  3 (D)). BIV1-CovIran had the highest probability of being the vaccine with the lowest incidence of SAEs (SUCRA value: 0.1), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. In contrast, the safety of CoVLP + AS03 was the lowest, with a SUCRA value of 0.89. There were no statistically significant differences between most of the vaccines. Details of the pairwise comparisons and SUCRA values are shown in Tables S10 and S11 .

Comparative efficacy of different types of vaccines in the elderly population

Data on efficacy in the elderly population were retrieved from 15 RCTs involving 14 vaccines. Vaccines are divided into four categories: inactivated virus vaccines, mRNA vaccines, viral vector vaccines, and protein subunit vaccines. The definition of the elderly population slightly differed across the included studies, ranging from 50 to 65 years. Star-shaped network diagram is shown in Figures S6 .

The mRNA, viral vector, and protein subunit vaccines were predictably more effective than the placebo, with RRs ranging from 0.18 [0.05, 0.67] for mRNA vaccines and 0.23 [0.07, 0.75] for protein subunit vaccines (Fig.  3 (E)). The inactivated virus vaccine (0.4 [0.1, 1.5]) was not statistically significant compared to the placebo. There were no significant differences between the various types of vaccines in the indirect pairwise comparisons (Table S12 ), although there was a trend in the mRNA vaccine for the lowest risk of symptomatic disease, with the lowest SUCRA value of 0.24 (Table S13 ). Funnel plots and Egger’s tests indicated no publication bias (Figure S7 ).

Comparative efficacy of individual vaccines in the elderly population

Star-shaped network diagram is shown in Figures S8 . 11 of the 14 vaccines had good preventive effects against COVID-19 compared with the placebo, with RRs ranging between 0.06 [0.01, 0.16] for BNT162b2 and 0.48 [0.21, 0.99] for Ad5-nCoV (Fig.  3 (F)). CVnCoV, CoVLP + AS03, and CoronaVac were interpreted as having no differences from the placebo. BNT162b2 had the lowest SUCRA value of 0.08, with the highest probability of being the most effective vaccine for the elderly, followed by Gam-COVID-Vac and mRNA-1273, whereas CVnCoV had the lowest probability, with the highest SUCRA value of 0.92. Details of the SUCRA values and pairwise comparisons are shown in Tables S14 and S15 .

Additional analyses

Sensitive analyses were performed after excluded trials with a follow-up time of less than 2 months. 18 RCTs were included in analyses. The results were stable and were similar to the main analysis after excluding 7 trials (Table S16 ). In addition, sensitivity analyses were performed after excluded the unpublished study, and the results are robust.

This study was based on 25 RCTs that included 915,370 patients randomly assigned to receive 22 vaccines or a placebo. This project updates and extends previous research and is the most comprehensive NMA to compare the efficacy of COVID-19 vaccines in preventing symptomatic disease and the incidence of SAEs in adults and the elderly.

In terms of safety, mRNA vaccines may increase SAEs versus the placebo, although this result was not statistically significant. Similar trends were described in an earlier meta-analysis of 11 trials [ 46 ]. Our results provided the following rankings according to RR in the indirect comparison: inactivated vaccines ≥ viral vector vaccines ≥ protein subunit vaccines > mRNA vaccines. This is unsurprising given the high safety of inactivated vaccines since no viral genetic material is involved. In addition to SAEs, inactivated vaccines have the lowest risk of local or systemic adverse events following immunization [ 47 ]. The ranking of individual vaccines was generally consistent with the vaccine type. BIV1-CovIran, an inactivated vaccine, had the lowest incidence of SAEs. Notably, most included studies did not specifically exclude patients with symptomatic COVID-19 from SAE, which may have affected the accuracy of the above ranking.

In terms of efficacy, all vaccine types versus placebo significantly prevented symptomatic SARS-CoV-2 infection, but the 95% CI for DNA vaccines indicated no effect. In the indirect comparison, our results provided the following ranking according to the RR: mRNA vaccines ≥ protein subunit vaccines ≥ viral vector vaccines ≥ inactivated vaccines ≥ DNA vaccines. The 95% CI for all vaccine types was compatible with no effect, although the RR values were significant. One possible explanation for the excellent efficacy of mRNA vaccines is the production of a fully functional protein through cellular translational machinery, which induces powerful and durable immunity against the coronavirus [ 48 ]. An earlier NMA compared nine vaccines to prevent symptomatic SARS-CoV-2 infection, based on the results of Phase III RCTs up to August 1, 2021 [ 12 ]. BNT162b2 had the highest efficacy, followed by mRNA‑1273, Gam‑COVID‑Vac, NVX‑CoV2373, CoronaVac, BBIBP-CorV, WIBP-CorV, and Ad26.COV2.S [ 12 ]. Similarly, one recent NMA reported that BNT126b2 conferred the highest protection, followed by mRNA-1273, Gam‑COVID‑Vac and NVX-CoV2373 [ 13 ]. In line with previous evidence, we ranked BNT162b2 with the highest efficacy, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. We also found that BNT162b2 and mRNA-1273 mRNA vaccines performed best in preventing symptomatic COVID-19, while CVnCoV ranked lower. A possible explanation is that approximately 85% of COVID-19 cases in the CVnCoV trial were caused by variants that might alter VE owing to the increased transmissibility and evasion of neutralizing humoral immunity [ 49 ]. In addition, 12 µg mRNA contained in CVnCoV may be insufficient to elicit a protective immune response compared to 30 µg in BNT162b2 and 100 µg in mRNA-1273.

We found that BNT162b2 had the highest efficacy in terms of the efficacy in preventing symptomatic SARS-CoV-2 infection in the elderly population. This was consistent with the conclusion of an earlier study [ 47 ]. CVnCoV, CoVLP + AS03, and CoronaVac were interpreted as having no difference from the placebo, possibly owing to an insufficient absolute number of events in the short follow-up duration. In fact, the VE of CoronaVac in the real world has reached 66.6% in individuals aged > 60 [ 50 ]. In addition to the elderly, the impact of vaccines on children is gradually emphasized. Recently published Phase III clinical trials show that mRNA-1273 [ 51 , 52 , 53 ], BNT162b2 [ 54 ], and BBIBP-CorV [ 55 ] are safe in populations younger than 18 years and trigger an immune response no less than that in young people. There is a lack of large-scale clinical trials to support the active use of COVID-19 vaccines for other populations, such as pregnant women, immunodeficient patients, and people that were previously exposed to SARS-CoV-2.

Our review has some limitations; the above results should be cautiously interpreted since inconsistencies were not assessed in the absence of trials that directly compared the two COVID-19 vaccines. The transitivity assumption underlying the NMA was evaluated by comparing key clinical features, including participant characteristics (age, sex, and race), and outcome assessment (definition and measurement). However, there are some differences in the research background and protocols, such as vaccine dose and different SARS-CoV-2 variants, which might lead to deviations in analytical results. Furthermore, vaccines face great challenges in terms of increasing the diversity of variants, and the ranking of VE can change. Booster vaccines are necessary to prevent SARS-CoV-2 variant infections and provide durable immunity. These data suggest that homologous and heterologous booster vaccines have an acceptable safety profile and heterologous boosting may be more immunogenic than homologous boosting [ 56 ]. Our conclusion aims to provide a primary reference for vaccine selection. However, other important factors such as the prevention of severe COVID-19, long-term side effects, and economic considerations should also be considered practical scenarios.

Our study is the most comprehensive NMA exploring the efficacy and safety of type-specific and individual COVID-19 vaccines based on the latest data. Our analysis showed that BIV1-CovIran inactivated vaccine had the lowest incidence of SAEs in adults, and BNT162b2 mRNA vaccine had the highest efficacy in preventing symptomatic SARS-CoV-2 infections in adults and the elderly population.

Data Availability

All data generated or analyzed during this study are included in this published article and its additional information files.

Abbreviations

Confidence interval

Markov chain Monte Carlo

Network meta-analysis

Randomized controlled trials

Serious adverse events

Severe acute respiratory syndrome coronavirus 2

Surface under the cumulative ranking curve

Vaccine efficacy

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Xiaodi Wu and Ke Xu contributed equally to this work and should be regarded as co-first authors.

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Xiaodi Wu, Ke Xu, Yong Song & Tangfeng Lv

Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China

Ping Zhan, Hongbing Liu, Fang Zhang, Yong Song & Tangfeng Lv

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XDW and KX contributed equally as first authors. XDW, KX and FZ conceived and designed the study; YS and TFL provided administrative support; XDW and KX carried out the literature searches; XDW, KX, HBL and PZ extracted the data, and assessed the study quality; XDW performed the statistical analysis and wrote the manuscript; all authors read and approved the final manuscript.

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Wu, X., Xu, K., Zhan, P. et al. Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis. BMC Infect Dis 24 , 234 (2024). https://doi.org/10.1186/s12879-023-08754-3

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Cochrane review of COVID-19 vaccines shows they are effective

COVID-19 vaccination

A comprehensive review of all the evidence available from randomised controlled trials of COVID 19 vaccines up to November 2021 has concluded that most protect against infection and severe or critical illness caused by the virus.

The review, a collaboration of independent, international experts, also found there was little or no difference between the number of people experiencing serious side effects after vaccination compared to those who were unvaccinated.

The researchers, led by Isabelle Boutron, Professor of Epidemiology at Universit é Paris Cité and Director of Cochrane France, analysed published data from 41 randomised controlled trials of 12 different COVID-19 vaccines, involving 433,838 people in various countries around the world. They assessed the certainty of the evidence and the risk of bias in the different studies.

The trials compared COVID-19 vaccines with placebo, no vaccine, or each other, and were published before 5 November 2021.  The vaccines investigated were: Pfizer/BioNTech, Moderna, Oxford-AstraZeneca, Bharat (Covaxin), Janssen, Sinopharm-Beijing (WIBP-CorV and BBIBP-CorV), Novavax, Coronavac-Sinovac, Soberana 2 (Finlay-FR-2), Sputnik V (Gam-COVID-Vac) and Cure Vac AG (CVnCoV).  Most trials were no longer than two months in length.

The review found that the following vaccines reduced or probably reduced the risk of COVID-19 infection compared to placebo: Pfizer/BioNTech, Moderna, CureVac COVID-19, Oxford-AstraZeneca, Janssen, Sputnik V (Gam-COVID-Vac), Sinopharm (WIBP CorV and BBIBP-CorV), Bharat (Covaxin), Novavax and Soberana 2 (Finlay-FR-2) . The following reduced or probably reduced the risk of severe or critical disease: Pfizer/BioNTech, Moderna, Janssen, Sputnik V, Bharat and Novavax. In addition, the Janssen and Soberana 2 vaccines probably decreased the risk of death from any cause. There were very few deaths recorded in all the trials and so evidence on mortality for the other vaccines is uncertain.

For most of the vaccines investigated, more people who had been vaccinated reported localised or temporary side effects compared to those who had no treatment or placebo. These included tiredness, headache, muscle pains, chills, fever and nausea. With respect to the very rare side effects associated with some vaccines such as thrombosis, the team found that the reporting of these events was inconsistent, and the number of events reported in the trials was very low.

Given the evidence of efficacy of these vaccines, the researchers question whether further placebo-controlled trials are ethical. They suggest that further research compares new vaccines with those already in use.

covid 19 vaccination efficacy and safety literature review

The current review analysed data available up to November 2021. Since then, analyses have been updated and will continue to be made publicly available every two weeks by the COVID-NMA Initiative , which provides live mapping of COVID-19 trials. A living, systematic review of clinical trials is available to researchers and policy-makers alike on the COVID-NMA platform. This enables the team to provide the most up-to-date evidence on which to base further research and decisions about prevention and treatment for COVID-19.

Prof. Boutron said:

“The evidence on COVID-19 vaccines is constantly changing and updating. Everything moves so quickly that by the time the next Cochrane review is published, or other papers are published, the data are likely to be out of date. There are more than 600 randomised trials of vaccines registered at present, and about 200 of them are recruiting. COVID-NMA is the only initiative that continues to monitor the developing evidence from trials and provides a platform for researchers to conduct their own analyses via the metaCOVID tool on the website. Researchers, clinicians and policy-makers have to take very rapid decisions about what to do to prevent and treat COVID-19. I hope that this initiative will help them to have access to the most up-to-date evidence on which to base their decisions.”
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Full citation: Graña C, Ghosn L, Evrenoglou T, Jarde A, Minozzi S, Bergman H, Buckley BS, Probyn K, Villanueva G, Henschke N, Bonnet H, Assi R, Menon S, Marti M, Devane D, Mallon P, Lelievre J-D, Askie LM, Kredo T, Ferrand G, Davidson M, Riveros C, Tovey D, Meerpohl JJ, Grasselli G, Rada G, Hróbjartsson A, Ravaud P, Chaimani A, Boutron I. Efficacy and safety of COVID-19 vaccines. Cochrane Database of Systematic Reviews TBD, Issue TBD. Art. No.: CD015477. DOI: 10.1002/14651858.CD015477.

About Cochrane Cochrane is a global independent network of researchers, professionals, patients, carers, and people interested in health. Cochrane produces reviews which study all of the best available evidence generated through research and make it easier to inform decisions about health. These are called systematic reviews. Cochrane is a not-for profit organization with collaborators from more than 130 countries working together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest. Our work is recognized as representing an international gold standard for high quality, trusted information.  https://www.cochrane.org/

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Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis

  • Qiao Liu 1   na1 ,
  • Chenyuan Qin 1 , 2   na1 ,
  • Min Liu 1 &
  • Jue Liu   ORCID: orcid.org/0000-0002-1938-9365 1 , 2  

Infectious Diseases of Poverty volume  10 , Article number:  132 ( 2021 ) Cite this article

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To date, coronavirus disease 2019 (COVID-19) becomes increasingly fierce due to the emergence of variants. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance. We aimed to systematically evaluate the effectiveness and safety of COVID-19 vaccines in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

We searched PubMed, Embase and Web of Science from inception to July 22, 2021. Observational studies that examined the effectiveness and safety of SARS-CoV-2 vaccines among people vaccinated were included. Random-effects or fixed-effects models were used to estimate the pooled vaccine effectiveness (VE) and incidence rate of adverse events after vaccination, and their 95% confidence intervals ( CI ).

A total of 58 studies (32 studies for vaccine effectiveness and 26 studies for vaccine safety) were included. A single dose of vaccines was 41% (95% CI : 28–54%) effective at preventing SARS-CoV-2 infections, 52% (31–73%) for symptomatic COVID-19, 66% (50–81%) for hospitalization, 45% (42–49%) for Intensive Care Unit (ICU) admissions, and 53% (15–91%) for COVID-19-related death; and two doses were 85% (81–89%) effective at preventing SARS-CoV-2 infections, 97% (97–98%) for symptomatic COVID-19, 93% (89–96%) for hospitalization, 96% (93–98%) for ICU admissions, and 95% (92–98%) effective for COVID-19-related death, respectively. The pooled VE was 85% (80–91%) for the prevention of Alpha variant of SARS-CoV-2 infections, 75% (71–79%) for the Beta variant, 54% (35–74%) for the Gamma variant, and 74% (62–85%) for the Delta variant. The overall pooled incidence rate was 1.5% (1.4–1.6%) for adverse events, 0.4 (0.2–0.5) per 10 000 for severe adverse events, and 0.1 (0.1–0.2) per 10 000 for death after vaccination.

Conclusions

SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Graphical Abstract

covid 19 vaccination efficacy and safety literature review

Since its outbreak, coronavirus disease 2019 (COVID-19) has spread rapidly, with a sharp rise in the accumulative number of infections worldwide. As of August 8, 2021, COVID-19 has already killed more than 4.2 million people and more than 203 million people were infected [ 1 ]. Given its alarming-spreading speed and the high cost of completely relying on non-pharmaceutical measures, we urgently need safe and effective vaccines to cover susceptible populations and restore people’s lives into the original [ 2 ].

According to global statistics, as of August 2, 2021, there are 326 candidate vaccines, 103 of which are in clinical trials, and 19 vaccines have been put into normal use, including 8 inactivated vaccines and 5 protein subunit vaccines, 2 RNA vaccines, as well as 4 non-replicating viral vector vaccines [ 3 ]. Our World in Data simultaneously reported that 27.3% of the world population has received at least one dose of a COVID-19 vaccine, and 13.8% is fully vaccinated [ 4 ].

To date, COVID-19 become increasingly fierce due to the emergence of variants [ 5 , 6 , 7 ]. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance [ 6 , 8 ]. Several reviews systematically evaluated the effectiveness and/or safety of the three mainstream vaccines on the market (inactivated virus vaccines, RNA vaccines and viral vector vaccines) based on random clinical trials (RCT) yet [ 9 , 10 , 11 , 12 , 13 ].

In general, RNA vaccines are the most effective, followed by viral vector vaccines and inactivated virus vaccines [ 10 , 11 , 12 , 13 ]. The current safety of COVID-19 vaccines is acceptable for mass vaccination, but long-term monitoring of vaccine safety is needed, especially in older people with underlying conditions [ 9 , 10 , 11 , 12 , 13 ]. Inactivated vaccines had the lowest incidence of adverse events and the safety comparisons between mRNA vaccines and viral vectors were controversial [ 9 , 10 ].

RCTs usually conduct under a very demanding research circumstance, and tend to be highly consistent and limited in terms of population characteristics and experimental conditions. Actually, real-world studies differ significantly from RCTs in terms of study conditions and mass vaccination in real world requires taking into account factors, which are far more complex, such as widely heterogeneous populations, vaccine supply, willingness, medical accessibility, etc. Therefore, the real safety and effectiveness of vaccines turn out to be a major concern of international community. The results of a mass vaccination of CoronaVac in Chile demonstrated a protective effectiveness of 65.9% against the onset of COVID-19 after complete vaccination procedures [ 14 ], while the outcomes of phase 3 trials in Brazil and Turkey were 50.7% and 91.3%, reported on Sinovac’s website [ 14 ]. As for the Delta variant, the British claimed 88% protection after two doses of BNT162b2, compared with 67% for AZD1222 [ 15 ]. What is surprising is that the protection of BNT162b2 against infection in Israel is only 39% [ 16 ]. Several studies reported the effectiveness and safety of the COVID-19 vaccine in the real world recently, but the results remain controversial [ 17 , 18 , 19 , 20 ]. A comprehensive meta-analysis based upon the real-world studies is still in an urgent demand, especially for evaluating the effect of vaccines on variation strains. In the present study, we aimed to systematically evaluate the effectiveness and safety of the COVID-19 vaccine in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

Search strategy and selection criteria

Our methods were described in detail in our published protocol [PROSPERO (Prospective register of systematic reviews) registration, CRD42021267110]. We searched eligible studies published by 22 July 2021, from three databases including PubMed, Embase and Web of Science by the following search terms: (effectiveness OR safety) AND (COVID-19 OR coronavirus OR SARS-CoV-2) AND (vaccine OR vaccination). We used EndNoteX9.0 (Thomson ResearchSoft, Stanford, USA) to manage records, screen and exclude duplicates. This study was strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

We included observational studies that examined the effectiveness and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people vaccinated with SARS-CoV-2 vaccines. The following studies were excluded: (1) irrelevant to the subject of the meta-analysis, such as studies that did not use SARS-CoV-2 vaccination as the exposure; (2) insufficient data to calculate the rate for the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, or adverse events after vaccination; (3) duplicate studies or overlapping participants; (4) RCT studies, reviews, editorials, conference papers, case reports or animal experiments; and (5) studies that did not clarify the identification of COVID-19.

Studies were identified by two investigators (LQ and QCY) independently following the criteria above, while discrepancies reconciled by a third investigator (LJ).

Data extraction and quality assessment

The primary outcome was the effectiveness of SARS-CoV-2 vaccines. The following data were extracted independently by two investigators (LQ and QCY) from the selected studies: (1) basic information of the studies, including first author, publication year and study design; (2) characteristics of the study population, including sample sizes, age groups, setting or locations; (3) kinds of the SARS-CoV-2 vaccines; (4) outcomes for the effectiveness of SARS-CoV-2 vaccines: the number of laboratory-confirmed COVID-19, hospitalization for COVID-19, admission to the ICU for COVID-19, and COVID-19-related death; and (5) outcomes for the safety of SARS-CoV-2 vaccines: the number of adverse events after vaccination.

We evaluated the risk of bias using the Newcastle–Ottawa quality assessment scale for cohort studies and case–control studies [ 21 ]. and assess the methodological quality using the checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [ 22 ]. Cohort studies and case–control studies were classified as having low (≥ 7 stars), moderate (5–6 stars), and high risk of bias (≤ 4 stars) with an overall quality score of 9 stars. For cross-sectional studies, we assigned each item of the AHRQ checklist a score of 1 (answered “yes”) or 0 (answered “no” or “unclear”), and summarized scores across items to generate an overall quality score that ranged from 0 to 11. Low, moderate, and high risk of bias were identified as having a score of 8–11, 4–7 and 0–3, respectively.

Two investigators (LQ and QCY) independently assessed study quality, with disagreements resolved by a third investigator (LJ).

Data synthesis and statistical analysis

We performed a meta-analysis to pool data from included studies and assess the effectiveness and safety of SARS-CoV-2 vaccines by clinical outcomes (rates of the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, and adverse events after vaccination). Random-effects or fixed-effects models were used to pool the rates and adjusted estimates across studies separately, based on the heterogeneity between estimates ( I 2 ). Fixed-effects models were used if I 2  ≤ 50%, which represented low to moderate heterogeneity and random-effects models were used if I 2  > 50%, representing substantial heterogeneity.

We conducted subgroup analyses to investigate the possible sources of heterogeneity by using vaccine kinds, vaccination status, sample size, and study population as grouping variables. We used the Q test to conduct subgroup comparisons and variables were considered significant between subgroups if the subgroup difference P value was less than 0.05. Publication bias was assessed by funnel plot and Egger’s regression test. We analyzed data using Stata version 16.0 (StataCorp, Texas, USA).

A total of 4844 records were searched from the three databases. 2484 duplicates were excluded. After reading titles and abstracts, we excluded 2264 reviews, RCT studies, duplicates and other studies meeting our exclude criteria. Among the 96 studies under full-text review, 41 studies were excluded (Fig.  1 ). Ultimately, with three grey literatures included, this final meta-analysis comprised 58 eligible studies, including 32 studies [ 14 , 15 , 17 , 18 , 19 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] for vaccine effectiveness and 26 studies [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] for vaccine safety. Characteristics of included studies are showed in Additional file 1 : Table S1, Additional file 2 : Table S2. The risk of bias of all studies we included was moderate or low.

figure 1

Flowchart of the study selection

Vaccine effectiveness for different clinical outcomes of COVID-19

We separately reported the vaccine effectiveness (VE) by the first and second dose of vaccines, and conducted subgroup analysis by the days after the first or second dose (< 7 days, ≥ 7 days, ≥ 14 days, and ≥ 21 days; studies with no specific days were classified as 1 dose, 2 dose or ≥ 1 dose).

For the first dose of SARS-CoV-2 vaccines, the pooled VE was 41% (95% CI : 28–54%) for the prevention of SARS-CoV-2 infection, 52% (95% CI : 31–73%) for the prevention of symptomatic COVID-19, 66% (95% CI : 50–81%) for the prevention of hospital admissions, 45% (95% CI : 42–49%) for the prevention of ICU admissions, and 53% (95% CI : 15–91%) for the prevention of COVID-19-related death (Table 1 ). The subgroup, ≥ 21 days after the first dose, was found to have the highest VE in each clinical outcome of COVID-19, regardless of ≥ 1 dose group (Table 1 ).

For the second dose of SARS-CoV-2 vaccines, the pooled VE was 85% (95% CI : 81–89%) for the prevention of SARS-CoV-2 infection, 97% (95% CI : 97–98%) for the prevention of symptomatic COVID-19, 93% (95% CI: 89–96%) for the prevention of hospital admissions, 96% (95% CI : 93–98%) for the prevention of ICU admissions, and 95% (95% CI : 92–98%) for the prevention of COVID-19-related death (Table 1 ). VE was 94% (95% CI : 78–98%) in ≥ 21 days after the second dose for the prevention of SARS-CoV-2 infection, higher than other subgroups, regardless of 2 dose group (Table 1 ). For the prevention of symptomatic COVID-19, VE was also relatively higher in 21 days after the second dose (99%, 95% CI : 94–100%). Subgroups showed no statistically significant differences in the prevention of hospital admissions, ICU admissions and COVID-19-related death (subgroup difference P values were 0.991, 0.414, and 0.851, respectively).

Vaccine effectiveness for different variants of SARS-CoV-2 in fully vaccinated people

In the fully vaccinated groups (over 14 days after the second dose), the pooled VE was 85% (95% CI: 80–91%) for the prevention of Alpha variant of SARS-CoV-2 infection, 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. There was only one study [ 23 ] focused on the Beta variant, which showed the VE was 75% (95% CI : 71–79%) for the prevention of the Beta variant of SARS-CoV-2 infection. BNT162b2 vaccine had the highest VE in each variant group; 92% (95% CI : 90–94%) for the Alpha variant, 62% (95% CI : 2–88%) for the Gamma variant, and 84% (95% CI : 75–92%) for the Delta variant (Fig.  2 ).

figure 2

Forest plots for the vaccine effectiveness of SARS-CoV-2 vaccines in fully vaccinated populations. A Vaccine effectiveness against SARS-CoV-2 variants; B Vaccine effectiveness against SARS-CoV-2 with variants not mentioned. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, CI confidence interval

For studies which had not mentioned the variant of SARS-CoV-2, the pooled VE was 86% (95% CI: 76–97%) for the prevention of SARS-CoV-2 infection in fully vaccinated people. mRNA-1273 vaccine had the highest pooled VE (97%, 95% CI: 93–100%, Fig.  2 ).

Safety of SARS-CoV-2 vaccines

As Table 2 showed, the incidence rate of adverse events varied widely among different studies. We conducted subgroup analysis by study population (general population, patients and healthcare workers), vaccine type (BNT162b2, mRNA-1273, CoronaVac, and et al.), and population size (< 1000, 1000–10 000, 10 000–100 000, and > 100 000). The overall pooled incidence rate was 1.5% (95% CI : 1.4–1.6%) for adverse events, 0.4 (95% CI : 0.2–0.5) per 10 000 for severe adverse events, and 0.1 (95% CI : 0.1–0.2) per 10 000 for death after vaccination. Incidence rate of adverse events was higher in healthcare workers (53.2%, 95% CI : 28.4–77.9%), AZD1222 vaccine group (79.6%, 95% CI : 60.8–98.3%), and < 1000 population size group (57.6%, 95% CI : 47.9–67.4%). Incidence rate of sever adverse events was higher in healthcare workers (127.2, 95% CI : 62.7–191.8, per 10 000), Gam-COVID-Vac vaccine group (175.7, 95% CI : 77.2–274.2, per 10 000), and 1000–10 000 population size group (336.6, 95% CI : 41.4–631.8, per 10 000). Incidence rate of death after vaccination was higher in patients (7.6, 95% CI : 0.0–32.2, per 10 000), BNT162b2 vaccine group (29.8, 95% CI : 0.0–71.2, per 10 000), and < 1000 population size group (29.8, 95% CI : 0.0–71.2, per 10 000). Subgroups of general population, vaccine type not mentioned, and > 100 000 population size had the lowest incidence rate of adverse events, severe adverse events, and death after vaccination.

Sensitivity analysis and publication bias

In the sensitivity analyses, VE for SARS-CoV-2 infections, symptomatic COVID-19 and COVID-19-related death got relatively lower when omitting over a single dose group of Maria et al.’s work [ 33 ]; when omitting ≥ 14 days after the first dose group and ≥ 14 days after the second dose group of Alejandro et al.’s work [ 14 ], VE for SARS-CoV-2 infections, hospitalization, ICU admission and COVID-19-related death got relatively higher; and VE for all clinical status of COVID-19 became lower when omitting ≥ 14 days after the second dose group of Eric et al.’s work [ 34 ]. Incidence rate of adverse events and severe adverse events got relatively higher when omitting China CDC’s data [ 74 ]. P values of Egger’s regression test for all the meta-analysis were more than 0.05, indicating that there might not be publication bias.

To our knowledge, this is a comprehensive systematic review and meta-analysis assessing the effectiveness and safety of SARS-CoV-2 vaccines based on real-world studies, reporting pooled VE for different variants of SARS-CoV-2 and incidence rate of adverse events. This meta-analysis comprised a total of 58 studies, including 32 studies for vaccine effectiveness and 26 studies for vaccine safety. We found that a single dose of SARS-CoV-2 vaccines was about 40–60% effective at preventing any clinical status of COVID-19 and that two doses were 85% or more effective. Although vaccines were not as effective against variants of SARS-CoV-2 as original virus, the vaccine effectiveness was still over 50% for fully vaccinated people. Normal adverse events were common, while the incidence of severe adverse events or even death was very low, providing reassurance to health care providers and to vaccine recipients and promote confidence in the safety of COVID-19 vaccines. Our findings strengthen and augment evidence from previous review [ 75 ], which confirmed the effectiveness of the BNT162b2 mRNA vaccine, and additionally reported the safety of SARS-CoV-2 vaccines, giving insight on the future of SARS-CoV-2 vaccine schedules.

Although most vaccines for the prevention of COVID-19 are two-dose vaccines, we found that the pooled VE of a single dose of SARS-CoV-2 vaccines was about 50%. Recent study showed that the T cell and antibody responses induced by a single dose of the BNT162b2 vaccine were comparable to those naturally infected with SARE-CoV-2 within weeks or months after infection [ 76 ]. Our findings could help to develop vaccination strategies under certain circumstances such as countries having a shortage of vaccines. In some countries, in order to administer the first dose to a larger population, the second dose was delayed for up to 12 weeks [ 77 ]. Some countries such as Canada had even decided to delay the second dose for 16 weeks [ 78 ]. However, due to a suboptimum immune response in those receiving only a single dose of a vaccine, such an approach had a chance to give rise to the emergence of variants of SARS-CoV-2 [ 79 ]. There remains a need for large clinical trials to assess the efficacy of a single-dose administration of two-dose vaccines and the risk of increasing the emergence of variants.

Two doses of SARS-CoV-2 vaccines were highly effective at preventing hospitalization, severe cases and deaths resulting from COVID-19, while the VE of different groups of days from the second vaccine dose showed no statistically significant differences. Our findings emphasized the importance of getting fully vaccinated, for the fact that most breakthrough infections were mild or asymptomatic. A recent study showed that the occurrence of breakthrough infections with SARS-CoV-2 in fully vaccinated populations was predictable with neutralizing antibody titers during the peri-infection period [ 80 ]. We also found getting fully vaccinated was at least 50% effective at preventing SARS-CoV-2 variants infections, despite reduced effectiveness compared with original virus; and BNT162b2 vaccine was found to have the highest VE in each variant group. Studies showed that the highly mutated variants were indicative of a form of rapid, multistage evolutionary jumps, which could preferentially occur in the milieu of partial immune control [ 81 , 82 ]. Therefore, immunocompromised patients should be prioritized for anti-COVID-19 immunization to mitigate persistent SARS-CoV-2 infections, during which multimutational SARS-CoV-2 variants could arise [ 83 ].

Recently, many countries, including Israel, the United States, China and the United Kingdom, have introduced a booster of COVID-19 vaccine, namely the third dose [ 84 , 85 , 86 , 87 ]. A study of Israel showed that among people vaccinated with BNT162b2 vaccine over 60 years, the risk of COVID-19 infection and severe illness in the non-booster group was 11.3 times (95% CI: 10.4–12.3) and 19.5 times (95% CI: 12.9–29.5) than the booster group, respectively [ 84 ]. Some studies have found that the third dose of Moderna, Pfizer-BioNTech, Oxford-AstraZeneca and Sinovac produced a spike in infection-blocking neutralizing antibodies when given a few months after the second dose [ 85 , 87 , 88 ]. In addition, the common adverse events associated with the third dose did not differ significantly from the symptoms of the first two doses, ranging from mild to moderate [ 85 ]. The overall incidence rate of local and systemic adverse events was 69% (57/97) and 20% (19/97) after receiving the third dose of BNT162b2 vaccine, respectively [ 88 ]. Results of a phase 3 clinical trial involving 306 people aged 18–55 years showed that adverse events after receiving a third dose of BNT162b2 vaccine (5–8 months after completion of two doses) were similar to those reported after receiving a second dose [ 85 ]. Based on V-safe, local reactions were more frequently after dose 3 (5323/6283; 84.7%) than dose 2 (5249/6283; 83.5%) among people who received 3 doses of Moderna. Systemic reactions were reported less frequently after dose 3 (4963/6283; 79.0%) than dose 2 (5105/6283; 81.3%) [ 86 ]. On August 4, WHO called for a halt to booster shots until at least the end of September to achieve an even distribution of the vaccine [ 89 ]. At this stage, the most important thing we should be thinking about is how to reach a global cover of people at risk with the first or second dose, rather than focusing on the third dose.

Based on real world studies, our results preliminarily showed that complete inoculation of COVID-19 vaccines was still effective against infection of variants, although the VE was generally diminished compared with the original virus. Particularly, the pooled VE was 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. Since the wide spread of COVID-19, a number of variants have drawn extensive attention of international community, including Alpha variant (B.1.1.7), first identified in the United Kingdom; Beta variant (B.1.351) in South Africa; Gamma variant (P.1), initially appeared in Brazil; and the most infectious one to date, Delta variant (B.1.617.2) [ 90 ]. Israel recently reported a breakthrough infection of SARS-CoV-2, dominated by variant B.1.1.7 in a small number of fully vaccinated health care workers, raising concerns about the effectiveness of the original vaccine against those variants [ 80 ]. According to an observational cohort study in Qatar, VE of the BNT162b2 vaccine against the Alpha (B.1.1.7) and Beta (B.1.351) variants was 87% (95% CI : 81.8–90.7%) and 75.0% (95% CI : 70.5–7.9%), respectively [ 23 ]. Based on the National Immunization Management System of England, results from a recent real-world study of all the general population showed that the AZD1222 and BNT162b2 vaccines protected against symptomatic SARS-CoV-2 infection of Alpha variant with 74.5% (95% CI : 68.4–79.4%) and 93.7% (95% CI : 91.6–95.3%) [ 15 ]. In contrast, the VE against the Delta variant was 67.0% (95% CI : 61.3–71.8%) for two doses of AZD1222 vaccine and 88% (95% CI : 85.3–90.1%) for BNT162b2 vaccine [ 15 ].

In terms of adverse events after vaccination, the pooled incidence rate was very low, only 1.5% (95% CI : 1.4–1.6%). However, the prevalence of adverse events reported in large population (population size > 100 000) was much lower than that in small to medium population size. On the one hand, the vaccination population in the small to medium scale studies we included were mostly composed by health care workers, patients with specific diseases or the elderly. And these people are more concerned about their health and more sensitive to changes of themselves. But it remains to be proved whether patients or the elderly are more likely to have adverse events than the general. Mainstream vaccines currently on the market have maintained robust safety in specific populations such as cancer patients, organ transplant recipients, patients with rheumatic and musculoskeletal diseases, pregnant women and the elderly [ 54 , 91 , 92 , 93 , 94 ]. A prospective study by Tal Goshen-lag suggests that the safety of BNT162b2 vaccine in cancer patients is consistent with those previous reports [ 91 ]. In addition, the incidence rate of adverse events reported in the heart–lung transplant population is even lower than that in general population [ 95 ]. On the other hand, large scale studies at the national level are mostly based on national electronic health records or adverse event reporting systems, and it is likely that most mild or moderate symptoms are actually not reported.

Compared with the usual local adverse events (such as pain at the injection site, redness at the injection site, etc.) and normal systemic reactions (such as fatigue, myalgia, etc.), serious and life-threatening adverse events were rare due to our results. A meta-analysis based on RCTs only showed three cases of anaphylactic shock among 58 889 COVID-19 vaccine recipients and one in the placebo group [ 11 ]. The exact mechanisms underlying most of the adverse events are still unclear, accordingly we cannot establish a causal relation between severe adverse events and vaccination directly based on observational studies. In general, varying degrees of adverse events occur after different types of COVID-19 vaccination. Nevertheless, the benefits far outweigh the risks.

Our results showed the effectiveness and safety of different types of vaccines varied greatly. Regardless of SARS-CoV-2 variants, vaccine effectiveness varied from 66% (CoronaVac [ 14 ]) to 97% (mRNA-1273 [ 18 , 20 , 45 , 46 ]). The incidence rate of adverse events varied widely among different types of vaccines, which, however, could be explained by the sample size and population group of participants. BNT162b2, AZD1222, mRNA-1273 and CoronaVac were all found to have high vaccine efficacy and acceptable adverse-event profile in recent published studies [ 96 , 97 , 98 , 99 ]. A meta-analysis, focusing on the potential vaccine candidate which have reached to the phase 3 of clinical development, also found that although many of the vaccines caused more adverse events than the controls, most were mild, transient and manageable [ 100 ]. However, severe adverse events did occur, and there remains the need to implement a unified global surveillance system to monitor the adverse events of COVID-19 vaccines around the world [ 101 ]. A recent study employed a knowledge-based or rational strategy to perform a prioritization matrix of approved COVID-19 vaccines, and led to a scale with JANSSEN (Ad26.COV2.S) in the first place, and AZD1222, BNT162b2, and Sputnik V in second place, followed by BBIBP-CorV, CoronaVac and mRNA-1273 in third place [ 101 ]. Moreover, when deciding the priority of vaccines, the socioeconomic characteristics of each country should also be considered.

Our meta-analysis still has several limitations. First, we may include limited basic data on specific populations, as vaccination is slowly being promoted in populations under the age of 18 or over 60. Second, due to the limitation of the original real-world study, we did not conduct subgroup analysis based on more population characteristics, such as age. When analyzing the efficacy and safety of COVID-19 vaccine, we may have neglected the discussion on the heterogeneity from these sources. Third, most of the original studies only collected adverse events within 7 days after vaccination, which may limit the duration of follow-up for safety analysis.

Based on the real-world studies, SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its additional information files.

Abbreviations

Coronavirus disease 2019

Severe Acute Respiratory Syndrome Coronavirus 2

Vaccine effectiveness

Confidence intervals

Intensive care unit

Random clinical trials

Preferred reporting items for systematic reviews and meta-analyses

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (72122001; 71934002) and the National Science and Technology Key Projects on Prevention and Treatment of Major infectious disease of China (2020ZX10001002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. No payment was received by any of the co-authors for the preparation of this article.

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Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China

Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu

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LQ and QCY contributed equally as first authors. LJ and LM contributed equally as correspondence authors. LJ and LM conceived and designed the study; LQ, QCY and LJ carried out the literature searches, extracted the data, and assessed the study quality; LQ and QCY performed the statistical analysis and wrote the manuscript; LJ, LM, LQ and QCY revised the manuscript. All authors read and approved the final manuscript.

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Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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Liu, Q., Qin, C., Liu, M. et al. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis. Infect Dis Poverty 10 , 132 (2021). https://doi.org/10.1186/s40249-021-00915-3

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A narrative review of COVID-19 vaccination in pregnancy and breastfeeding

  • Jean L. Devera   ORCID: orcid.org/0000-0002-2030-4402 1 ,
  • Yunisse Gonzalez 1 &
  • Vishakha Sabharwal   ORCID: orcid.org/0000-0002-5092-4442 2  

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The Coronavirus pandemic has affected millions of people due to the spread of the Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) virus. Pregnant individuals and infants are most vulnerable given the increased risk of developing severe complications from SARS-CoV-2 infection. Recently, COVID-19 vaccination is recommended for pregnant women and infants starting at 6 months of age to prevent disease contraction and minimize disease severity. We conducted a review of the literature on COVID-19 vaccination to discuss vaccine safety and efficacy, immunity after maternal vaccination, transplacental transfer and persistence of antibodies, and public health implications. Current evidence supports the safety and efficacy of vaccination during pregnancy. Maternal vaccination provides greater antibody persistence in infants compared to immunity from natural infection. Furthermore, vaccination has demonstrated an increased rate of passive antibody transfer through the placenta and breast milk. Public health interventions are important in achieving herd immunity and ultimately ending the pandemic.

This article highlights the benefits of COVID-19 vaccination during pregnancy with a review of the data describing safety and efficacy, passive and active immunity after maternal immunization, trans-placental transfer and persistence of protective antibodies, and public health implications. With this information, healthcare providers can provide up-to-date knowledge to their pregnant patients to help them form an informed decision on vaccination and combat vaccine hesitancy.

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covid 19 vaccination efficacy and safety literature review

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Devera, J.L., Gonzalez, Y. & Sabharwal, V. A narrative review of COVID-19 vaccination in pregnancy and breastfeeding. J Perinatol 44 , 12–19 (2024). https://doi.org/10.1038/s41372-023-01734-0

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To introduce vaccine safety and efficacy, the two main public concerns for vaccine use. This is a review of the literature including but not limited to scientific publications and government documents that are related to vaccine safety and efficacy. The publication dates range from 1984 to 2020. Vaccine safety and efficacy are the two main concerns of vaccine use. The Food and Drug Administration (FDA) has a rigid policy for vaccine licensure and strict surveillance after vaccine deployment to ensure the safety of the vaccine. Vaccine efficacy is a critical criterion of the vaccine pre-licensure clinical trials and post-licensure surveillance. Double-blind, randomized, and clinical controlled studies and case-controlled studies are the two main methods to evaluate the vaccine efficacy. In this study, knowledge of vaccine safety and efficacy from numerous studies and researches are combined to provide an overall view and facilitate the understanding of vaccines. Vaccine administration is essentially a parental or personal decision. It is important to inform the public about the importance and benefits of vaccinations. As the number of vaccines increases, there is a need for a universal framework for vaccine assessment to facilitate international communications and encourage interdisciplinary studies. Vaccine inventions for contagious diseases like COVID-19 are urgent.

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ORIGINAL RESEARCH article

Global research on rna vaccines for covid-19 from 2019 to 2023: a bibliometric analysis.

Ziyi Chen,&#x;

  • 1 Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
  • 2 Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, the First Hospital of Nanchang, Nanchang, China
  • 3 Department of Pathology, Jiangxi Cancer Hospital, Nanchang, China
  • 4 Department of Pathology, Jiangxi Provincial Chest Hospital, Nanchang, China

Background: Since the global pandemic of COVID-19 has broken out, thousands of pieces of literature on COVID-19 RNA vaccines have been published in various journals. The overall measurement and analysis of RNA vaccines for COVID-19, with the help of sophisticated mathematical tools, could provide deep insights into global research performance and the collaborative architectural structure within the scientific community of COVID-19 mRNA vaccines. In this bibliometric analysis, we aim to determine the extent of the scientific output related to COVID-19 RNA vaccines between 2019 and 2023.

Methods: We applied the Bibliometrix R package for comprehensive science mapping analysis of extensive bibliographic metadata retrieved from the Web of Science Core Collection database. On January 11th, 2024, the Web of Science database was searched for COVID-19 RNA vaccine-related publications using predetermined search keywords with specific restrictions. Bradford’s law was applied to evaluate the core journals in this field. The data was analyzed with various bibliometric indicators using the Bibliometrix R package.

Results: The final analysis included 2962 publications published between 2020 and 2023 while there is no related publication in 2019. The most productive year was 2022. The most relevant leading authors in terms of publications were Ugur Sahin and Pei-Yong, Shi, who had the highest total citations in this field. The core journals were Vaccines, Frontiers in Immunology, and Viruses-Basel. The most frequently used author’s keywords were COVID-19, SARS-CoV-2, and vaccine. Recent COVID-19 RNA vaccine-related topics included mental health, COVID-19 vaccines in humans, people, and the pandemic. Harvard University was the top-ranked institution. The leading country in terms of publications, citations, corresponding author country, and international collaboration was the United States. The United States had the most robust collaboration with China.

Conclusion: The research hotspots include COVID-19 vaccines and the pandemic in people. We identified international collaboration and research expenditure strongly associated with COVID-19 vaccine research productivity. Researchers’ collaboration among developed countries should be extended to low-income countries to expand COVID-19 vaccine-related research and understanding.

Introduction

Since 2019, the global COVID-19 pandemic has affected the lives of billions of people worldwide ( 1 ). To deal with this situation, countries worldwide began to develop vaccines, including traditional inactivated vaccines, recombinant protein, live-attenuated vaccines, RNA vaccines, etc. ( 2 – 15 ). On October 2nd, 2023, the Nobel Assembly at the Karolinska Institutet decided to award the 2023 Nobel Prize in Physiology or Medicine jointly to Katalin Karikó and Drew Weissman for their discovery of nucleoside base modifications, which made it possible to develop an effective mRNA vaccine against COVID-19 ( 16 ). RNA vaccines have received widespread attention due to their high efficacy, specificity, versatility, rapid and large-scale development capabilities, low-cost production potential, and safety ( 17 , 18 ). RNA vaccines have been developed for several decades ( 19 , 20 ), and since COVID-19 has broken worldly, the RNA vaccines platform has enabled fast vaccine development in response to this pandemic ( 21 ). RNA vaccines provide flexibility in the design and expression of vaccine antigens, simulating the structure and expression of antigens during natural infections. RNA is necessary for protein synthesis and unconformity into the genome, and it is transiently expressed, metabolized, and eliminated by the body’s natural mechanism ( 22 ), so it is considered relatively safe. Many clinical trials have proven RNA-based preventive infectious disease vaccines and RNA therapeutic agents to be safe and well-tolerated ( 23 – 29 ). Generally speaking, vaccination with RNA can trigger a robust innate immune response. RNA guides the expression of vaccine antigens in host cells and has intrinsic adjuvant effects ( 30 – 32 ). One advantage of the RNA vaccine manufacturing platform is that it can quickly produce many vaccines targeting new pathogens, regardless of the encoded pathogen antigen ( 33 ). The bibliometric analysis of published articles provides insights into research prospects, gaps, and future directions in the research field. This study examined scientific publications related to RNA vaccines for COVID-19 through bibliometric analysis and trend analysis.

Search strategy

We conducted a literature search on the Web of Science Core Collection (WoSCC) database ( https://www.webofscience.com/wos/woscc/basic-search ) on January 11th, 2024. The search formula was TS= ((RNA vaccine AND COVID-19) OR (RNA vaccine AND SARS-COV-2)), the published year was set before 2024, and the type of documents was set to articles and reviews. The language filter was set in English ( Figure 1 ). According to our search strategies, there were 2962 studies of RNA vaccines for COVID-19 between 2020 and 2023 (0 publication in 2019), including 1956 articles and 1006 reviews. The analyzed publications were written by 23141 authors (93 with single-authored documents and 23048 with multi-authored documents) from 104 countries and 908 journals.

www.frontiersin.org

Figure 1 Flowchart of the related data collection and bibliometrics analysis.

Characteristics of the year of publication

Figure 2A shows that the number of annual related publications increased rapidly year by year from 2020 to 2022. In 2020, 271 articles were published, while 795 in 2021, 1144 in 2022, and 752 in 2023. The most productive year was 2022 (n = 1144) with the annual scientific growth rate of 143.9%. The total number of citations per article and the average citations per year have decreased ( Figure 2B ). In 2020, the average number of citations per article was 123.5, 45.9 in 2021, 17.3 in 2022, and 2.48 in 2023. The total average number of citations per year was 24.7 in 2020, 11.5 in 2021, 5.8 in 2022, and 1.2 in 2023.

www.frontiersin.org

Figure 2 (A) Annual related publication from 2019 to 2023 per year, and (B) average article and average article citations from 2019 to 2023 in COVID-19 RNA vaccine-related research. MeanTCperArt, mean total citation per article; MeanTCperYear, mean total citation per year.

Characteristics of the countries

We filtered and visualized 104 countries that published more than ten articles and constructed a collaborative network based on the number and relationship of publications in each country. From Figure 3A , we can point out that the United States has the highest literature output(n=4163) on COVID-19 RNA vaccines, and the number is significantly higher than that of China(n=1844) and Italy(n=936). Notably, there is much active cooperation between different countries. For example, the United States closely cooperates with China, the United Kingdom, Germany, and Italy; India actively cooperates with Saudi Arabia ( Figure 3B ). It shows that the United States has the most significant number of SCPs and MCPs, which indicates that the United States has the most researches on COVID-19 RNA vaccines and cooperation with other countries in this regard, followed by China on both SCP and MCP ( Figure 3C ).

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Figure 3 The geographical distribution (A) and visualization (B) of countries on the research of COVID-19 RNA vaccines. A choropleth map detailing the geographic distribution of collaborating countries. The intensity (from light blue to dark blue) is proportional to the number of publications. The number of links (presented as red lines) between any two countries represents the strength of collaboration. (C) Co-authorship analysis of countries in the related research SCP (Single country publications) indicates that the authors of this article are all from the same country, and MCP (Multiple country publications) indicates that the authors of this article are from different countries, indicating international cooperation.

Characteristics of the affiliations

In Figure 4A , Harvard University has the highest number of institutions that receive and publish articles (n=249), followed by the University of California System (n=160) and Harvard Medical School (n=76). Half the top 20 most relevant affiliations were from the United States, followed by the United Kingdom, China, France, and Israel. Subsequently, we selected 34 institutions based on visualization with a minimum number of publications equal to 5. We constructed a collaborative network based on the number of publications and relationships of each affiliation ( Figure 4B ). As shown in Figure 4B , Harvard University and Harvard Medical School cooperated the most, and Tel Aviv University and Sheba Medical Center also had active cooperation. In addition, we noticed that Harvard University had published the most papers and collaborated with the most significant number of affiliations.

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Figure 4 (A) Top 20 most relevant affiliations on the research of COVID-19 RNA vaccines. (B) Network map of co-authorship between affiliations with more than 5 citations.

Characteristics of the top 20 most productive authors

The number of academic publications by an author can represent research activities and contributions in the field to some extent. As shown in Table 1 , Ugur Sahin was the most influential author from University Medical Center, Johannes Gutenberg University, between 2020 and 2023 on COVID-19 RNA vaccines, who had published 14 articles in this field, whose h-index is 9, g-index is 14, m-index is 2.6. He also has the highest number of total citations(n=14203). Pei-Yong Shi’s h-index(n=12) is a close second. Pei-Yong Shi published 16 articles in this field between 2020 and 2023; his g-index is 16, and his m-index is 2.4. Notably, we can find that Pei-Yong Shi and Ugur Sahin had the most significant academic influence on COVID-19 RNA vaccines.

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Table 1 The author’s impact in relevant field.

Characteristics of the top 20 journals and co-cited journals

Followed by Frontiers in Immunology (n=105, 3.54%) and Viruses-Basel (n = 58, 2.94%), the Vaccines published the most articles on COVID-19 RNA vaccines (n =171, 5.77%) throughout four years. However, the New England Journal of Medicine, Nature, and Science were the most cited journals. Bradford’s law was applied to assess the core journals in the field of COVID-19 RNA vaccines. As shown in Figure 5A , the core journals in COVID-19 RNA vaccines were Vaccines, Frontiers in Immunology, Viruses-Basel, Clinical Infectious Diseases, Journal of Medical Virology, etc. As for co-cited journals in Figure 5B , journals were categorized into different clusters. The nodes with different colors in the graph represent different clusters. The node size represents the number of articles published in the journal, and the thickness of the lines represents the number of connections between nodes. Frontiers in Immunology, Vaccines, and Journal of Medical Virology were the top three most influential journals in this field. This result can help scholars to select the best-fit journals for submitting their research findings. Also, Table 2 lists the top 20 most-cited publications on COVID-19 RNA vaccines. All these productions were published between 2020 and 2023, and 65% obtained more than 1000 citations. Table 2 shows that the New England Journal of Medicine was the highest-cited journal with the highest h-index, m-index, and total citations. Frontiers in Immunology has the highest g-index. These indexes showed the importance of these two journals on COVID-19 RNA vaccines.

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Figure 5 (A) Journals (Sources) clustering through Bradford’s law. (B) Co-cited Journals of COVID-19 RNA vaccines.

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Table 2 The journal’s impact on COVID-19 RNA vaccines.

Relations between journals (left), authors (middle), and affiliations(right)

The relations between journals, authors, and affiliations were visualized using the three-field plot (TFP). In this instance, the significant features were represented in the diagram by rectangles with different colors. The height of the rectangles in the diagram of the TFP depended on the rate or value of the summation of the relations arising between the component the rectangle represents (journals, authors, and affiliations) and the diagram of other elements. The more relations the component or element had, the higher the rectangle represented. Figure 6 shows the TFP analysis of publications on COVID-19 RNA vaccines centered on relations between the journals, authors, and affiliations. The diagram demonstrated the top journals, authors, and affiliations relations in publications on COVID-19 RNA vaccines and their related studies during these four years.

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Figure 6 Three-Fields Plot revealed the relations between journals (left), authors (middle), and affiliations (right) for research in COVID-19 RNA vaccines.

Characteristics of the top 20-most cited articles and co-cited references

The top 20 most cited articles were published in 11 journals between 2020 and 2023 ( Table 3 ). Seven articles were published in The New England Journal of Medicine, and four were published in Nature. With 8609 citations, the top-cited article was published by Fernando P Polack from the New England Journal of Medicine in 2020. The total citations per year were 1721.80, and the normalized total citation was 69.69. The following one was published by Edward E Walsh and received 1574 citations, whose total citations per year was 314.80, and the normalized total citation was 12.74.

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Table 3 Main characteristics of the top 20-most cited articles.

There are 50 references of co-citation with more than five citations. As shown in Figure 7 , Wrapp d 2020 ( 34 ) has the highest number of connections with other references, followed by Hoffmann m 2020 ( 35 ). Polack fp 2020 ( 24 ) has the highest value of PageRank to get other references, which shows the importance of a node to get other nodes, followed by Baden lr 2021 ( 36 ).

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Figure 7 Network map of co-citation between references with more than five citations.

Keyword co-occurrence, clusters

Keywords are always the core research content highly condensed and summarized by researchers, which can reflect the central theme of the research. Therefore, keyword co-occurrence analysis is a crucial way to determine the main research direction and hot research topics of a specific discipline. Among Figure 8B , the most frequent author’s keywords were “covid-19” (n =1166,25%), “sars-cov-2” (n=1054,22%), “vaccine” (n=323,7%), “coronavirus” (n =183,4%), “vaccines” (n =174,4%), and “vaccination” (n = 170,4%). The overall keyword network visualization is presented in Figure 8 . It can be seen that the frequency of the words COVID-19 and SARS-COV-2 has significantly increased from 2020 to 2023.

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Figure 8 Keyword co-occurrence map (A) and the cluster of COVID-19 RNA vaccines (B) .

In this study, R studio quantitative analysis software was used to analyze the references related to the COVID-19 RNA vaccines and summarize the research results and progress. Quantitative analysis of annual publication quantity, country, author, institution, journal, and other essential information are also included. According to the number of articles published on the COVID-19 RNA vaccines in 2020, the number of documents published in this field is 271, showing an overall increasing trend. The higher the number of citations in a paper, the more excellent its impact on the field and the higher its quality. The total number of citations in this field increases between 2020 and 2022. The number of related articles in 2023 is lower than in 2022.

Through statistical analysis of the number of papers published by countries/regions and institutions, it can be determined that the key countries/regions and research institutions that have published many COVID-19 RNA vaccine literature and have a significant influence can determine their cooperation relationship. The United States and China are major countries conducting research on RNA vaccines for COVID-19, and the United States ranks first. Half of the top 20 research institutions are in the United States, followed by the United Kingdom, China, France and Israel. We noticed the close cooperation among five countries: the United States, China, the United Kingdom, Germany, and Italy. In addition, the United States has active collaborations with China, the United Kingdom, and Germany. The United States is undoubtedly the main driving force for the development of this field. The publications and cooperation between countries are significantly higher in developed countries than in developing countries. Regarding research affiliations, 50% of the top 20 most relevant affiliations were from the United States, which may be one of the essential reasons for the rapid development of the United States in this field. Regarding institutions, Harvard University is the most prolific institution, followed by the University of California System and Harvard Medical School. Affiliations like Tel Aviv University and Sheba Medical Center have an excellent cooperative relationship. Also, we found that Harvard University published the most papers and collaborated with the most institutions, which will be detrimental to the long-term development of academic research. Although some countries have cooperative relations, the frequency, breadth, and intensity of cooperation between institutions are not ideal. For example, there is only a small amount of collaboration between institutions in the United States and China. This situation will hinder the development of the research field in the long run. Therefore, we strongly recommend that research institutions in various countries carry out extensive cooperation and communication to jointly promote the development of RNA vaccines for COVID-19. Close collaboration and communication between countries and institutions are conducive to eliminating academic barriers and further developing research related to the COVID-19 RNA vaccines.

From the perspective of the author, SAHIN U, SHI PY, LIU Y, TÜRECI Ö, and LEE J published the most articles. Professor Uğur Şahin, who had the highest number of total citations, had published 14 papers, 9 of which were concerned with the immunogenicity and effectiveness of COVID-19 mRNA vaccines, and pointed out that BNT162b2 has neutralizing activity on different COVID-19 variants. They also found that BNT162B2 can elicit the response of TH1 cells and antibodies. In addition, the safety of these vaccines has also been proved ( 37 – 46 ). Pei-Yong Shi, whose h-index was second only to Uğur Şahin, has published 16 articles during these four years, most of which pointed out the safety and immunogenicity of COVID-19 RNA vaccines. These vaccines can induce the persistent response of the human germinal center. He also found that some SARS-CoV-2 variants resist these RNA vaccines ( 25 , 27 , 37 , 39 , 47 – 56 ).

Most of the research on COVID-19 RNA vaccines was published in Vaccines (IF=7.8, Q1), indicating it is currently the most productive journal in this research field. Among the journals, the journal with the highest impact factor is the New England Journal of Medicine (IF=158.5, Q1), followed by Nature (IF=64.8, Q1). As for the co-cited journals, we could find that most of them are high-impact Q1 journals. These journals are high-quality international journals providing support for the study of COVID-19 RNA vaccines.

The top 20 most cited articles were mainly published between 2020 and 2021, and all seven were published in the New England Journal of Medicine, indicating the influence of the New England Journal of Medicine in this regard. In addition, the first four articles are all about the safety and effectiveness of the COVID-19 RNA vaccines. It can be seen that the safety and effectiveness of RNA vaccines have always been a hot topic in the discussion of the COVID-19 RNA vaccines.

Vaccines, Frontiers in Immunology, and Virus Basel are the journals that publish the most articles about the COVID-19 RNA vaccines. However, regarding influence, the New England Journal of Medicine has the highest h-index, m-index, and total citations, proving that it currently has the most significant influence in this field. Frontiers in Immunology has the highest g-index, proving its importance in the field of COVID-19 RNA vaccines. Frontiers in Immunology, Vaccines, and Journal of Medical Virology were the top three most influential journals in this field, which may be listed in the journal consideration for the relevant researchers.

According to the keywords, COVID-19, SAR-COV-2, and vaccine are currently the most concerning topics conducive to further research. The research hotspots in this field mainly include COVID-19, SAR-COV-2, and vaccine. We hope this work can provide new ideas for promoting scientific research and clinical applications of COVID-19 RNA vaccines.

In general, this study is the first comprehensive analysis that summarizes the research of the COVID-19 RNA vaccines using literature metrology methods. Our research findings provide valuable information for researchers in this field to understand the basic knowledge landscape, current research hotspots, and future opportunities and identify potential collaborators in the future.

The wide application of the COVID-19 RNA vaccines provides a good platform for the development of RNA vaccine, not only contributes to the research and development of COVID-19 RNA vaccines but also proves the effectiveness and safety of RNA vaccine to a certain extent and provides sufficient theoretical and technical support for the future application of RNA vaccine in other fields, such as cancer treatment.

Limitations

Firstly, to ensure high-quality bibliometric analysis, the analysis of this study is based on articles in the Web of Science database, one of the most commonly used scientific publication databases. However, some studies may be omitted as they are published in non-SCI journals or other databases. Secondly, bibliometric analyses cannot completely replace system retrieval. Third, metrology cannot evaluate the quality of a single study because the citation index is time-dependent, meaning that recent articles may be less cited than earlier, even if they are more valuable. These limitations may slightly impact the overall results but are unlikely to alter the main trends presented in this article. In general, our research has provided a basis for understanding the research topics of the COVID-19 RNA vaccines and the production and application of the RNA vaccine.

Eligibility criteria and data source

In this study, research articles on RNA vaccines for COVID-19 published between 2020 and 2023 as original articles or reviews in English were considered eligible. Web of Science core collection database was used.

In the advanced search option of the Web of Science database, using an appropriate combination of Boolean and wildcard search operators, the following keywords were searched: “Corona Virus Disease 2019”, “COVID-19”, “RNA”, and “vaccines”. The search was performed on January 11th, 2024, and the entire search strategy is presented in TS = ((RNA vaccine AND COVID-19) OR (RNA vaccine AND SARS-COV-2, the type of documents is set to “articles” and “reviews”. The language of articles is set as English only. Then, all the resulted information, including full records and cited references, was downloaded in txt format.

Bibliometric analyses

Data management and bibliometric analyses were conducted using the Bibliometrix package (version 3.1.4) ( 57 ) and Biblioshiny ( 57 ) web apps under R (version 4.0.2). We retrieved all the main information and features included in the study. Publications and citation trends were constructed over four years. From 2020 to 2023, the most influential countries on COVID-19 RNA vaccine research were retrieved and presented as a cluster collaboration network. The cooperative world map represents world research cooperation, with the minimum edge set at 10. In addition, we identified the most productive institutions based on the highest number of paper contributions to the topic over the past four years. We used leading eigenvalue clustering algorithms to construct a collaborative network between institutions with more than five citations. We determined the author with the highest contribution based on the highest number of papers and the top 20 co-citation networks of influential authors. The 20 most cited references and the most influential journals were also identified, and some characteristics were searched, such as h-index, g-index, m-index, the total number of citations, the number of papers on the subject published in the journal, and the year when the journal began to publish COVID-19 RNA vaccine-related topics. In order to observe the inflow and outflow of journals, authors, and affiliated institutions that have contributed to the COVID-19 RNA vaccines in the past four years, a three-field plot was constructed. A tree chart was prepared to display keywords published on this topic from 2020 to 2023.

Conclusions

RNA vaccine has essential research value and application prospects in COVID-19. The rapid increase in the number of publications shows that the research on the RNA vaccine for COVID-19 has attracted more attention from scholars worldwide. The main countries are the United States and China. However, cooperation and communication between countries and institutions still need to be strengthened. On the one hand, studying the immunogenicity and safety of RNA vaccines will help us to prevent COVID-19 variants infection and reduce vaccine side effects ( 58 ). On the other hand, compared with traditional vaccines, RNA vaccines have significant advantages in preventing COVID-19. Therefore, the study of COVID-19 RNA vaccines has essential application value in preventing COVID-19 infection and alleviating symptoms in the future ( 59 ). In addition to the related prevention research of COVID-19, attention can also be paid to the transformation of research achievements, that is, the clinical application of RNA vaccines in other diseases ( 58 ).

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 authors.

Author contributions

ZC: Conceptualization, Visualization, Writing – original draft. ZL: Software, Validation, Writing – review & editing. YF: Writing – review & editing. AS: Writing – original draft. LW: Writing – review & editing. YS: Conceptualization, Funding acquisition, Supervision, Writing – original draft. CL: Conceptualization, Software, Supervision, Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Jiangxi Provincial Natural Science Foundation of China (20204BCJL23052, 20212ACB216013) and by Nanchang Natural Science Foundation No.129 in 2021.

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.

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Keywords: COVID-19, SARS-CoV-2, RNA vaccines, web of science, bibliometrics

Citation: Chen Z, Liu Z, Feng Y, Shi A, Wu L, Sang Y and Li C (2024) Global research on RNA vaccines for COVID-19 from 2019 to 2023: a bibliometric analysis. Front. Immunol. 15:1259788. doi: 10.3389/fimmu.2024.1259788

Received: 16 July 2023; Accepted: 01 February 2024; Published: 15 February 2024.

Reviewed by:

Copyright © 2024 Chen, Liu, Feng, Shi, Wu, Sang and Li. 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: Yi Sang, [email protected] ; Chenxi Li, [email protected]

† These authors have contributed equally to this work

Disclaimer: 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.

  • Research article
  • Open access
  • Published: 20 February 2024

Immunogenicity and safety of RAZI recombinant spike protein vaccine (RCP) as a booster dose after priming with BBIBP-CorV: a parallel two groups, randomized, double blind trial

  • Saeed Erfanpoor 1   na1 ,
  • Seyed Reza Banihashemi 2   na1 ,
  • Ladan Mokhbaeralsafa 3 ,
  • Saeed Kalantari 4 ,
  • Ali Es-haghi 5 ,
  • Mojtaba Nofeli 6 ,
  • Ali Rezaei Mokarram 7 ,
  • Fariba Sadeghi 7 ,
  • Monireh Hajimoradi 2 ,
  • Seyad Hossein Razaz 2 ,
  • Maryam Taghdiri 2 ,
  • Mohsen Lotfi 8 ,
  • Akbar Khorasani 6 ,
  • Akram Ansarifar 1 ,
  • Safdar Masoumi 9 ,
  • Arash Mohazzab 1 , 10 ,
  • Sara Filsoof 11 ,
  • Vahideh Mohseni 1 ,
  • Masoumeh Shahsavan 1 ,
  • Niloufar Gharavi 11 ,
  • Seyed Amin Setarehdan 1 , 12 ,
  • Mohammad Hasan Rabiee 13 ,
  • Mohammad Hossein Fallah Mehrabadi 3 &
  • Masoud Solaymani-Dodaran 12 , 14 , 15  

BMC Medicine volume  22 , Article number:  78 ( 2024 ) Cite this article

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The immunity induced by primary vaccination is effective against COVID-19; however, booster vaccines are needed to maintain vaccine-induced immunity and improve protection against emerging variants. Heterologous boosting is believed to result in more robust immune responses. This study investigated the safety and immunogenicity of the Razi Cov Pars vaccine (RCP) as a heterologous booster dose in people primed with Beijing Bio-Institute of Biological Products Coronavirus Vaccine (BBIBP-CorV).

We conducted a randomized, double-blind, active-controlled trial in adults aged 18 and over primarily vaccinated with BBIBP-CorV, an inactivated SARS-CoV-2 vaccine. Eligible participants were randomly assigned (1:1) to receive a booster dose of RCP or BBIBP-CorV vaccines. The primary outcome was neutralizing antibody activity measured by a conventional virus neutralization test (cVNT). The secondary efficacy outcomes included specific IgG antibodies against SARS-CoV-2 spike (S1 and receptor-binding domain, RBD) antigens and cell-mediated immunity. We measured humoral antibody responses at 2 weeks (in all participants) and 3 and 6 months (a subgroup of 101 participants) after the booster dose injection. The secondary safety outcomes were solicited and unsolicited immediate, local, and systemic adverse reactions.

We recruited 483 eligible participants between December 7, 2021, and January 13, 2022. The mean age was 51.9 years, and 68.1% were men. Neutralizing antibody titers increased about 3 (geometric mean fold increase, GMFI = 2.77, 95% CI 2.26–3.39) and 21 (GMFI = 21.51, 95% CI 16.35–28.32) times compared to the baseline in the BBIBP-CorV and the RCP vaccine groups. Geometric mean ratios (GMR) and 95% CI for serum neutralizing antibody titers for RCP compared with BBIBP-CorV on days 14, 90, and 180 were 6.81 (5.32–8.72), 1.77 (1.15–2.72), and 2.37 (1.62–3.47) respectively. We observed a similar pattern for specific antibody responses against S1 and RBD. We detected a rise in gamma interferon (IFN-γ), tumor necrosis factor (TNF-α), and interleukin 2 (IL-2) following stimulation with S antigen, particularly in the RCP group, and the flow cytometry examination showed an increase in the percentage of CD3 + /CD8 + lymphocytes. RCP and BBIBP-CorV had similar safety profiles; we identified no vaccine-related or unrelated deaths.

Conclusions

BBIBP-CorV and RCP vaccines as booster doses are safe and provide a strong immune response that is more robust when the RCP vaccine is used. Heterologous vaccines are preferred as booster doses.

Trial registration

This study was registered with the Iranian Registry of Clinical Trial at www.irct.ir , IRCT20201214049709N4. Registered 29 November 2021.

Peer Review reports

The World Health Organization declared SARS-CoV-2 pandemic on 11 March 2020 [ 1 ]. Globally, until June 2023, more than 767 million confirmed cases of COVID-19 have been recorded, and nearly 7 million people have died due to this disease [ 2 ]. The COVID-19 pandemic has led to global efforts to develop safe and effective vaccines against the rapidly spreading virus [ 3 , 4 ]. The COVID-19 vaccination programs have effectively protected against severe disease, hospitalization, and death [ 5 , 6 ]. Protection against SARS-CoV-2 infection caused by primary vaccination wanes significantly over time [ 7 ], and this is more alarming considering the continuous emergence of new SARS-CoV-2 strains [ 8 ]. Regardless of the type and platform of COVID-19 vaccines, their effectiveness decreases after 3 to 6 months. It has been reported that following a complete vaccination, the effectiveness of the BNT162b2 vaccine against COVID-19 infection decreased from 90.8% in the early period (first 2 months) to 79.3% in the late period (3 to 5 months later). The corresponding figures of vaccine effectiveness for the CoronaVac vaccine were 74.5% and 30.4% [ 9 ].

People who received a booster dose (either homologous or heterologous) had more robust immune responses and less severe illness or infection with COVID-19 than those that did not receive it, regardless of the type of the primary vaccine [ 10 , 11 ]. Furthermore, there are reports that a heterologous boosting may provide additional immunity and protection against SARS-CoV-2 infection variants [ 1 , 12 , 13 , 14 ]. Adminstration of viral vector, mRNA, or recombinant protein-based vaccines in individuals with a history of two doses of inactivated vaccine has resulted in strong immunogenicity with acceptable adverse events [ 1 , 13 , 15 ]. There are also reports that heterologous boosting by recombinant subunit vaccines, such as NVSI-06–07, V-01, ZF2001, and SpikoGen®, in individuals primed with two doses of inactivated vaccines is immunogenically superior to homologous boosting [ 15 , 16 , 17 , 18 ].

RAZI Cov Pars (RCP) is a recombinant spike protein COVID-19 vaccine developed by the Razi Vaccine and Serum Research Institute of Iran. It comprises three components of monomeric S1 (amino acid 1–674), S2 (amino acid 685–1211) subunits, and trimeric S protein formulated in an oil-in-water adjuvant system RAS-01 (Razi Adjuvant System-01). A detailed description of RCP preparation has been published before [ 19 ]. RCP has shown promising safety and induced robust and long-lasting humoral and cellular immune responses in preclinical and all three phases of clinical trials [ 20 , 21 , 22 ] (phase III trial results are under publication). Sinopharm inactivated virus vaccine (BBIBP-CorV), which the World Health Organization approves, has been widely used in many countries, including Iran’s vaccination program (about 70% of the coverage) [ 23 ]. Based on the above, using a recombinant protein sub-unit such as RCP is an appropriate choice of booster vaccine in the face of declining immunity [ 24 , 25 , 26 ] following primary vaccination with BBIBP-CorV. The current study explores the safety and immunogenicity of heterologous boosting with RCP compared to homologous boosting with BBIBP-CorV in adults who have previously received two doses of the inactivated BBIBP-CorV.

Study design

We conducted a multicenter, randomized, double-blind, parallel-group, active control trial in adults 18 and older who were vaccinated primarily with an inactivated SARS-CoV-2 vaccine-BBIBP-CorV. Participants were randomly assigned (1:1) to receive a booster dose of RCP or BBIBP-CorV vaccine in the two trial centers. The study protocol was approved by the National Research Ethics Committee (approval number IR.NREC.1400.013) and registered with the Iranian Registry of Clinical Trial (Ref: IRCT20201214049709N4).

Participants

Participants were adult Iranian nationals or legal residents aged 18 years or older who had completed their primary vaccination with two doses of BBIBP-CorV vaccine at least 75 days and at most 195 days before their enrollment. The main exclusion criteria were as follows: history of allergic diseases such as angioedema or anaphylactic reactions after receiving previous COVID-19 vaccines; any current or new diagnosis of acute or chronic illness requiring continuous ongoing medical care; pregnancy and lactation; immunodeficiency diseases (suspected and definitive); history of uncontrolled serious psychiatric illnesses; history of blood disorders (dyscrasia, coagulopathy, platelet deficiency or disorder, or deficiency of blood clotting factors); history of chronic neurological diseases (including seizures and epilepsy) and acute febrile illness at the time of booster vaccine injection.

Randomization and masking

A stratified block randomization method with a block size of 4 was used to assign each participant to the intervention groups. Stratification was based on four-time strata of 2.5–3.5, 3.5–4.5, 4.5–5.5, and 5.5–6.5 months passed from the participants’ primary vaccination. The rand () function of Excel software was used to generate a random sequence within each block. A non-repetitive five-digit random code was used to conceal the chain of randomization. In this study, the BBIBP-CorV vaccine had different packaging and shape than RCP. Once the participant reached the vaccine injection stage, the assigned vaccine type was temporarily displayed on the computer screen and disappeared following the confirmation of the injection. Therefore, the person responsible for injecting the vaccine was the only research team member who was aware of the intervention type and trained not to disclose this to others.

We enrolled volunteers via a website. Those who successfully passed the online screening were invited to attend the two trial centers. Potential participants were asked to sign a written informed consent and further evaluated for eligibility. Eligible participants randomly received an intramuscular dose of either 10 μg/200 μL RAZI recombinant spike protein (RCP) or 0.5 ml Sinopharm inactivated virus (BBIBP-Corv) vaccines. Blood samples for immunogenicity were collected from the participants at the time of booster vaccination and on days 14, 90, and 180 after that.

Participants were monitored for half an hour after receiving the injection for acute anaphylactic reactions. They were asked to report their local (pain, tenderness, erythema/redness, and swelling) and systemic (nausea, diarrhea, headache, fatigue, and myalgia) adverse reactions every day for 7 days via an application installed on their mobile phone. A 24/7 follow-up center with a resident physician could be contacted by phone during the 1-month follow-up period. Participants had to report weekly any visit to a medical center or medication use through their mobile application; otherwise, they were flagged for active follow-up by the research team.

The primary outcome was neutralizing antibody titer on days 14, 90, and 180 following the injection measured by conventional virus neutralization test (cVNT). The test was conducted in a biosafety level 3 laboratory facility using the original live alpha SARS-CoV-2 strain isolated from the Iranian COVID-19 patients. We defined seroconversion as a four-fold or more increase in the antibody titer compared to the baseline (day 0). Secondary efficacy outcomes were specific IgG antibody levels against S1 and RBD spike antigens of SARS-CoV-2 measured by ELISA on days 14, 90, and 180 and cellular immunity on day 14. We measured specific IgG levels in six serum dilutions (0·1, 0·01, 0·001, 0·0001, 0·00001, and 0·000001) for each specimen and estimated the response by calculating the area under the curve (AUC). Peripheral blood mononuclear cell cultures were used to assess the cellular immunity responses. We tested them for specific cytokine-secreting T cells before and after the stimulation by specific COVID-19 S1 antigens. The secretion of gamma interferon (IFN-γ), tumor necrosis factor (TNF-α), and interleukin IL-2, 4, 6, and 17 were detected by enzyme-linked immunosorbent assay (ELISA) (R&D, USA). CD3, CD4, CD8, CD3/CD8, and CD3/CD4 cell counts were analyzed by flow cytometer (BD FACSLyric, USA). Lymphocyte proliferative potential response was measured by CFSE (carboxyfluorescein succinimidyl ester) cell staining assay. For more details, please see Additional file 1 [ 21 , 27 ].

Secondary safety outcomes were abnormal vital signs and anaphylactic reactions immediately after the vaccination, solicited local and systemic adverse reactions, medically attended adverse events, and serious adverse events up to 1 month after receiving the booster dose. We used FDA toxicity grading scales to classified solicited local and systemic adverse reactions [ 28 ]. We assessed the causality for the detected adverse events during the one-month follow-up period [ 29 ].

Statistical analysis

All participants who underwent randomization were included in the safety population. The immunogenicity population consisted of all randomized participants who provided at least one serum sample after receiving the booster dose (modified intention to treat approach). Means and proportions were used to summarize demographic characteristics. Baseline comparisons were performed to examine the homogeneity between the study groups. Geometric mean for neutralizing antibody titers (GMT) and specific IgG antibody responses (area under the curve, AUC) were calculated. Geometric mean ratios (GMR) and their 95% confidence interval for RCP compared to BBIBP-CorV were estimated at different time intervals based on Dunnett’s test, which is used to adjust multiple comparisons with one control. Geometric mean fold increases (GMFI) were calculated for each vaccine by dividing the geometric mean response by that of the baseline. The data was analyzed by Stata 14.2 (Stata Corporation, Texas, USA).

Participant characteristics and baseline comparison

Between December 7, 2021, and January 13, 2022, 483 eligible participants randomly received BBIBP-CorV (241) or RCP (242) vaccines (Fig.  1 ) and followed for 7260 and 7207 person-days, respectively. The mean age of the participants in the study was 51.9 years, and 68.1% were men. A comparison of baseline characteristics indicates a balanced distribution of participants in the study groups (Table  1 ).

figure 1

Participant flow diagram. Randomization and analysis populations. A total of 783 participants were enrolled, and 483 received booster vaccinations. The participants were randomly assigned to receive a booster dose of either RCP or BBIBP-CorV. All the 483 participants receiving booster vaccination were included in the safety set for safety analysis. We evaluated the immunogenicity in 417 participants who visited the research center for blood sampling on day 14 and a subgroup of 101 participants on 3 and 6 months after the booster dose

Immunogenicity

Humoral immune response.

Neutralizing antibody response 2 weeks after the booster dose (day 14) was statistically significantly higher in the RCP group compared with BBIBP-CorV (GMR = 6.8, 95% CI 5.3–8.7). The geometric mean of neutralizing antibody titers statistically significantly increased about 3 and 21 times the baseline in the BBIBP-CorV (GMFI = 2.8, 95% CI 2.2–3.3) and RCP (GMFI = 21.5, 95% CI 16.3–28.3) groups. The neutralizing antibody response remained high 3 and 6 months after the booster dose in both RCP and BBIBP-CorV groups (Table  2 , Fig.  2 C, and Additional file 1 : Table S1). Similarly, specific antibody responses against S1 and RBD antigens on day 14 were statistically significantly higher in the RCP group compared with BBIBP-CorV (GMR = 3.1, 95% CI 2.7–3.7 and GMR = 3.6, 95% CI 3.1–4.3). The geometric mean of specific antibody response on day 14 increased about 4.4 and 15.7 times the baseline against S1 antigen and 4.3 and 18.2 times the baseline against RBD antigen in the BBIBP-CorV and RCP groups, respectively, and the increases were statistically significant. The specific antibody responses against S1 and RBD antigens gradually decreased over the next 6 months but remained 4 and 7 times the baseline level in the BBIBP-CorV and RCP groups (Table  2 , Fig.  2 A, B, and Additional file 1 : Table S1). The baseline antibody levels and the antibody responses were similar across the time strata used for the randomization (Additional file 1 : Table S2-S4 and Figure S2).

figure 2

Geometric mean and 95% CI of specific antibody responses (AUC) to A S1, B RBD, and C neutralizing antibody titer in the BBIBP-CorV and RCP groups over the predefined study time schedule. Error bars are 95% CIs

Cellular immune response

Following stimulation with S antigen, IFN-γ, TNF-α, and IL-2 increased on day 14 compared with day 0 in both vaccine groups. Still, the response was statistically significantly higher in the RCP group than in BBIBP-CorV ( P -value < 0.05) (Fig.  3 A). Increase in IL-4, IL-17, and lymphocyte proliferation were seen in response to stimulation with S antigen in both vaccines, and the increase was higher (though not statistically significant) in the RCP vaccine than BBIBP-CorV ( P -value > 0.05) (Fig.  3 A, B). In flow cytometry, we observed a noticeable increase in the percentage of CD3 + /CD8 + in the RCP group (though it did not reach statistical significance), but it remained relatively unchanged in the BBIBP-CorV group (Fig.  3 C). Overall, it seems that T helper 1 differentiation of T cells (increase in IFN-γ, IL-2, and percentage of CD3 + /CD8 +) is more marked in RCP vaccine recipients in response to stimulation with S antigen (see Fig.  3 A, C).

figure 3

Comparison of the mean differences of the cell-mediated responses between days 0 and 14 in the BBIBP-CorV and RCP study groups in a subgroup of 18 participants. P -values for the t -test have been presented in the figures. Error bars are 95% CIs. A Specific cytokines were detected by ELISA (IFN-γ, TNF-α, interleukin 2, interleukin 4, interleukin 17), B lymphocyte proliferative potential response following stimulation by S antigen was measured by CFSE method, and C cell counts for lymphocytic subpopulations (CD3/CD4 ratio, CD3/CD8 ratio) using flow cytometry

Safety and reactogenicity

We did not observe any immediate allergic reaction in the study participants. The most common solicited local adverse reaction within the first-week post-vaccination was tenderness (20.6% in BBIBP-CorV and 19.5% in RCP groups). Other local reactions were pain, swelling, and redness (Fig.  4 A). Grade III local adverse reactions were seen in 29 (12%) and 38 (16%) of BBIBP-CorV and RCP participants, all of which were fully recovered. The most prevalent solicited systemic adverse reaction within the first-week post-vaccination was myalgia (16% in BBIBP-CorV participants and 11% in RCP groups), followed by headache and fatigue (Fig.  4 B). Grade III headache were seen in 12% of BBIBP-CorV and 10% of RCP participants. Two grade III and two grade IV cases of myalgia (0.8%) were seen only in the BBIBP-CorV group. No other grade III or IV solicited local and systemic adverse reaction was observed, and all of them were resolved during the follow-up period.

figure 4

Local and systemic adverse reactions were reported within seven days after injection of RCP and BBIBP-CorV. Adverse reactions are graded according to the FDA toxicity grading scales. A Local adverse reactions. B Systemic adverse reactions

We identified 111 unsolicited adverse events (AE) during the month following the booster dose injection. All the cases received the necessary treatments and were followed until complete recovery (Additional file 1 : Table S5). The rate of AEs occurrence was 6.52 (95% CI, 4.79–8.67) and 8.82 (95% CI, 6.79–11.26) per 1000 person-day in the RCP and BBIBP-CorV groups, and the difference was not statistically significant (Incidence rate ratio = 0.74, 95% CI 0.49, 1.09). Causality assessment identified seven unsolicited AEs with probable/suspected relationship to the study intervention, 4 in the RCP and 3 in the BBIBP-CorV groups (Additional file 1 : Table S6). No vaccine-related or unrelated deaths were reported. In total, 2 cases of hospitalization were observed. The first one was a 62 years old woman diagnosed with myocardial infarction 15 days after receiving a BBIBP-CorV injection and discharged four days later. The other one is a 42 years old man that was admitted because of chest pain 12 days after receiving an RCP injection. The angiography was normal, and the patient was discharged 2 days later.

Our findings showed that neutralizing antibodies in RCP booster recipients increased 21 times the baseline after 2 weeks, indicating a robust boosting effect. This increase was about three times the baseline in the BBIBP-CorV booster recipients. The magnitude of neutralizing antibody response in the RCP group was about seven times higher than in the BBIBP-CorV group. We observed a similar pattern about the specific IgG antibodies against S1 and RBD antigens. The time interval between the booster dose and the primary vaccination did not affect the baseline antibody levels, and the differences were not statistically significant. We saw no immediate allergic vaccine reactions, and both groups’ self-limited solicited local and systemic reactions had similar frequencies. The occurrence of unsolicited adverse events over the one-month follow-up period did not differ significantly between the two groups.

We observed more robust antibody responses in the RCP vaccine booster dose recipients. Various explanations could be provided for this finding. First, BBIBP-CorV and RCP prime-boost combination is a heterologous boosting. Studies have reported that a heterologous boost offers a more robust immune response than a homologous boost [ 3 , 12 , 13 , 18 ] and exposure to multiple spike variants broadens the neutralization [ 30 , 31 ]. Second, BBIBP-CorV belongs to inactivated vaccine platform. Inactivated virus vaccines have a low spike protein compared to the total amount of virus protein content, and because some cleavage of S1 from S2 occurs during beta-propiolactone inactivation, they commonly present various and small amounts of spike protein to the immune system. Exposure of individuals primed with inactivated vaccines to a recombinant spike protein vaccine such as RCP with an enormous quantity of spike protein may trigger a particularly strong recall memory B cell response, causing a significant rise in neutralizing antibodies [ 18 ]. Third, the type of adjuvant used affects the antibody response. The use of adjuvants is common in order to boost the effectiveness of vaccines through mimicry of conserved molecules called pathogen-associated molecular patterns (PAMPs). Vaccine adjuvants enhance innate immune responses by stimulating dendritic cells, lymphocytes, and macrophages by imitating a natural infection [ 32 ]. RCP contains Razi Adjuvant System-01 (an oil-in-water emulsion), which may have contributed to a more significant antibody response in RCP booster dose recipients. Oil-in-water emulsion adjuvants could significantly reduce antigen doses and enhance the production of antigen-specific antibodies [ 32 ]. On the other hand, aluminum hydroxide adjuvant used in BBIBP-CorV results in limited T cell immunity due to alum’s tendency to attach to membranes instead of entering dendritic cells (DCs) and no intracellular transfer of antigens [ 33 ].

We observed slight differences in baseline antibody levels and post-booster antibody responses among the four tested groups with different prime-boosting intervals. Studies have shown that the level of antibodies starts to decline following the peak after primary vaccination and reaches critical levels after 3 to 6 months [ 34 , 35 , 36 ], so booster vaccination has been recommended after this period. General population vaccination against COVID-19 in Iran started in August and September 2021, about 3 to 4 months before the start of the current study. In addition, the timing of this study coincided with a surge in COVID-19 disease predominantly involving the Omicron strain in the Iranian population during the winter of 2022. Therefore, we had a high prevalence of COVID-19 disease and a subsequent high degree of wild virus circulation among the population in this period. Similar baseline antibody levels, regardless of the time of primary vaccination in our study, could be due to continuous exposure of the participants to various virus strains, albeit without clinical manifestation, following their first two doses of the BBIBP-CorV vaccine. This also explains similar post-booster antibody responses among the four tested groups with different prime-boosting intervals.

The incidence of adverse reactions was relatively low in RCP and BBIBP-CorV booster vaccinations, and most reported local and systemic adverse reactions were of grade I or II. The overall safety profile of RCP was similar to that of BBIBP-CorV boost, which was also comparable to the safety of the priming with two doses of BBIBP-CorV as reported previously [ 37 ]. Our safety data in the current study is consistent with data from other trials of homologous and heterologous third-dose boosters [ 12 , 15 , 18 ].

One of our study’s limitations was the short follow-up duration. Our study could be improved if all participants’ neutralizing antibody activity and antibody responses against S1 and RBD antigens were evaluated in months 3 and 6 after the booster dose, as it better reflects the effect of the booster vaccination. Furthermore, the coincidence of this study with a high prevalence of COVID-19 disease among the population may have contributed to the strengths of the observed immune responses. Measuring the humoral and cellular immune responses to booster doses in the absence of a concurrent COVID-19 outbreak could provide a more accurate assessment of the boosting ability of the vaccine. The few choices of vaccines available for primary vaccination within the national vaccination program also limited us. Making comparisons within a wider selection of prime and boost vaccines could improve our understanding of the population’s immune response to booster doses.

In summary, this study showed that both RCP and BBIBP-CorV are safe and effective booster vaccines. RCP induced much more robust humoral and cellular immune responses than BBIBP-CorV, most likely due to its spike protein subunit platform and heterologous boosting characteristics in the current study participants.

Availability of data and materials

The data and materials that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Area under the curve

Cluster of differentiation 3

Clusters of differentiation 4

Clusters of differentiation 8

Geometric mean

Geometric mean fold increase

Geometric mean ratio

Geometric means titers

Gamma interferon

Interleukin 17

Interleukin 2

Interleukin 4

Receptor-binding domain

Razi Cov Pars vaccine

Tumor necrosis factor

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Acknowledgements

The investigators express their gratitude for the contribution of all trial participants. The investigators would like to thank the members of the National Ethics Committee (Dr. Akbar Fotouhi), the Ministry of Health’s Food and Drug Organization (Dr. Mosaed), and Communicable Disease Control (Dr. Zahraei), as well as the staff of Razi Vaccine and Serum Research Institute, other IUM-CTC members, and Hazrat Rasol hospital staff for their cooperation in the conduction of trial.

The study sponsor (Razi Vaccine and Serum Research Institute) helped with the design the study but had no roles in data collection, data management, analysis, interpretation, and writing of the report. These were done by IUMS clinical trial center.

Author information

Saeed Erfanpoor and Seyed Reza Banihashemi contribute equally to this work.

Authors and Affiliations

School of Public Health, Department of Epidemiology, Iran University of Medical Science, Tehran, Iran

Saeed Erfanpoor, Akram Ansarifar, Arash Mohazzab, Vahideh Mohseni, Masoumeh Shahsavan & Seyed Amin Setarehdan

Department of Immunology, Agricultural Research, Education and Extension Organization (AREEO), Razi Vaccine and Serum Research Institute, Karaj, Iran

Seyed Reza Banihashemi, Monireh Hajimoradi, Seyad Hossein Razaz & Maryam Taghdiri

Department of Epidemiology, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran

Ladan Mokhbaeralsafa & Mohammad Hossein Fallah Mehrabadi

Departments of Infectious Diseases and Tropical Medicine, Iran University of Medical Sciences, Tehran, Iran

Saeed Kalantari

Department of Physico Chemistry, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran

Ali Es-haghi

Department of Research and Development, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran

Mojtaba Nofeli & Akbar Khorasani

Department of QA, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran

Ali Rezaei Mokarram & Fariba Sadeghi

Department of Quality Control, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran

Mohsen Lotfi

Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Safdar Masoumi

Reproductive Biotechnology Research Center, Avicenna Research Institute Tehran, ACECR, Tehran, Iran

Arash Mohazzab

School of Medicine, Iran University of Medical Science, Tehran, Iran

Sara Filsoof & Niloufar Gharavi

Minimally Invasive Surgery Research Center, Hazrat-E-Rasool Hospital, Iran University of Medical Science, Tehran, Iran

Seyed Amin Setarehdan & Masoud Solaymani-Dodaran

Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

Mohammad Hasan Rabiee

Clinical Trial Center, Iran University of Medical Science, Tehran, Iran

Masoud Solaymani-Dodaran

Division of Epidemiology and Public Health, University of Nottingham, Nottingham, NG7 2UH, UK

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Contributions

SE, MSD, SRB, and MHFM conceived the trial, and SK is the chief investigator. SE, MSD, AA, and LM contributed to the protocol and design of the study. MHFM, SK, AE, and SRB led the implementation of the study. SE, MSD, and SM did the statistical analysis and verified the underlying data. SE and MSD wrote the first draft of the manuscript. MN, ARM, FS, MH, SHR, MT, ML, AKH, AA, SM, AM, SF, VM, MSH, NGH, SAS, and MHR have made substantial contributions to the conduct, data collection, interpretation of the results, and revising the draft of the manuscript. SRB, MHM, SHR, and MT were responsible for laboratory analyses. All authors reviewed and approved the final report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Mohammad Hossein Fallah Mehrabadi or Masoud Solaymani-Dodaran .

Ethics declarations

Ethics approval and consent to participate.

The study was approved by Iran National Committee for Ethics in Biomedical Research (the approval number was IR.NREC.1400.013) and performed in accordance with the Declaration of Helsinki and Good Clinical Practice and other relevant laws and regulations. Written informed consent signed and dated by the patients has been obtained. The trial protocol is registered at www.irct.ir (IRCT20201214049709N4).

Consent for publication

Not applicable.

Competing interests

As an academic CRO, the Iran University of medical sciences clinical trial center (IUMS-CTC) contributed to the conduct of the trial. SK contributed to the conduct of the trial as principal investigator. SRB, AE, MN, ARM, LM, FS, MHM, SHR, MT, ML, AK, and MHFM are Razi Vaccine and Serum Research Institute employees. SRB is the inventor of the RCP vaccine. The remaining authors are employees of IUMS.

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Supplementary Information

Additional file 1: table s1..

Geometric mean and 95% CI of specific antibody responses (AUC) to S1, RBD and Neutralizing antibody titer in the BBIBP-CorV and RCP groups over the predefined study time schedule. Tables S2-S4. Geometric mean, Geometric mean ratio, Geometric mean fold increase and Seroconversion and their 95% CI for Neutralizing antibodies, anti-RBD, and anti-S1 specific IgG antibodies in the BBIBP-CorV and Razi Cov Pars groups in the participants who received primary vaccination 3, 4, 5 and 6 month before booster dose over the predefined study time schedule. Table S5. Unsolicited adverse events with Not Related, Unlikely, Suspected/Possible, Probable and not assessable relationship to the BBIBP-CorV and Razi Cov Pars vaccines within one-month post-vaccination using ICD-10 code. Table S6. Unsolicited adverse events with probable/suspected relationship to the BBIBP-CorV and Razi Cov Pars vaccines using ICD-10 code. Figure S1. Gating strategy for CD3/CD4/CD8 and IFN-γ flow cytometry data analysis. Figure S2 . Comparison of the baseline antibody levels and post-booster antibody responses among the four tested groups with different prime-boosting intervals (3, 4, 5 and 6 months before booster dose) on days 0 and 14.

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Erfanpoor, S., Banihashemi, S.R., Mokhbaeralsafa, L. et al. Immunogenicity and safety of RAZI recombinant spike protein vaccine (RCP) as a booster dose after priming with BBIBP-CorV: a parallel two groups, randomized, double blind trial. BMC Med 22 , 78 (2024). https://doi.org/10.1186/s12916-024-03295-1

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Received : 08 February 2023

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Published : 20 February 2024

DOI : https://doi.org/10.1186/s12916-024-03295-1

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Phase II/III Double-Blind Study Evaluating Safety and Immunogenicity of a Single Intramuscular Booster Dose of the Recombinant SARS-CoV-2 Vaccine “Patria” (AVX/COVID-12) Using an Active Newcastle Disease Viral Vector (NDV) during the Omicron Outbreak in Healthy Adults with Elevated Baseline Antibody Titers from Prior COVID-19 and/or SARS-CoV-2 Vaccination

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Background The urgent need for safe, effective, and economical coronavirus disease 2019 (COVID-19) vaccines, especially for booster campaigns targeting vulnerable populations, prompted the development of the AVX/COVID-12 vaccine candidate. AVX/COVD-12 is based in a Newcastle disease virus La Sota (NDV-LaSota) recombinant viral vector. This vaccine expresses a stabilized version of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the ancestral Wuhan strain. The study aimed to assess its safety, immunogenicity, and potential efficacy as an anti-COVID-19 booster vaccine.

Methods In a phase II/III clinical trial conducted from November 9, 2022, to September 11, 2023, a total of 4,056 volunteers were enrolled. Participants received an intramuscular booster dose of either AVX/COVID-12 or AZ/ChAdOx-1-S vaccines. Safety, immunogenicity, and potential efficacy were assessed through various measures, including neutralizing antibody titers, interferon (IFN)-γ-producing CD4+ T cells, and CD8+ T cells. The evaluation also involved immunobridging, utilizing the AZ/ChAdOx-1-S vaccine as an active comparator, and monitoring the incidence of COVID-19 cases.

Findings The AVX/COVID-12 vaccine induced neutralizing antibodies against both the ancestral SARS-CoV-2 and the BA.2 and BA.5 Omicron variants. The geometric mean ratio of neutralizing antibody titers between individuals immunized with the AVX/COVID-12 vaccine and those with the AZ/ChAdOx-1-S vaccine at 14 days is 0.96, with a confidence interval (CI) of 0.85-1.06. The outcome aligns with the non-inferiority criterion recommended by the World Health Organization (WHO), indicating a lower limit of the CI greater than or equal to 0.67. Induction of IFN-γ-producing CD8+ T cells at day 14 post-immunization was exclusively observed in the AVX/COVID-12 group. Finally, a trend suggested a potentially lower incidence of COVID-19 cases in AVX/COVID-12 boosted volunteers compared to AZ/ChAdOx-1-S recipients.

Conclusion The AVX/COVID-12 vaccine proved safe, well-tolerated, and immunogenic. AVX/COVID-12 meets the WHO non-inferiority standard compared to AZ/ChAdOx-1-S. These results strongly advocate for AVX/COVID-12 as a viable booster dose, supporting its utilization in the population.

Competing Interest Statement

The vaccine candidate administered in this study was developed by faculty members at the Icahn School of Medicine at Mount Sinai including P.P., F.K. and A.G.-S. Mount Sinai is seeking to commercialize this vaccine; therefore, the institution and its faculty inventors could benefit financially. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-849 CoV-2 serological assays (USA Provisional Application Numbers: 62/994,252, 63/018,457, 63/020,503, and 63/024,436) and NDV-based SARS-CoV-2 vaccines (USA Provisional Application Number: 63/251,020) which list FK as co-inventor. A.G.-S. and P.P. are a co-inventor in the NDV-based SARS-CoV-2 vaccine patent application. Patent applications were submitted by the Icahn School of Medicine at Mount Sinai. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, CastleVax, to commercialize SARS-CoV-2 vaccines. F.K., P.P. and A.G.-S. serve on the scientific advisory board of CastleVax and are listed as co-founders of the company. F.K. has consulted for Merck, Seqirus, Curevac, and Pfizer, and is currently consulting for Gritstone, Third Rock Ventures, GSK, and Avimex. The F.K. laboratory has been collaborating with Pfizer on animal models of SARS-CoV-2. C.L.-M. has consulted for AstraZeneca. The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer and Prosetta. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and AstraZeneca. P.P. has a consulting agreement with Avimex. Members of Avimex developed the live vaccine used in this study. Avimex filed patent applications with Mount Sinai and CONAHCYT. M.T., D.S.-M., C.L.-M., H.E.C.-C., F.C.-P., G.P.D.L., and B.L.-D. are named as inventors on at least one of those patent applications. The clinical study was entirely performed in Mexico and Mount Sinai had no role in the clinical study. The rest of the participants are employees of their corresponding institutions and declare no competing interests.

Clinical Trial

NCT05710783

Funding Statement

The funding for the clinical study was provided by the National Council for Humanities, Science and Technology (CONAHCYT, Mexico), except for all the production and vaccine product supply, which was funded solely by Laboratorio Avi-Mex, S. A. de C. V. (Avimex). CONAHCYT did not participate in the trial design but did evaluate it and approved the project through their National Committee for Science, Technology and Innovation in Public Health. Funding was managed by Avimex and used to pay for all laboratory tests, clinical sites, and clinical professionals. CONAHCYT also facilitated the identification, purchase, and importation of certain supplies and the communication with other entities of the Federal Mexican Government to facilitate the study.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics approval for the study was obtained from the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) in Mexico, with the assigned number RNEC2022-AVXSARSCoV2VAC005. As a prerequisite, local ethics clearance was secured from the institutional ethics committees at each participating research site. 1.Research Site: Unidad de Investigacion Medica en Epidemiologia Clinica, UMAE Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico, Mexico. Ethics Committee: IMSS Scientific Research National Committee. Approval Number: CNIC-2022-785-10. 2.Research Site: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion del Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Reference: 4371. 3.Research Site: CAIMED Investigacion en Salud, S.A. de C.V., Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion de Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6030.sEswXEyH. 4.Research Site: Oaxaca Site Management Organization (OSMO) S.C., Oaxaca, Mexico. Ethics Committee: Comite de Etica en Investigacion de Oaxaca Site Management Organization S. C. Approval Number: CEI-OSMO: 1597/2022. 5.Research Site: Centro de Investigacion Clinica Acelerada (CICA), S.C., Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion de Centro de Investigacion Clinica Acelerada, S.C. Approval Date: 03-sep-22. 6.Research Site: Clinical Research Institute (CRI) S.C., Estado de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6389.gjx2xhoih. 7.Research Site: Centro de Investigacion Clinica Chapultepec, Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion de Sociedad Administradora de Servicios de Salud S.C. Approval Number: 967.hL3XFeyCZscR. 8.Research Site: Unidad de Atencion Medica e Investigacion en Salud (UNAMIS), Yucatan, Mexico. Ethics Committee: Comite de Etica en Investigacion de Unidad de Atencion Medica e Investigacion en Salud. Approval Number: 89244E882AF143D. 9.Research Site: Kohler & Milstein Research (K&M) Facultad de Medicina, Universidad Autonoma de Yucatan, Merida, Yucatan, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6007.MHWWA1. 10.Research Site: Centro Multidisciplinario para el Desarrollo Especializado de la Investigacion Clinica en Yucatan (CEMDEICY) S.C.P, Yucatan, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6007.MHWWA1. 11.Research Site: Centro de Investigacion Clinica del Pacifico (CICPA), Guerrero, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6429.85DQ2ND. 12.Research Site: Red OSMO, Centro de Investigacion y Avances Medicos Especializados (CIAME), Quintana Roo, Mexico. Ethics Committee: Comite de Etica en Investigacion de Oaxaca Site Management Organization S. C. Approval Number: CEI-OSMO: 1732/2022. 13.Research Site: Instituto Veracruzano de Investigacion Clinica (IVIC) S.C., Veracruz, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6676.UjTJ4KUpK. 14.Research Site: Hospital de Cardiologia Aguascalientes, Aguascalientes, Mexico. Ethics Committee: Comite de Etica en Investigacion de Promotora Medica Aguascalientes S.A. DE C.V. Approval Number: 2394.ceipma.2022. The research was conducted in full compliance with Mexican regulations and in accordance with the principles outlined in the Declaration of Helsinki and Good Clinical Practice

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Data Availability

The protocol was registered in the National Registry of Clinical Studies under number RNEC2022-AVXSARSCoV2VAC005 and published under NCT05710783 . Individual de-identified participant data will not be shared beyond the limits permitted by the informed consent and Mexican law. Specifically, this includes the sharing of the study protocol, statistical analysis plan, informed consent form, and approved clinical study report. Additionally, other de-identified data allowed under the informed consent and Mexican law may be shared. The data will be made available immediately upon publication and for 12 months thereafter. Access to the data will be granted solely to investigators with methodologically sound proposals, subject to authorization by an independent review committee and the ethics committees involved in approving the protocol. If required by law, authorization from the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) in Mexico will also be obtained. Any use of the data must strictly adhere to the authorized purposes outlined during the approval process.

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Coronavirus Disease 2019 (COVID-19) Vaccines

Available vaccines, package inserts, and factsheets.

Common Side Effects

A Closer Look at the Safety Data

  • How CDC Monitors Vaccine Safety

Related Scientific Articles

About coronavirus disease 2019 (covid-19).

Coronavirus disease 2019 , or (COVID-19), is a respiratory disease caused by the SARS-CoV-2 virus, a coronavirus discovered in 2019. The virus spreads mainly from person-to-person through respiratory droplets produced when an infected person coughs, sneezes, or talks. Some people who are infected may not have symptoms. For people who have symptoms, illness can range from mild to severe. Everyone 6 months and older should receive at least one dose of an updated COVID-19 vaccine  to protect against serious illness, hospitalization, and death.

Learn more about COVID-19.

COVID-19 vaccines can help reduce the risk of illness from COVID-19 and its potentially serious complications.

Vaccine Information Statements (VISs) are information sheets produced by CDC that explain both the benefits and risks of a vaccine.

Vaccine Information Statement | Current VISs | CDC VISs are available for mRNA vaccines for people ages 12 years and older. For more information, go to COVID-19 vaccine EUA Factsheets. Pfizer-BioNTech COVID-19 vaccine Moderna COVID-19 vaccine Novavax COVID-19 vaccine

There are two types of COVID-19 vaccines approved for use or authorized for emergency use by the Food and Drug Administration (FDA) in the United States. For most people, these vaccines are given as an injection in the muscle of the upper arm. For infants and toddlers, these vaccines are usually given as an injection in the thigh muscle.

  • Pfizer-BioNTech (Comirnaty ® ) and Moderna (Spikevax ® ) – are mRNA vaccines  that use mRNA created in a laboratory to teach cells how to make a protein that triggers an immune response inside the body. These vaccines are authorized for children ages 6 months through 11 years and approved for people ages 12 years and older. CDC recommends everyone 6 months and older receive at least one dose of an updated COVID-19 vaccine.
  • Novavax – is a protein subunit vaccine  that contains spike proteins of the virus that causes COVID-19. After learning how to respond to the spike protein, the immune system will respond quickly to protect against the actual COVID-19 virus. It is authorized for people 12 years and older.

To learn more about how the different types of COVID-19 vaccines work, go to Understanding How COVID-19 Vaccines Work | CDC .

Talk with your healthcare provider about vaccines.

They can answer questions and offer advice based on your specific health needs.

Child and Adult Immunization Schedules Get CDC’s official recommended immunization schedules for children, adolescents, and adults.

Manufacturer Package Inserts and Factsheets

There are currently two mRNA COVID-19 vaccines available in the United States that have full approval from the United States Food and Drug Administration (FDA) for use in people ages 12 and older (Pfizer-BioNTech [Comirnaty ® ] and Moderna [Spikevax ® ]). These vaccines are authorized for emergency use in children ages 6 months through 11 years. They are designed to protect people ages 6 months and older against COVID-19.

Novavax, a protein subunit COVID-19 vaccine, is also available in the United States. Novavax is authorized for use in people ages 12 years and older.

These vaccines have been updated for 2023-2024 to protect against circulating variants of the virus that causes COVID-19. CDC recommends that people receive the age-appropriate vaccine product and dosage based on their age on the day of vaccination.

Comirnaty (2023-2024 Formula) – [PDF – 37 Pages] : FDA approved this Pfizer-BioNTech COVID-19, mRNA vaccine in 2021. It is approved for use in people 12 years of age and older. This is a single dose injection.

Spikevax (2023-2024 Formula) – [PDF – 45 Pages] : FDA approved this Moderna COVID-19, mRNA vaccine in 2022. It is approved for use in people 12 years of age and older.

Pfizer-BioNTech COVID-19 vaccine (2023-2024 Formula) – [PDF – 61 Pages] : FDA authorized this vaccine for emergency use in children ages 6 months to 11 years.

Moderna COVID-19 vaccine (2023-2024 Formula) – [PDF – 55 Pages] : FDA authorized this vaccine for emergency use in children ages 6 months to 11 years.

Novavax COVID-19 vaccine (2023-2024 Formula) – [PDF – 50 Pages] : FDA authorized this vaccine for emergency use in people ages 12 years and older.

Vaccines, like any medicine, can have side effects. Side effects after getting a COVID-19 vaccine vary from person to person. The most common side effects are usually mild, such as soreness in the area where the shot was given.

Important!

Severe allergic reactions following vaccination are rare but can be life threatening. Symptoms of a severe allergic reaction may include:

  • Anaphylaxis, which is a life-threatening reaction that needs to be treated with epinephrine (EpiPen) and may require hospitalization. Symptoms include wheezing, difficulty breathing, or low blood pressure; and sometimes hives.
  • Swelling of the airway, which includes the tongue, uvula, or larynx.
  • A widespread rash involving the skin and inside places like your mouth or nose that required hospitalization.
  • Pain, soreness, redness at injection site
  • Muscle pain
  • Nausea/vomiting (Moderna)
  • In infants and toddlers, common symptoms include irritability or crying, decreased appetite, and sleepiness

Who Should Not Get an mRNA Vaccine

People should not get an mRNA COVID-19 vaccine if they:

  • Are younger than 6 months
  • Have had a severe allergic reaction (e.g., anaphylaxis) after a previous dose or to an ingredient of the mRNA COVID-19 vaccine

People should talk to their healthcare provider before getting an mRNA COVID-19 vaccine if they:

  • Have had an immediate allergic reaction to a previous dose of an mRNA COVID-19 vaccine that was not severe
  • Have had an allergic reaction to an ingredient in the mRNA COVID-19 vaccine that was not severe
  • Have a recent history of COVID-19 infection
  • Are sick with a moderate or severe illness, with or without a fever
  • Have a history of MIS-C or MIS-A
  • Have a history of myocarditis or pericarditis within 3 weeks after a dose of any COVID-19 vaccine
  • Pain, soreness, redness, swelling at injection site
  • Nausea/vomiting

Who Should Not Get a Protein Subunit Vaccine

People should not get a protein subunit COVID-19 vaccine if they:

  • Are younger than 12 years
  • Have had a severe allergic reaction (e.g., anaphylaxis) after a previous dose or to an ingredient of Novavax vaccine

People should talk to their healthcare provider before getting a protein subunit COVID-19 vaccine if they:

  • Have had an immediate allergic reaction to a previous dose of a Novavax COVID-19 vaccine that was not severe
  • Have had an allergic reaction to an ingredient in the Novavax COVID-19 vaccine that was not severe
  • COVID-19 Vaccination: What everyone should know What everyone should know about COVID-19 and the vaccines that can protect against it.
  • Who Should Not Get Vaccinated? Some people should not get certain vaccines or should wait before getting them. Read the CDC guidelines for each vaccine.
  • COVID-19 ACIP Vaccine Recommendations Official recommendations for COVID-19 vaccines from the Advisory Committee on Immunization Practices (ACIP).
  • COVID-19 Vaccination Provider Requirements and Support Guidance for healthcare professionals about the CDC COVID-19 vaccination program.

COVID-19 vaccines meet the Food and Drug Administration’s (FDA’s) standards for safety and effectiveness. In rare cases, people have experienced serious health events after COVID-19 vaccination. Any health problem that happens after vaccination is considered an adverse event following immunization. An adverse event can be caused by the vaccine or be a coincidental event that is not related to the vaccine, such as an unrelated fever, that happened following vaccination.

To date, the systems in place to monitor the safety of these vaccines have found two serious types of adverse events following COVID-19 vaccination.

The two serious adverse events following COVID-19 vaccination currently used in the United States are anaphylaxis and myocarditis or pericarditis.

Anaphylaxis is a severe type of allergic reaction that can rarely happen after any vaccine. Anaphylaxis needs to be treated with epinephrine (for example, EpiPen) and may require hospitalization. Anaphylaxis can involve wheezing, difficulty breathing, or low blood pressure; and sometimes is accompanied by hives. Anaphylaxis after COVID-19 vaccination is rare.

Myocarditis is inflammation of the heart muscle, and pericarditis is inflammation of the outer lining of the heart. Myocarditis and pericarditis after COVID-19 vaccination are rare.

The evidence suggests that, although rare, these events are linked to certain types of COVID-19 vaccinations that were administered.

Learn more about these Selected Adverse Events Reported after COVID-19 Vaccination .

Which adverse events are considered “serious?”

By regulation, an adverse event is defined as serious if it involves any of the following outcomes:

  • A life-threatening adverse event
  • A persistent or significant disability or incapacity
  • A congenital anomaly or birth defect
  • Hospitalization, or prolongation of existing hospitalization

How CDC Monitors the Safety of COVID-19 Vaccines

CDC and FDA monitor the safety of vaccines  after they are approved. If a problem is found with a vaccine, CDC and FDA will inform health officials, healthcare providers, and the public.

Phillips A, Jiang Y, Walsh D, Andrews N, Artama M, Clothier H, Cullen L, Deng L, Escolano S, Gentile A, Gidding G, Giglio N, Junker T, Huang W, Janjua N, Kwong J, Li J, Nasreen S, Naus M, Naveed Z, Pillsbury A, Stowe J, Vo T, Buttery J, Petousis-Harris H, Black S, Hviid A. Background rates of adverse events of special interest for COVID-19 vaccines: A multinational Global Vaccine Data Network (GVDN) analysis .  Vaccine . 2023 Oct 6;41(42):6227-6238. Online ahead of print.

Kauffman TL, Irving SA, Brooks N, Vesco KK, Slaughter M, Smith N, Tepper NK, Olson CK, Weintraub ES, Naleway AL, Vaccine Safety Datalink Menstrual Irregularities Workgroup. Postmenopausal bleeding after COVID-19 vaccination .  Am J Obstet Gynecol , 2023 Sept 17; S0002-9378(23)00613-0. Online ahead of print. https://doi.org/10.1016/j.ajog.2023.09.007 .

Kenigsberg TA, Goddard K, Hanson KE, Lewis N, Klein N, Irving SA, Naleway AL, Crane B, Kauffman TL, Xu S, Daley MF, Hurley LP, Kaiser R, Jackson LA, Jazwa A, Weintraub ES. Simultaneous administration of mRNA COVID-19 bivalent booster and influenza vaccinesSimultaneous administration of mRNA COVID-19 bivalent booster and influenza vaccines . Vaccine. 2023 Sep 7; https://doi.org/10.1016/j.vaccine.2023.08.023 . Online ahead of print.

Yih WK, Daley MF, Duffy J, Fireman B, McClure DL, Nelson JC, Qian L, Smith N, Vazquez-Benitez G, Weintraub E, Williams JTB, Xu S, Maro JC. Safety signal identification for COVID-19 bivalent booster vaccination using tree-based scan statistics in the Vaccine Safety DatalinkSafety signal identification for COVID-19 bivalent booster vaccination using tree-based scan statistics in the Vaccine Safety Datalink . Vaccine. 2023 Aug 14; https://doi.org/10.1016/j.vaccine.2023.07.10  Online ahead of print.

Romanson B, Moro PL, Su JR, Marquez P, Nair N, Day B, DeSantis A, Shimabukuro TT. Notes from the Field: Safety Monitoring of Novavax COVID-19 Vaccine Among Persons Aged ≥ 12 Years – United States, July 13, 2022 – March 13, 2023July 13, 2022 – March 13, 2023 . MMWR Morb Mortal Wkly Rep. 2023 Aug 4. 72(31);850-851.

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Schmader KE, Liu CK, Flannery B, Rountree W, Auerbach H, Barnett ED, Schlaudecker EP, Todd CA, Poniewierski M, Staat MA, Harrington T, Li R, Broder KR, Walter EB. Immunogenicity of adjuvanted versus high-dose inactivated influenza vaccines in older adults: a randomized clinical trial . Immun Ageing . 2023 Jul 1; 20(1):30. doi: 10.1186/s12979-023-00355-7.

Zhou ZH, Cortese MM, Fang JL, Wood R, Hummell DS, Risma KA, Norton AE, KuKuruga M, Kirshner S, Rabin RL, Agarabi C, Staat MA, Halasa N, Ware RE, Stahl A, McMahon M, Browning P, Maniatis P, Bolcen S, Edwards KM, Su JR, Dharmarajan S, Forshee R, Broder KR, Anderson S, Kozlowski S. Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination . Vaccine . 2023 Jun 23; https://doi.org/10.1016/j.vaccine.2023.05.029  Online ahead of print.

Miller ER, Moro PL, Shimabukuro TT, Carlock G, Davis SN, Freeborn EM, Roberts AL, Gee J, Taylor AW, Gallego R, Suragh T, Su JR. COVID-19 vaccine safety inquiries to the centers for disease control and prevention immunization safety office . Vaccine . 2023 Jun 19; https://doi.org/10.1016/j.vaccine.2023.05.054  Online ahead of print.

Kharbanda EO, Haapala J, Lipkind HS, DeSilva MB, Zhu J, Vesco KK, Daley MF, Donahue JG, Getahun D, Hambidge SJ, Irving SA, Klein NP, Nelson JC, Weintraub ES, Williams JTB, Vazquez-Benitez G. COVID-19 Booster Vaccination in Early Pregnancy and Surveillance for Spontaneous Abortion . JAMA Network Open. 2023 May 19;6(5):e2314350.

Vazquez-Benitez G, Haapala J, Lipkind HS, DeSilva MB, Zhu J, Daley MF, Getahun D, Klein NP, Vesco KK, Irving SA, Nelson JC, Williams JTB, Hambidge SJ, Donahue J, Fuller CC, Weintraub ES, Olson C, Kharbanda EO. COVID-19 Vaccine Safety Surveillance in Early Pregnancy in the United States: Design Factors Affecting the Association Between Vaccine and Spontaneous Abortion . American Journal of Epidemiology. 2023 Mar 16;kwad059. Online ahead of print.

Cortese MM, Taylor AW, Akinbami LJ, Thames-Allen A, Yousaf AR, Campbell AP, Maloney SA, Harrington TA, Anyalechi EG, Munshi D, Kamidani S, Curtis CR, McCormick DW, Staat MA, Edwards KM, Creech CB, Museru O, Marquez P, Thompson D, Su JR, Schlaudecker EP, Broder KR. Surveillance For Multisystem Inflammatory Syndrome in US Children Aged 5-11 Years Who Received Pfizer-BioNTech COVID-19 Vaccine, November 2021 through March 2022 . J Infect Dis . 2023 Feb 23;jiad051. Online ahead of print.

Abara WE, Gee J, Marquez P, Woo J, Myers TR, DeSantis A, Baumblatt JAG, Woo EJ, Thompson D, Nair N, Su JR, Shimabukuro TT, Shay DK. Reports of Guillain-Barré Syndrome After COVID-19 Vaccination in the United States . JAMA Network. 2023 Feb 1;6(2):e2253845. doi:10.1001/jamanetworkopen.2022.53845.

Myers TR, Marquez PL, Gee JM, Hause AM, Panagiotakopoulos L, Zhang B, McCullum I, Licata C, Olson CK, Rahman S, Kennedy SB, Cardozo M, Patel CR, Maxwell L, Kallman JR, Shay DK, Shimabukuro TT. The v-safe after vaccination health checker: Active vaccine safety monitoring during CDC’s COVID-19 pandemic response . Vaccine . 2023 Jan 23; https://doi.org/10.1016/j.vaccine.2022.12.031  Online ahead of print.

Yih WK, Daley MF, Duffy J, Fireman B, McClure D, Nelson J, Qian L, Smith N, Vazquez-Benitez G, Weintraub E, Williams JTB, Xu S, Maro JC. A broad assessment of covid-19 vaccine safety using tree-based data-mining in the vaccine safety datalink . Vaccine . 2023 Jan 16; https://doi.org/10.1016/j.vaccine.2022.12.026 . Online ahead of print.

Xu S, Huang R, Sy LS, Hong V, Glenn SC, Ryan DS, Morrissette K, Vazquez-Benitez G, Glanz JM, Klein NP, Fireman B, McClure D, Liles EG, Weintraub ES, Tseng HF, Qian L. A safety study evaluating non-COVID-19 mortality risk following COVID-19 vaccination . Vaccine . 2023 Jan 16; https://doi.org/10.1016/j.vaccine.2022.12.036 . Online ahead of print.

Yih WK, Daley MF, Duffy J, Fireman B, McClure D, Nelson J, Qian L, Smith N, Vazquez-Benitez G, Weintraub E, Williams JTB, Xu S, Maro JC. Tree-based data mining for safety assessment of first COVID-19 booster doses in the Vaccine Safety Datalink . Vaccine . 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.11.053 . Online ahead of print.

Moro PL, Zhang B, Ennulat C, Harris M, McVey R, Woody G, Marquez P, McNeil MM, Su JR. Safety of Co-administration of mRNA COVID-19 and seasonal inactivated influenza vaccines in the Vaccine Adverse Event Reporting System (VAERS) during July 1, 2021 – June 30, 2022 . Vaccine . 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.12.069  Online ahead of print.

Malden DE, Gee J, Glenn S, Li Z, Mercado C, Ogun OA, Kim S, Lewin BJ, Ackerson BK, Jazwa A, Weintraub ES, McNeil MM, Tartof S. Reactions following Pfizer-BioNTech COVID-19 mRNA vaccination and related healthcare encounters among 7,077 children aged 5-11 years within an integrated healthcare system . Vaccine . 2023 Jan 9; https://doi.org/10.1016/j.vaccine.2022.10.079 . Online ahead of print.

Haq K, Anyalechi EG, Schlaudecker EP, McKay R, Kamidani S, Manos C, Oster ME. Multiple MIS-C Readmissions and Giant Coronary Aneurysm After COVID-19 Illness and Vaccination: A Case Report . The Pediatric Infectious Disease Journal . 2022 Dec 16; DOI: 10.1097/INF.0000000000003801. Online ahead of print.

Tompkins LK, Baggs J, Myers TR, Gee JM, Marquez PL, Kennedy SB, Peake D, Dua D, Hause AM, Strid P, Abara W, Rossetti R, Shimabukuro TT, Shay DK. Association between history of SARS-CoV-2 infection and severe systemic adverse events after mRNA COVID-19 vaccination among U.S. adults . Vaccine . 2022 Dec 12;S0264-410X(22)01342-1. Online ahead of print.

Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, Blanc PG, Thomas A, Thompson D, Shimabukuro TT, Shay DK. Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Persons Aged ≥ 12 Years – United States, August 31 – October 23, 2022 . MMWR Morb Mortal Wkly Rep. 2022 Nov 4; 71(44);1401–1406.

Goddard K, Hanson KE, Lewis N, Weintraub E, Fireman B, Klein NP. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States . Annals of Internal Medicine . 2022 Oct 4. doi.org/10.7326/M22-2274.

Nelson JC, Ulloa-Perez E, Yu O, Cook AJ, Jackson ML, Belongia EA, Daley MF, Harpaz R, Kharbanda EO, Klein NP, Naleway AL, Tseng HF, Weintraub ES, Duffy J, Yih WK, Jackson LA. Active Post-Licensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data . Am J Epidemiol . 2022 Oct 4. doi: 10.1093/aje/kwac170. Online ahead of print.

Daley MF, Reifler LM, Glanz JM, Hambidge SJ, Getahun D, Irving SA, Nordin JD, McClure DL, Klein NP, Jackson ML, Duffy J, DeStefano F. Association Between Aluminum Exposure from Vaccines Before Age 24 Months and Persistent Asthma at Age 24-59 Months [PDF – 10 Pages] . Academic Pediatrics . 2022 Sept 27. Online ahead of print.

Kracalik I, Oster ME, Broder KR, Cortese MM, Glover M, Shields K, Creech CB, Romanson B, Novosad S, Soslow J, Walter EB, Marquez P, Dendy JM, Woo J, Valderrama AL, Ramirez-Cardenas A, Assefa A, Campbell MJ, Su JR, Magill SS, Shay DK, Shimabukuro TT, Basavaraju SV. Outcomes at least 90 days onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults in the USA: a follow-up surveillance study . Lancet Child Adolesc Health . 2022 Nov 6;6(11):788-798. Epub 2022 Sept 22.

Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, Parker C, Thompson D, Panchanathan SS, Shimabukuro TT, Shay DK. COVID-19 mRNA Vaccine Safety Among Children Aged 6 Months–5 Years — United States, June 18, 2022–August 21, 2022 . MMWR Morb Mortal Wkly Rep . 2022 Sep 2;71(35);1115-1120.

Moro PL, Olson CK, Zhang B, Marquez P, Strid P. Safety of Booster Doses of Coronavirus Disease 2019 (COVID-19) Vaccine in Pregnancy in the Vaccine Adverse Event Reporting System . Obstet Gynecol. 2022 Sept 1; 40(3):421-427.

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The Role of the European Medicines Agency in the Safety Monitoring of COVID-19 Vaccines and Future Directions in Enhancing Vaccine Safety Globally

  • Leading Article
  • Open access
  • Published: 23 February 2024

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  • Irina Caplanusi   ORCID: orcid.org/0009-0006-0694-4469 1   na1 ,
  • Agnieszka Szmigiel   ORCID: orcid.org/0009-0006-6049-9634 1   na1 ,
  • Menno van der Elst   ORCID: orcid.org/0009-0005-6151-6419 2 , 3 ,
  • Marie Louise Schougaard Christiansen   ORCID: orcid.org/0009-0000-1963-0895 3 , 4 ,
  • Steffen Thirstrup   ORCID: orcid.org/0000-0003-0903-682X 5 ,
  • Cosimo Zaccaria   ORCID: orcid.org/0000-0002-1441-6061 1 ,
  • Bénédicte Cappelli   ORCID: orcid.org/0009-0007-5119-6508 1 ,
  • Georgy Genov   ORCID: orcid.org/0009-0000-5139-3981 1 &
  • Sabine Straus   ORCID: orcid.org/0009-0006-9266-3312 2 , 3  

The European Union (EU) regulatory network was at the forefront of the safety monitoring of COVID-19 vaccines during the pandemic. An unprecedented number of case reports of suspected adverse reactions after vaccination called for huge efforts for the assessment of this safety information, to ensure that any possible risks were detected and managed as early as possible, while ruling out coincidental but temporally related adverse health outcomes. We describe the role of the European Medicines Agency alongside the EU regulatory network in the safety monitoring of the COVID-19 vaccines, and provide an insight into challenges, particularities and outcomes of the scientific assessment and regulatory decisions in the complex, dynamic international environment of the pandemic. We discuss the flexible procedural tools that were used to ensure an expedited scientific assessment of safety issues, and subsequent updates of the product information (i.e., labelling) when available evidence (e.g., spontaneous reports, findings from observational studies and/or scientific literature) suggested that causal association is at least a reasonable possibility. The safety monitoring was accompanied by enhanced transparency measures, proactive communication, and easy access to information, which played a key role in public reassurance. The pandemic has been a powerful booster for worldwide collaboration, exchange of information and work-sharing. The safety monitoring of COVID-19 vaccines continues, and the lessons learned will be applied in future safety reviews, as well as future health emergencies.

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1 Introduction

The COVID-19 pandemic required a global effort to make effective vaccines available to the public in a timely and efficient manner to prevent people from developing severe disease, thus reducing hospitalisations. Following the distribution and administration of the vaccines, a large volume of safety information had to be managed in a short time. In the European Union (EU), the medicines regulatory network, comprised of the National Competent Authorities (NCAs) in EU Member States (MSs), the European Medicines Agency (EMA) and the European Commission (EC), played a key role in the response to the pandemic.

The World Health Organisation (WHO) declared a Public Health Emergency of International Concern (PHEIC) on 30 January 2020, further characterised the outbreak as a pandemic on 11 March 2020, and concluded that the PHEIC could be considered over on 5 May 2023 [ 1 ]. EMA initiated its Public Health Threats Plan on 4 February 2020, to support the development of new vaccines and treatments [ 2 ], and established the Emergency Task Force (ETF) to provide scientific support on medicinal products targeting the emergency [ 3 ].

Shortly before the authorisation of the first COVID-19 vaccines, EMA published the Pharmacovigilance Plan of the EU regulatory network for COVID-19 vaccines [ 4 ], building on the experience gained during the 2009 (H1N1) influenza pandemic. This plan proved essential for the timely and efficient organisation of activities, resources and priorities, thus enabling a rapid crisis response.

As for all the medicinal products authorised in the EU/EEA, suspected adverse reactions following administration of COVID-19 vaccines have been continuously reported to the European database, EudraVigilance (EV), operated by the EMA on behalf of the network. The first ever spontaneous case report in association with a COVID-19 vaccine was submitted to EV on 30 December 2020, after which their number increased rapidly (over 2.2 million such reports received by the end of 2022), in line with the expansion of the vaccination campaigns in MSs. The handling of this extraordinary influx of data represents a significant achievement, made possible through the network’s efforts and continuous commitment to public health, rapid scientific assessments, flexible regulatory tools and sharing of worldwide expertise.

We describe the role of the EU regulatory network in the safety monitoring of COVID-19 vaccines, providing an insight into challenges, particularities and outcomes of the scientific assessment and regulatory decisions, in the complex environment of the pandemic. The period covered is from the beginning of 2021 (start of vaccination campaign) until the end of 2022. We aim to describe (a) how the safety of COVID-19 vaccines is reviewed in the EU, (b) examples of the evidentiary documentation for labelling an adverse reaction, (c) challenges of performing a rapid and solid scientific assessment, (d) the flexible regulatory tools used, (e) measures for proactively addressing public concerns, and (f) the global effort and collaboration.

We refer to the four COVID-19 vaccines, namely the mRNA platform vaccines: Comirnaty (authorised on 21/12/2020) and Spikevax—previously COVID-19 Vaccine Moderna (authorised on 06/01/2021), and the adenoviral platform vaccines: Vaxzevria—previously COVID-19 Vaccine AstraZeneca (authorised on 29/01/2021) and Jcovden—previously COVID-19 Vaccine Janssen (authorised on 11/03/2021), as these were used predominantly in the EU/EEA to impede the spread of the virus during these years. By mid-June 2023 [ 5 ], the EU/EEA exposure to the original versions of these vaccines exceeded 534 million doses for Comirnaty, 128 million doses of Spikevax, followed by 56 million doses of Vaxzevria and 16 million doses of Jcovden, respectively.

2 The Continuous Safety Review of COVID-19 Vaccines in the European Union (EU)

2.1 the role of the pharmacovigilance risk assessment committee (prac).

The PRAC is EMA’s committee responsible for assessing the safety of human medicinal products. It convenes once per month and includes members from all EU/EEA countries, healthcare professional/patients’ and EC representatives. The Committee is responsible for providing recommendations to the Committee for Medicinal Products for Human Use (CHMP) on all aspects relating to pharmacovigilance and risk management systems, including on the detection, assessment, risk minimisation and communication relating to adverse drug reactions [ 6 ]. While PRAC covers all matters related to pharmacovigilance, the CHMP is responsible for issuing opinions with regards to marketing authorisation status, after assessing the entirety of the evidence. When the assessed evidence shows convincingly that the benefits of the vaccine are greater than any potential risks, the CHMP issues a positive opinion. During the pandemic, international regulatory authorities were invited to participate to the PRAC and CHMP plenaries, according to their topic of interest.

As with all centrally authorised medicinal products, each COVID-19 vaccine has a Rapporteur, selected among the PRAC members nominated by an EU/EEA MS, whose role is to lead on assessments (supported by their national team).

PRAC leads the assessment of all pharmacovigilance procedures such as Periodic Safety Update Reports (PSURs), Post-authorisation Safety Studies (PASSs), and safety signals. In the context of mass vaccination, to promptly identify any new safety concerns, the PRAC assessed additionally expedited Summary Safety Reports (SSRs), initially monthly, then every 2 months. In total, 56 SSRs were assessed until December 2022 [ 7 ], when in view of the expanding availability of real-world evidence, the PRAC switched to routine 6-monthly PSUR submissions. PSURs allow for a cumulative assessment of safety in the context of a medicinal product’s benefits and risks [ 8 ]. PASSs aim to complement data collected in clinical trials, to characterise important identified and potential risks and missing information [ 9 ].

2.2 COVID-19 Signals Discussed at PRAC

We refer to safety signals as defined in the Guideline on Good Pharmacovigilance Practices, Module IX—Signal management (Rev 1) [ 10 ], as information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association (e.g., changes in frequency, severity) between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action. In the context of safety monitoring, only signals related to adverse reactions are considered.

In procedural terms, after a signal is detected, it needs to be confirmed by the Rapporteur before being further analysed and prioritised by the PRAC. Subsequently, different stakeholders (e.g., Marketing Authorisation Holders (MAHs), authors of independent studies) collaborate with the PRAC to submit requested data or comment on study findings. Unlike in a non-pandemic setting, where most signal procedures are adopted in writing (i.e., without discussion) at the initial stage, all COVID-19 vaccines’ signals were brought to PRAC plenary, thus allowing members to discuss and refine the recommendations, including any late-breaking information.

As an outcome of continuous safety monitoring of COVID-19 vaccines, including review of spontaneous reports in EV and in the scientific literature, 18 safety signals were prioritised and discussed by the PRAC (Table 1 ). A safety signal can refer to more than one vaccine. For eight of them, the accumulated evidence at the time of assessment was sufficient to establish a causal association, thus allowing for an update of the product information. The EU product information, which is continuously updated in line with the developing scientific knowledge, is publicly available, and serves, alongside other materials (e.g., country-specific), as a resource for vaccine safety data, supporting stakeholders such as NCAs, healthcare professionals, and the public in their decisions related to vaccines. The section below provides some insights into this assessment.

For the remaining signals, no update of the product information was recommended, these being further subject to ‘routine pharmacovigilance/monitoring in the PSURs’. These pharmacovigilance activities may include safety monitoring and signal detection based on various sources (e.g., EV, literature), from which any significant findings are brought to the attention of the regulatory authorities, as per routine practice. Safety topics assessed for mRNA and adenoviral vector vaccines may provide a background for assessment of similar platform vaccines in the future. Notwithstanding signal procedures, specific adverse reactions were added to the labelling following PRAC assessments of SSRs or PSURs (Table 2 ).

3 Insights into the Assessment of Several Safety Signals

3.1 high-profile signals.

Shortly after authorisation of the vaccines, the PRAC established that a causal association between the adenoviral platform vaccines and the thrombosis with thrombocytopenia syndrome (TTS), as well as between the mRNA vaccines and myocarditis/pericarditis was likely. The particularities of the evaluation of these signals have been previously described [ 11 ]—in both, EV data as well as observed-to-expected (O/E) analyses, played a crucial role.

For myocarditis/pericarditis evaluation, two observational studies [ 12 , 13 ] provided the attributable risk of vaccination. Estimates of the number of excess cases of myocarditis were reflected in the product information as follows: 0.26 (French data) and 0.57 (Nordic data) per 10,000 vaccinated for Comirnaty, 1.3 and 1.9 per 10,000 vaccinated, respectively, for Spikevax. This risk evaluation considered the second dose of mRNA vaccine in young male vaccinees compared to unexposed.

In the case of TTS, the EU network received initial notifications of suspected adverse reactions from independent teams, including from Austria and Norway [ 14 ]. In the absence of a case definition and a Medical Dictionary for Regulatory Activities (MedDRA) term, the signal was initially investigated based on case reports in which embolic and thrombotic events (Standardised MedDRA Query, SMQ) were co-reported with manually adjudicated MedDRA terms suggestive of thrombocytopenia.

On 7 April 2021, following an Ad Hoc Expert Group organised by EMA, PRAC recommended an update of the Vaxzevria product information with TTS. While the product information does not include an attributable risk of vaccination, it informs that severe and very rare cases of TTS have been reported post-marketing, that the reporting rates after the second dose are lower compared to after the first dose and that most of the cases of TTS occurred within the first three weeks following vaccination. The risk was further contextualized in a referral (Art. 5.3 of Reg 726/2004) [ 15 , 16 ].

For myocarditis/pericarditis, the existence of MedDRA terms made the reactions easier to describe. The measure of disproportionate reporting (Reporting Odds Ratio, ROR) in EV increased significantly around the time of EU labelling in July 2021 (Fig. 1 ), after findings from large population studies in Israel and the USA were published [ 17 , 18 ]. The need to better characterise the adverse reactions’ frequency, severity or gender distribution resulted in the conduct of two studies, one in the Nordic countries and one in France. Both study consortia made their preliminary findings available for PRAC assessment (e.g., in the case of the Nordic consortium, these findings were assessed even before their publication on 20 April 2022) [ 12 ]. The recommendation for labelling was issued on 2 December 2021, confirming that the risk was more significant after the second vaccine dose in younger men.

3.2 Ad hoc Safety Studies by the European Medicines Agency (EMA)

To support the assessment of the signals of vulval ulceration with Comirnaty [ 19 ] and pemphigus and pemphigoid with the mRNA vaccines and Vaxzevria [ 20 ], EMA conducted two studies (using data sources to which the Agency has direct access). Both signals were initiated by the network following case series of vulval ulceration in adolescent girls [ 21 ] or bullous conditions [ 22 , 23 ] involving several COVID-19 vaccines.

The EU network capability to (a) describe the use of Comirnaty in the general population and (b) estimate incidence rates of vulval ulceration in the general and exposed female population was paramount. A self-controlled case series (SCCS) study was conducted to further investigate a causal association. No differences were found in post-vaccination incidence rates of vulval ulceration compared to incidence rates from time not-at-risk, nor in the 30 or 90 days after receiving the respective vaccines (Comirnaty, Spikevax or Vaxzevria).

In the case of pemphigus and pemphigoid signal, EMA calculated the incidence rates using a cohort design in the UK general population and patients visiting general practices in Spain. A SCCS was also performed as a sensitivity analysis. No consistent associations were seen based on these studies. The studies are publicly available in the EU PAS Register [ 19 , 20 ].

3.3 New Aspects of Known Adverse Reactions

While hypersensitivity reactions were added to the product information of COVID-19 vaccines [ 24 , 25 ] based on pre-authorisation studies, new aspects of hypersensitivity were labelled following authorisation, based only on the review of clusters of spontaneous post-marketing case reports. These new aspects include anaphylactic reactions (Vaxzevria), erythema multiforme (EM) (mRNA COVID-19 vaccines), and localised swelling in persons with a history of dermal filler injections (Comirnaty). Published, medically verified reports of EM [ 26 , 27 ] including skin biopsies and topical corticosteroid treatments contributed to the understanding of these reactions. Based on cumulative data assessed in SSRs, the product information of Spikevax was updated to include the median number of days to onset of injection site reactions, as well as urticaria with either acute onset (within a few days) or delayed onset (up to approximately 2 weeks), respectively [ 28 ].

3.4 Challenges of Drawing Conclusions from Consumer Data

Changes to menstruation are not routinely collected in clinical trials. Following vaccines' authorisation, cases of heavy menstrual bleeding (HMB) have been flagged as disproportionate in EV [ 29 ] since mid-2021, mainly based on consumer reports. These cases, while often lacking case definition details, and often containing solely the event in relation to time after the vaccination played an important role in the detection of this signal. The scale of reporting to national spontaneous databases [ 30 , 31 ] was crucial to draw the attention of the EU network and direct resources to process the EV data to further investigate menstruation irregularities (i.e., heavy bleeding and lack of menstruation). About a tenth of the cases were reported by healthcare professionals.

In January 2022, the Norwegian Public Institute [ 32 ] issued a survey of the occurrence of menstrual disturbances in 18- to 30-year-old women after COVID-19 vaccination, which was the basis for the PRAC to initiate the signal procedure of HMB. As in the case of the myocarditis/pericarditis signal, the PRAC benefited from collaboration with authors of independent studies who made preliminary data available for assessment (the relevant article was published in January 2023 [ 33 ]).

Ultimately, HMB was added to the EU labelling on 27 October 2022, with unknown frequency. Several independent observational studies on the association were published at the time of the PRAC recommendation and later on [ 34 , 35 , 36 ]. Both the spontaneous reports and the observational research pointed to a transient and non-serious nature of changes to the flow of menstruation.

3.5 Labelling in Specific Patient Groups

In specific patient groups, namely with relapse of capillary leak syndrome (CLS) or experiencing corneal graft rejection (CGR) following COVID-19 vaccination, the signal assessment relied solely on data from EV case reports or published in scientific journals. Subsequently, PRAC recommended restriction of the use of adenoviral vector vaccines in patients with a history of CLS [ 37 ], as at that time, review of available data showed that severe cases of CLS following vaccination occurred, including with fatal outcome. No restriction of use was recommended for mRNA platform vaccines, as in their case, the PRAC considered newly available data, including unique experiences from vaccination in specific patient registries. The EurêClark Study Group showed that in patients with CLS/Clarkson disease, the burden of COVID-19 infection leads to severe disease flares, with a high fatality rate. The researchers concluded that the benefit/risk ratio favours COVID-19 vaccination in these patients, under pre-medication with intravenous immunoglobulins [ 38 ].

No product information update was recommended for the CGR signals, as the assessed evidence did not suggest that a causal association was at least a reasonable possibility. While the cases were reported in close temporal association with vaccination, with several providing good documentation (i.e., literature cases), there was no clear mechanism of action, no signal of disproportionality observed in EV, no imbalance in the O/E analysis, as well as no increased rates of CGR observed during the pandemic [ 39 ]. The challenges with the assessment of this signal have been described elsewhere [ 40 ].

4 Challenges of the Safety Assessment During the COVID-19 Pandemic

All medicinal products, including vaccines, have benefits and risks, which are continuously assessed throughout their life cycle. During the COVID-19 pandemic, the scientific assessment was hampered by the COVID-19 disease burden itself, i.e., difficulties in disentangling risks caused by the infection versus the vaccines. Adverse events observed in the population during mass vaccination that had incidence rates exceeding the expected ranges were considered a priori more likely causally associated with the vaccines.

4.1 Aetiologies Overlapping with SARS-CoV-2 Infection

Several well-designed natural history disease or observational studies suggested multi-organ complications in individuals suffering from COVID-19. A large SCCS from England found that the risk of myocarditis is greater after SARS-CoV-2 infection and that the risk after COVID-19 vaccination, albeit present, remains modest [ 41 , 42 ]. The signal of myocarditis/pericarditis emerged at the time when these conditions were increasingly observed following COVID-19 infection. Review of the effects of COVID-19 on the heart showed that over two-thirds of those infected (including young and asymptomatic individuals) have some degree of inflammation/myocarditis, thus predisposing to cardiovascular events [ 43 ]. The signals of histiocytic necrotising lymphadenitis (Kikuchi-Fujimoto disease) or multisystem inflammatory syndrome (MIS) were investigated while their aetiologies were not fully elucidated, and both were increasingly observed after COVID-19 disease itself [ 44 , 45 ].

4.2 Broad Case Definitions and Medical Dictionary for Regulatory Activities (MedDRA) Terms

The myocarditis/pericarditis signal was assessed based on the 30 May 2021 Brighton Collaboration interim case definition, which was then updated several times to reflect the necessary level of detail [ 46 ]. The lack of MedDRA terms created an additional layer of complexity. In the case of TTS, no MedDRA matching term existed at the time of signal identification in March 2021 (Table 1 ). The initial PRAC discussion used broad case definitions within embolic and thrombotic events (SMQ), co-reported with a list of terms describing thrombocytopenia, with manual adjudication of cases to describe the new clinical entity. ‘Thrombosis with thrombocytopenia syndrome’ was added as a preferred term (PT) and low-level term (LLT) in MedDRA version 24.1, in September 2021 [ 47 ].

The signal of MIS in children (initial PRAC discussion September 2021) was assessed simultaneously with the addition of the term ‘Multisystem inflammatory syndrome in children’ and ‘Multisystem inflammatory syndrome in adults’ as MedDRA PTs (version 24.1.) [ 47 ], while previously no specific term existed for the condition in children.

4.3 Availability of Vaccine Exposure Data in the European Economic Area (EEA)

Since O/E analyses [ 48 ] were used by PRAC to identify adverse events with incidence rates exceeding the expected unvaccinated population ranges, both vaccine coverage data and background incidence rates of events were required. While data on vaccine exposure in the EU/European Economic Area (EEA) has been widely accessible, as published by the European Centre for Disease Prevention and Control (ECDC) since the early days of the pandemic, vaccine coverage data by gender was not readily available. This was a limitation when assessing risks differently distributed across sexes, for example, myocarditis observed mainly in males and after the second dose. Observed cases were collected from EV for all O/E analyses, with inherent limitations of spontaneous reporting systems, including lack of information on the total population exposed to the medicinal product (denominator), some cases not meeting the case definition criteria, and under-reporting—although the latter was less likely for serious events such as myocarditis. To address these limitations, sensitivity analyses adjusting for under-reporting were performed. The O/E analyses were useful for signal strengthening (i.e., validation).

4.4 Generation of Observational Studies to Further Characterise Adverse Reactions

To support PRAC’s safety assessments and characterise new safety issues, EMA contracted 11 studies to consortia specialising in observational research, such as pharmacoepidemiological studies using large EU electronic healthcare databases, vaccine effectiveness studies and studies on patient-reported information. Six of these studies were completed and five were ongoing as of December 2022.

The studies utilised population-based healthcare databases across Europe, thus providing generalisable data, for example, ARS Toscana Database, PEDIANET (Italy); FISABIO, BIFAP and SIDIAP (Spain); PHARMO (Netherlands); CPRD (UK); GePaRD (Germany); SNDS (France); Norwegian Health Registers; and Danish Registries.

Early generation of background incidence rates was facilitated by the EMA-funded ACCESS [ 49 , 50 ] (vACCine covid-19 monitoring readinESS) project as of mid-December 2020, but some challenges remained for safety issues not prespecified or not previously described in the scientific literature (TTS), or for background incidence rates of relatively common symptoms (HMB) [ 51 ].

Studies were also commissioned to characterise adverse reactions that emerged with COVID-19 vaccines (e.g., characterisation and quantification of risk of TTS and COVID-19 vaccines [ 52 ], characterisation of the occurrence of cases of myocarditis and pericarditis after vaccination with mRNA vaccines [ 53 ]).

5 Flexible Regulatory Procedures for COVID-19 Signals

A signal procedure [ 54 ] routinely follows a 60-day timetable (i.e., 60 days for the MAH to provide data, and 60 days for the Rapporteur’s assessment, including MSs and MAHs comments), or a 30-day timetable, if deemed urgent.

Timetables shorter than 30 days were applied in nine procedures, for example, at the first and subsequent discussions of myocarditis/pericarditis signal. Similarly, all procedures for the TTS signal with Vaxzevria and Jcovden were expedited. The shortest time between two consecutive PRAC recommendations was approximately 2 weeks (this occurred four times). To enable rapid decision-making, seven extraordinary PRAC meetings were convened during 2021 [ 55 ], in addition to the routine monthly plenaries. Safety topics for vaccines sharing the same technology (Comirnaty with Spikevax or Vaxzevria with Jcovden) were often investigated as a class effect, as per previous practice with other vaccines (e.g., Cervarix, Gardasil/Silgard and Gardasil-9 [ 56 ]). In addition, according to the data available, simultaneous assessment of signals for multiple vaccines was also carried out (e.g., signal of MIS or CGR). This ensured that PRAC recommendations were issued on the same day for the respective vaccines, providing the advantage of comprehensive communication with stakeholders.

To allow for a thorough review when several topics awaited regulatory scrutiny, the signal of HMB was assessed through work-sharing between Rapporteurs, which demonstrated the flexibility and prioritisation of PRAC, in the interest of public health.

Another example of expedited decision-making was the implementation of changes to the product information. A variation is a change to the terms of a Marketing Authorisation [ 57 ], which can be requested by PRAC following regulatory procedures (e.g., signal procedures, PSURs). The usual timeline for amending the product information is 2 months from the publication of the PRAC signal recommendation (routinely published monthly, post-PRAC plenary), alongside translations in the 24 EU/EEA languages.

Fifteen signal procedures resulted in an update of the product information. The time span for submission of the respective variations ranged from 4 working days after publication (e.g., signals of EM, HMB, CLS with Spikevax) to 2 weeks (anaphylactic reaction with Vaxzevria, localised swelling in persons with history of dermal filler injections with Comirnaty) (Table 3 ).

In eight signal procedures, the variations were submitted ahead of the publication of the PRAC recommendation (Table 4 ). Translations were prioritised for the Vaxzevria—CLS and immune thrombocytopenia signals, followed by expedited product information updates. The time span from the day of the PRAC recommendation ranged from only two consecutive days (for the two variations submitted for each of the signal procedures of TTS with Vaxzevria and Jcovden) to four consecutive days (for the myocarditis/pericarditis initial signal procedure and myocarditis/pericarditis—Nordic study signal with mRNA platform vaccines).

6 Transparency Measures and Proactive Communication of Safety Issues Discussed in PRAC

Transparency [ 58 ] on the safety of COVID-19 vaccines played an important role in maintaining public trust and understanding the regulatory process and actions taken.

Since 2012, snapshots of EV data are made publicly available and updated weekly at https://www.adrreports.eu/ . In anticipation of public interest, this tool was enhanced with tailored access to all COVID-19 vaccines [ 59 ]. Nevertheless, EMA noted misrepresentation of this data circulating in articles and on social media, mostly due to its misunderstanding. Several online visuals have used EMA’s and EV’s graphics/logo without the Agency’s consent, thus allowing for the spread of false information and risking further vaccine hesitancy. Dedicated webinars for fact checkers were organised on how to correctly use and interpret www.adrreports.eu , and on the monitoring of the safety of COVID-19 vaccines.

EMA published the assessment reports of the TTS [ 60 ], myocarditis/pericarditis [ 61 , 62 ] and HMB [ 63 , 64 ] signals. In addition, EMA published Comirnaty PSURs and PRAC PSUR assessment reports, thus providing insight on how the vast amount of safety data was processed by the EU regulators [ 65 ].

To tackle misinformation, EMA continued to provide science-based data through all its communication channels, engaged in social media, responded to queries from journalists, and organised press briefings and public stakeholder meetings [ 66 ]. Following authorisation of the COVID-19 vaccines, a dedicated EMA webpage provided the latest information, including on changes to the product information, relevant studies, as well as monthly safety updates.

6.1 Media Attention

Public concerns regarding menstrual disorders in COVID-19 vaccinees were covered by the media, thus signals of HMB or amenorrhea were of high interest. EMA investigated the impact of media attention on menstrual bleeding and COVID-19 vaccines in the EU/EEA and the reporting trends of HMB to EV. The analysis found some media stimulation on EV case reports. In this context, EMA provided regular information on the progress of the review and reassured regarding no evidence to suggest that the menstrual disorders have any impact on reproduction and fertility. A review by the EU network indicated that mRNA COVID-19 vaccines do not cause pregnancy complications and are as effective at reducing the risk of hospitalisation and deaths in pregnant as in non-pregnant women [ 67 ].

High media interest was also observed for the signals of TTS and myo- and pericarditis. For the latter, since the MedDRA term existed prior to the emergence of the signal, higher reporting was observed after EMA communications on the topic, which peaked following the PRAC label update at the beginning of July 2021 (Fig. 1 ).

figure 1

Dynamic reporting odds ratio (ROR) for worldwide cases for COVID-19 vaccines and myocarditis/pericarditis. Spikevax Original (INN elasomeran) and Comirnaty Original (INN tozinameran) were used for a pooled ROR calculation. The suspected adverse reaction was defined using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms ‘myocarditis’ and ‘pericarditis’. The dashed line represents the lower bound of the 95% confidence interval (LCI) threshold, with a signal of disproportionate reporting considered in the presence of at least three cases and the LCI of the ROR ≥ 1.  MedDRA Medical Dictionary for Regulatory Activities;  PT   Preferred term;  ROR  Reporting Odds Ratio

6.2 Understanding of Cases of Suspected Side Effects with Reported Fatal Outcome

The EV database analyses information by grouping cases by type of suspected ADR. As more than one suspected ADR may have been included in a single case report, the total number of ADRs will never match the number of individual cases. This also applies to the total number of cases of suspected ADRs for which a fatal outcome has been reported. Therefore, an overestimation of the actual total number of cases for a vaccine may occur when one sums up the case figures published by EMA by suspected ADR type.

Cases of suspected ADRs with reported fatal outcome shortly after use of any medicine or vaccine may create concern. This becomes apparent during mass vaccination campaigns. A given medical event (whether fatal or not) may not have been caused by the vaccine, or it may have been caused by the vaccine but was not the cause of death. Fatal events can happen in the context of a complexity of causal factors. In extremely rare instances, adverse reactions can have a fatal outcome, as in the case of TTS. Following investigation of causality, specificities and frequency of occurrence, EMA issued dedicated communication (e.g., DHPCs, press briefings) when a new safety issue represented a truly serious adverse reaction [ 68 ].

7 International Collaboration

As part of the EU Health Union [ 69 ], EMA collaborated with its partners in the EU regulatory network, the EC (Directorate-general For Health And Food Safety and Health Emergency Preparedness And Response Authority) and the ECDC.

In May 2022, EMA and ECDC established a Vaccine Monitoring Platform (VMP) in accordance with the regulation on EMA's reinforced role and ECDC’s extended mandate. The VMP’s roles include maintenance of a system for prioritisation, initiation, registration and supervision of vaccine studies at EU level, as well as facilitation and coordination of the conduct of post-authorisation safety and effectiveness studies to monitor vaccine performance and impact over time.

The pandemic has been a powerful booster for collaboration between EMA and regulatory bodies and public health agencies such as the Centres for Disease Control and Prevention, US Food and Drug Administration, Health Canada, UK Medicines and Healthcare Products Regulatory Agency, WHO, Therapeutic Goods Administration, Japanese Pharmaceuticals and Medical Devices Agency, Ministry of Health of Israel, National Immunization Technical Advisory Groups. A broad network of independent researchers and experts was deployed for the review of COVID-19 vaccines. EMA has been chairing the International Coalition of Medicines Regulatory Authorities, thus supporting the exchange of information, the strategic directions, the work-sharing efforts among regulators and researchers, and the approaches to address common challenges [ 70 ]. These exchanges were based on already-existing agreements [ 71 ], but also ad hoc, time-limited, COVID-19-specific agreements. Harmonisation of actions was achieved through provision of advance notice of anticipated regulatory actions and their scientific rationale.

8 Conclusion

Throughout the COVID-19 pandemic, the EU Regulatory Network played a crucial role in the early identification and evaluation of safety issues, rapid communication to the public, and inclusion in the product information when warranted. The lessons learned from the pandemic are applied for improving future pharmacovigilance activities, enabling the EU Regulatory Network to be better prepared for potential future public health emergencies, including in safety monitoring of future pandemic vaccines. Lessons learned applicable to pharmacovigilance relate to the importance of crisis preparedness, agile structures for real-world safety monitoring, network collaboration and resources, flexible regulatory procedures, international collaboration, transparency, stakeholder engagement and communication [ 72 ].

In the EU, preparedness proved essential for timely and efficient organisation of activities, resources and priorities, enabling a rapid crisis response. Spontaneous data played a crucial role for the early detection of emerging safety issues. Enhanced collaboration allowed addressing challenges and leveraging experience. The safety monitoring of COVID-19 vaccines required tailored tools, combination of scientific methods and contextualisation of risks, complemented by real-world monitoring through EMA-funded pharmacoepidemiological studies. Accelerated assessments were possible due to flexible regulatory tools and EU network experts’ commitment. The enhanced measures for publication of COVID-19 vaccines data, communication and public engagement played an important role in maintaining public confidence.

The EU regulatory network will continue to closely monitor the safety of the COVID-19 vaccines, evaluate emerging data, and make information on vaccines and regulatory decisions easily accessible for the public.

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Acknowledgements

The authors thank Thomas Larsson and Catherine Cohet for their review of the manuscript prior to submission, and María Gordillo-Marañón for her help with the graph.

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Irina Caplanusi and Agnieszka Szmigiel have shared first authorship.

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European Medicines Agency, Pharmacovigilance Office, Domenico Scarlattilaan 6, 1083 HS, Amsterdam, The Netherlands

Irina Caplanusi, Agnieszka Szmigiel, Cosimo Zaccaria, Bénédicte Cappelli & Georgy Genov

Medicines Evaluation Board, Utrecht, The Netherlands

Menno van der Elst & Sabine Straus

Pharmacovigilance Risk Assessment Committee, Amsterdam, The Netherlands

Menno van der Elst, Marie Louise Schougaard Christiansen & Sabine Straus

Danish Medicines Agency, Copenhagen, Denmark

Marie Louise Schougaard Christiansen

Chief Medical Officer, European Medicines Agency, Amsterdam, The Netherlands

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Caplanusi, I., Szmigiel, A., van der Elst, M. et al. The Role of the European Medicines Agency in the Safety Monitoring of COVID-19 Vaccines and Future Directions in Enhancing Vaccine Safety Globally. Drug Saf (2024). https://doi.org/10.1007/s40264-024-01405-9

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FactCheck.org

Review Article By Misinformation Spreaders Misleads About mRNA COVID-19 Vaccines 

By Catalina Jaramillo

Posted on February 16, 2024 | Updated on February 19, 2024

SciCheck Digest

The mRNA COVID-19 vaccines have a good safety record and have saved millions of lives. But viral posts claim the contrary, citing a recent peer-reviewed article authored by known COVID-19 misinformation spreaders and published in a controversial journal. The paper repeats previously debunked claims.

covid 19 vaccination efficacy and safety literature review

More than  half a billion doses of COVID-19 vaccines have now been administered in the U.S. and only a few, very rare, safety concerns have emerged. The vast majority of people experience only minor, temporary side effects such as pain at the injection site, fatigue, headache, or muscle pain — or no side effects at all. As the Centers for Disease Control and Prevention has said , these vaccines “have undergone and will continue to undergo the most intensive safety monitoring in U.S. history.”

A small number of severe allergic reactions known as anaphylaxis, which are expected with any vaccine, have occurred with the authorized and approved COVID-19 vaccines. Fortunately, these reactions are rare, typically occur within minutes of inoculation and can be treated. Approximately 5 per million people vaccinated have experienced anaphylaxis after a COVID-19 vaccine, according  to the CDC.

To make sure serious allergic reactions can be identified and treated, all people receiving a vaccine should be observed for 15 minutes after getting a shot, and anyone who has experienced anaphylaxis or had any kind of immediate allergic reaction to any vaccine or injection in the past should be monitored for a half hour. People who have had a serious allergic reaction to a previous dose or one of the vaccine ingredients should not be immunized. Also, those who shouldn’t receive one type of COVID-19 vaccine should be monitored for 30 minutes after receiving a different type of vaccine.

There is evidence that the Pfizer/BioNTech and Moderna mRNA vaccines may rarely cause inflammation of the heart muscle (myocarditis) or of the surrounding lining (pericarditis), particularly in male adolescents and young adults .

Based on data collected through August 2021, the reporting rates of either condition in the U.S. are highest in males 16 to 17 years old after the second dose (105.9 cases per million doses of the Pfizer/BioNTech vaccine), followed by 12- to 15-year-old males (70.7 cases per million). The rate for 18- to 24-year-old males was 52.4 cases and 56.3 cases per million doses of Pfizer/BioNTech and Moderna vaccines, respectively.

Health officials have emphasized that vaccine-related myocarditis and pericarditis cases are rare and the benefits of vaccination still outweigh the risks. Early evidence suggests these myocarditis cases are less severe than typical ones. The CDC has also noted that most patients who were treated “responded well to medicine and rest and felt better quickly.”

The Johnson & Johnson vaccine has been linked to an  increased risk of rare blood clots combined with low levels of blood platelets, especially in women ages 30 to 49 . Early symptoms of the condition, which is known as thrombosis with thrombocytopenia syndrome, or TTS, can appear as late as three weeks after vaccination and  include  severe or persistent headaches or blurred vision, leg swelling, and easy bruising or tiny blood spots under the skin outside of the injection site.

According to the CDC, TTS has occurred in around 4 people per million doses administered. As of early April ,  the syndrome has been confirmed in 60 cases, including nine deaths, after more than 18.6 million doses of the J&J vaccine. Although TTS remains rare, because of the availability of mRNA vaccines, which are not associated with this serious side effect, the FDA on May 5 limited authorized use of the J&J vaccine to adults who either couldn’t get one of the other authorized or approved COVID-19 vaccines because of medical or access reasons, or only wanted a J&J vaccine for protection against the disease. Several months earlier, on Dec. 16, 2021 ,  the CDC had recommended the Pfizer/BioNTech and Moderna shots over J&J’s.

The J&J vaccine has also been linked to an increased risk of Guillain-Barré Syndrome, a rare disorder in which the immune system attacks nerve cells.  Most people  who develop GBS fully recover, although some have permanent nerve damage and the condition can be fatal.

Safety surveillance data suggest that compared with the mRNA vaccines, which have not been linked to GBS, the J&J vaccine is associated with 15.5 additional GBS cases per million doses of vaccine in the three weeks following vaccination. Most reported cases following J&J vaccination have occurred in men 50 years old and older.

Link to this

The  safety  of the mRNA COVID-19 vaccines from Pfizer/BioNTech and Moderna is supported by the rigorous clinical trials run prior to their release and numerous studies conducted since. Hundreds of millions of people have been vaccinated in the U.S., many with multiple doses, and serious side effects are rare .

covid 19 vaccination efficacy and safety literature review

COVID-19 vaccines have also been shown to be  effective  in reducing the risk of severe forms of the disease. Multiple studies have estimated that the COVID-19 vaccines saved millions of lives across the globe.

But an  article  — written by misinformation spreaders who oppose COVID-19 vaccination — that claims to have reviewed the original trials and “other relevant studies” largely ignores this body of evidence. Instead, the review, which calls for a “global moratorium” on the mRNA vaccines, cites multiple flawed or criticized studies —  many   of   which   we’ve   written about before — to falsely claim the mRNA COVID-19 vaccines have caused “extensive, well-documented” serious adverse events and have killed nearly 14 times as many people as they saved.

The article was peer-reviewed and published in Cureus, an open-access online medical journal that prioritizes fast publication and has published problematic studies before, as we will explain.

Update, Feb. 19: In a Substack post , one of the paper’s authors announced that he had been informed by the journal that the editors had decided to retract the article, based on an internal review that found multiple instances of data misrepresentation and incorrect or unsubstantiated claims.

Social   media   posts  that share the incorrect conclusions of the review have gone viral. 

“mRNA COVID-19 vaccines caused more deaths than saved: study,” reads a Feb. 4  Instagram post  that shared a screenshot of a headline by the Epoch Times. 

One author of the review — as well as other social media users — are also using the fact that the paper was published as proof that the mRNA COVID-19 vaccines are unsafe.

“People have said I’m a misinformation spreader because since  May 2021, I have been publicly saying the COVID vaccines are not safe . Now the medical peer-reviewed literature shows I was right.  Do you believe me now? ” Steve Kirsch, a review co-author and a former tech entrepreneur who lacks biomedical training, said in a post on X, formerly known as Twitter, on Jan. 30 (emphasis is his). 

“!! TRUST THE #SCIENCE !!,” the author of a  viral post  wrote on Instagram on Feb. 7. The post included a screenshot of a news story titled “Mainstream science mulls ‘global moratorium’ on COVID vaccines as cancers rise, boosters flub,” and the statement “Covid vaccines *may* cause cancer. You don’t say.” 

Just because a paper is published does not make it correct. While peer review is useful in weeding out bad science, it’s not foolproof, and the rigor and processes vary by journal. This review, which many experts have criticized, is an outlier, not “mainstream science.” And as  we’ve   written , there’s no evidence mRNA COVID-19 vaccines cause cancer and resulted in millions of deaths. 

Anti-Vaccine Authors and Debunked Claims

Many of the review’s authors have a history of spreading COVID-19 or vaccine misinformation. This includes Kirsch , who has repeatedly pushed the incorrect idea that the COVID-19 vaccines have killed millions of people worldwide, as well as Dr. Peter McCullough , Stephanie Seneff and Jessica Rose.

McCullough still   recommends  treating COVID-19 patients with hydroxychloroquine and ivermectin, even though both have been shown not to work against the disease. He also promotes and sells “spike protein detoxification” products for people who have been vaccinated, despite no evidence that vaccinated people need any such detox.

Seneff is a computer scientist who has promoted the false notion that vaccines cause autism. She previously co-authored a review paper with McCullough, which the Cureus review cites, that misused data from the Vaccine Adverse Event Reporting System to baselessly claim the mRNA COVID-19 vaccines suppress the innate immune system, as we  reported . Rose has also been  accused  of misusing VAERS data to claim vaccines are not safe — a common deception among the anti-vaccination community.

The Cureus review cites and even republishes a figure from one of Rose’s Substack posts about the supposedly alarming number of VAERS reports for “autoimmune disorders” following COVID-19 vaccination compared with influenza vaccines. The review claims the increased reporting “represents an immense safety signal.” But as we’ve explained   before , the higher number of VAERS reports for the COVID-19 vaccines can be explained by multiple factors, such as increased awareness and stricter reporting requirements – and does not in and of itself constitute a safety signal. A report can be submitted by anyone and does not mean that a vaccine caused a particular problem.

The review paper, titled “COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign,” repeats many claims we’ve already written about, based on studies or analyses that have been widely criticized or debunked. 

To claim the vaccines cause “serious harms to humans,” for example, the review draws on a problematic reanalysis of the adverse events reported in the original trials that was published in the journal Vaccine in 2022. Florida Gov. Ron DeSantis and Dr. Joseph Ladapo, the state’s surgeon general, have cited the paper to argue that the vaccines are too risky. But as  we’ve   written — and is detailed in a commentary article published in the same journal — the paper has multiple methodological flaws, including how it counted the adverse events.

The review also uncritically cites an unpublished analysis by former physics professor Denis Rancourt that alleged that some 17 million people died from the COVID-19 vaccines. We recently explained that the report erroneously ignored deaths from COVID-19 and that such estimates are implausible. And the review recycles unsupported claims about “high levels of DNA contamination” in the mRNA vaccines and the possibility that such DNA fragments “will integrate into the human genome” and cause cancer. As we’ve detailed , trace amounts of residual DNA are expected in vaccines, but there is no evidence the DNA can alter a person’s DNA or cause cancer.

covid 19 vaccination efficacy and safety literature review

Finally, the review highlighted findings from a Cleveland Clinic observational study that it called the “best evidence for the failure of the COVID-19 mRNA vaccine’s ability to confer protection against COVID-19.” The study, which identified a correlation between more COVID-19 vaccine doses and a higher rate of testing positive for a coronavirus infection, has frequently been cited by those opposed to vaccination. But as  we’ve   explained , the finding runs counter to that of many other studies, which have generally found increased protection with more doses. And the paper did not demonstrate that more doses actually cause an increased risk of infection. In fact, many experts suspect that the association is likely the result of other differences between people who received a different number of doses. Moreover, the primary purpose of vaccination is to protect against severe disease — and there is abundant evidence that the COVID-19 vaccines have been very successful on that front.

“Lessons learned? More like conspiracies spun,” wrote surgical oncologist Dr.  David Gorski  in a  post  about the review in his blog Respectful Insolence.

The authors of the review have also been criticized for citing their own studies in the review and for including non-scientific publications as primary sources. 

“BTW, the McCullough, Kirsch, etc. Cureus paper that is purportedly a scientific review article references trialsitetnews, epoch times, brownstone, the spectator, children’s health defense, and conservative review as primary sources for some of their points, as well as 11 substack articles/blogs, a youtube/twitter video, and 2 explicit anti-vaccine books, plus a large number of self-citations from the review authors,”  Jeffrey S. Morris , director of the division of biostatistics in the department of biostatistics, epidemiology and informatics at the University of Pennsylvania Perelman School of Medicine,  wrote on X  on Feb. 1.

Peer Review Doesn’t Guarantee Scientific Quality

Much of the complimentary coverage of the review paper by some of the usual misinformation spreaders has emphasized that it was published in a peer-reviewed journal.

“A review paper published last week in the journal Cureus is the first peer-reviewed paper to call for a global moratorium on the COVID-19 mRNA vaccines,” declared a Jan. 29  article  published on Robert F. Kennedy’s anti-vaccine website, Children’s Health Defense. The story also received attention on  social media .

Peer review , or the process of having fellow scientists provide feedback on a manuscript and whether it is good enough to publish, can be immensely helpful in ensuring that a given paper does not contain major flaws or errors. But peer review is only as good as the feedback provided — and it does not automatically mean the paper can be trusted. Nor are all peer-reviewed journals  the same , since each has different standards and reputations.

Cureus is unusual in that it focuses on publishing papers quickly and advertises “efficient” peer review and a “hassle-free” publishing experience. The journal’s metrics for the last six months indicate that the average time from submission to publication is 33 days and that the acceptance rate is 51%. For context, the prestigious journal  Nature — which some posts have misleadingly likened Cureus to, as they share the same parent publisher — has a median time of 267 days for submission to acceptance and an 8%  acceptance rate . Per the  article information  for this review paper, the peer-review process took  77  days.

In 2015, responding to concerns about the journal and its fast peer-review process, the founder, president and co-editor-in-chief of Cureus, Dr. John R. Adler, said that “by design peer rejection is not a big part of our review process,” and that the journal also relies on post-publication review to “sort out what is quality/important.”

A paper by Emory University librarians that was presented at a 2022 conference classified Cureus as potentially “untrustworthy or predatory.” The journal is available on PubMed Central, the National Institutes of Health’s database of biomedical research, but is not indexed on MEDLINE, which requires some vetting for inclusion. (A paper’s appearance in either database does not imply any kind of endorsement by the NIH.)

Cureus, notably, published  two problematic  studies about ivermectin for COVID-19 in 2022. As we reported at the time, the results of the studies were inconsistent with stronger studies that did not find any benefit of using ivermectin for COVID-19. Both studies had methodological flaws and were authored by ivermectin activists —  a fact that was not disclosed  at the time of publication.

Although even the best journals occasionally retract published studies, Cureus has ended up  multiple   times  in the pages of Retraction Watch, a blog and online database of retractions — most recently on Jan. 26 for  56 studies  retracted for faked authorship nearly two years after they were first flagged. In 2022, Retraction Watch  reported  that a study retracted by Frontiers in Medicine was later updated and published in Cureus.

Editor’s note: SciCheck’s articles providing accurate health information and correcting health misinformation are made possible by a grant from the Robert Wood Johnson Foundation. The foundation has no control over FactCheck.org’s editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation.

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Efficacy, safety, and public attitude toward COVID-19 vaccines: A systematic review

Affiliations.

  • 1 Department of Nursing, Turks and Caicos Islands Community College, Grand Turk, Turks and Caicos Islands; Department of Research and Statistics, Institute of Nursing Research, Oshogbo, Nigeria.
  • 2 Windsor University School of Medicine, Brighton's Estate, Cayon, St. Kitts and Nevis.
  • 3 Freelance Financial Consultant, Basseterre, St. Kitts and Nevis.
  • 4 Department of Nursing, Turks and Caicos Islands Community College, Grand Turk, Turks and Caicos Islands; Adult Critical Care Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
  • 5 Medical, Surgical, and Neuro Intensive Care Units, Scripps Hospital, San Diego, California, United States of America.
  • PMID: 38358138
  • PMCID: PMC10775944
  • DOI: 10.4103/aam.aam_13_23

Abstract in English, French

Background: This paper reviews some of the literature on the safety and efficacy of different COVID-19 vaccines, the attitudes, and perceptions of people towards the vaccines, and the factor underlying such perceptions and behavior.

Methods: Two major databases (PubMed and Epistemonikos) were checked using search expansion mechanisms and several search strings. After the title, abstract, and full-text analysis, 19 studies were selected for review.

Results: The seven different vaccines studied all have supporting data on their efficacy in the reduction of COVID-19 cases, prevention of hospitalization after infection, and reduction in the mortality rate of COVID-19 patients. There was high hesitancy about the COVID-19 vaccine and the perceived efficacy and safety of the vaccines are less than recorded in clinical data. Distrust of the vaccines, their manufacturers and different institutions and governments, personal beliefs and feelings, age, gender, education, and socioeconomic status were identified factors affecting behaviors towards the COVID-19 vaccines.

Conclusion: Several articles support the efficacy of COVID-19 vaccines, but general awareness and conception about them vary, including hesitancy, distrust, and some acceptance. Many factors affected the perception and attitude of people toward these vaccines. More clinical data on the efficacy and safety of COVID-19 vaccines should be generated to help boost confidence among users.

Résumé Contexte: Cet article passe en revue une partie de la littérature sur l'innocuité et l'efficacité de différents vaccins COVID-19, les attitudes et les perceptions des personnes à l'égard des vaccins, ainsi que les facteurs sous-jacents et le facteur sous-jacent à ces perceptions et comportements. Méthode: Deux bases de données majeures (PubMed et Epistemonikos) ont été vérifiées à l'aide de mécanismes d'expansion de la recherche et de plusieurs chaînes de recherche. Après l'analyse du titre, du résumé et du texte intégral, 19 études ont été sélectionnées pour examen. Résultat: Les 7 vaccins différents étudiés ont tous des données à l'appui sur leur efficacité dans la réduction des cas de COVID-19, la prévention des hospitalisations après infection et la réduction du taux de mortalité des patients COVID-19. Il y avait une grande hésitation à propos du vaccin COVID-19 et l'efficacité et l'innocuité perçues des vaccins sont inférieures à celles enregistrées dans les données cliniques. La méfiance à l'égard des vaccins, de leurs fabricants et des différentes institutions et gouvernements, les croyances et sentiments personnels, l'âge, le sexe, l'éducation et le statut socio-économique ont été identifiés comme des facteurs affectant les comportements à l'égard des vaccins COVID-19. Conclusion: Plusieurs articles soutiennent l'efficacité des vaccins COVID-19, mais la sensibilisation et la conception générales à leur sujet varient, y compris l'hésitation, la méfiance et une certaine acceptation. De nombreux facteurs ont affecté la perception et l'attitude des gens envers ces vaccins. Plus de données cliniques sur l'efficacité et l'innocuité des vaccins COVID-19 devraient être générées pour aider à renforcer la confiance des utilisateurs. Mots-clés: Attitude, COVID-19, vaccins COVID-19, efficacité, innocuité.

Keywords: Attitude; COVID-19; COVID-19 vaccines; efficacy; safety.

Publication types

  • Systematic Review
  • COVID-19 Vaccines* / adverse effects
  • COVID-19* / prevention & control
  • Educational Status
  • Hospitalization
  • Vaccination
  • COVID-19 Vaccines

IMAGES

  1. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

    covid 19 vaccination efficacy and safety literature review

  2. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

    covid 19 vaccination efficacy and safety literature review

  3. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6

    covid 19 vaccination efficacy and safety literature review

  4. Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine

    covid 19 vaccination efficacy and safety literature review

  5. Safety & Efficacy of COVID-19 Vaccines

    covid 19 vaccination efficacy and safety literature review

  6. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

    covid 19 vaccination efficacy and safety literature review

COMMENTS

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

    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.

  2. COVID-19 Vaccination Efficacy and Safety Literature Review

    Currently, no vaccine has a safety threat and the efficacies are 95% for COVID-19 mRNA vaccine BNT162b2 (Pfizer), 94.1% for mRNA-1273 vaccine (Moderna), 70.4%forChAdOx1 nCoV-19...

  3. Comparative efficacy and safety of COVID-19 vaccines in phase III

    Background Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis. Methods We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized ...

  4. COVID-19 Vaccination Efficacy and Safety Literature Review

    Currently, no vaccine has a safety threat and the efficacies are 95% for COVID-19 mRNA vaccine BNT162b2 (Pfizer), 94.1% for mRNA-1273 vaccine (Moderna), 70.4%forChAdOx1 nCoV-19 vaccine / AZD1222 (AstraZeneca) vaccine and 78% for sinovac respectively. Findings of this paper show that other vaccines are awaiting clinical roll out for trials.

  5. Safety & effectiveness of COVID-19 vaccines: A narrative review

    The literature shows that these eight vaccines are highly effective in protecting the population from severe disease and death, but there are some issues concerning safety and adverse effects. Further, booster shots and variant-specific vaccines would also be required.

  6. Comprehensive literature review on COVID-19 vaccines and role of SARS

    Since the outbreak of the COVID-19 pandemic, there has been a rapid expansion in vaccine research focusing on exploiting the novel discoveries on the pathophysiology, genomics, and molecular biology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

  7. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

    A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be safe and 95% effective against Covid-19. The vaccine met both primary efficacy end points, with more than a 99 ...

  8. Cochrane review of COVID-19 vaccines shows they are effective

    The review found that the following vaccines reduced or probably reduced the risk of COVID-19 infection compared to placebo: Pfizer/BioNTech, Moderna, CureVac COVID-19, Oxford-AstraZeneca, Janssen, Sputnik V (Gam-COVID-Vac), Sinopharm (WIBP CorV and BBIBP-CorV), Bharat (Covaxin), Novavax and Soberana 2 (Finlay-FR-2).

  9. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a

    A single dose of vaccines was 41% (95% CI: 28-54%) effective at preventing SARS-CoV-2 infections, 52% (31-73%) for symptomatic COVID-19, 66% (50-81%) for hospitalization, 45% (42-49%) for Intensive Care Unit (ICU) admissions, and 53% (15-91%) for COVID-19-related death; and two doses were 85% (81-89%) effective at preventing SARS-CoV-2 infection...

  10. Long-term effectiveness of COVID-19 vaccines against infections

    Interpretation Our analyses indicate that vaccine effectiveness generally decreases over time against SARS-CoV-2 infections, hospitalisations, and mortality. The baseline vaccine effectiveness levels for the omicron variant were notably lower than for other variants.

  11. A narrative review of COVID-19 vaccination in pregnancy and ...

    We conducted a review of the literature on COVID-19 vaccination to discuss vaccine safety and efficacy, immunity after maternal vaccination, transplacental transfer and persistence of antibodies ...

  12. Comparing reactogenicity of COVID-19 vaccine boosters: a systematic

    Other published systematic reviews and meta-analyses have reported the efficacy and safety of COVID-19 boosters [Citation 49-51] but not the detailed reactogenicity, nor an analysis by subgroups of vaccine combinations and doses. Our review adds a more granular analysis of the available reactogenicity data to the literature.

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

    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. Publication types Systematic Review MeSH terms Aged

  14. Vaccine safety and efficacy: A literature review

    Vaccine safety and efficacy: A literature review. To introduce vaccine safety and efficacy, the two main public concerns for vaccine use. This is a review of the literature including but not limited to scientific publications and government documents that are related to vaccine safety and efficacy. The publication dates range from 1984 to 2020.

  15. Global research on RNA vaccines for COVID-19 from 2019 to 2023: a

    The top 20 most cited articles were mainly published between 2020 and 2021, and all seven were published in the New England Journal of Medicine, indicating the influence of the New England Journal of Medicine in this regard. In addition, the first four articles are all about the safety and effectiveness of the COVID-19 RNA vaccines.

  16. Immunogenicity and safety of RAZI recombinant spike protein vaccine

    The immunity induced by primary vaccination is effective against COVID-19; however, booster vaccines are needed to maintain vaccine-induced immunity and improve protection against emerging variants. Heterologous boosting is believed to result in more robust immune responses. This study investigated the safety and immunogenicity of the Razi Cov Pars vaccine (RCP) as a heterologous booster dose ...

  17. Phase II/III Double-Blind Study Evaluating Safety and Immunogenicity of

    Background: The urgent need for safe, effective, and economical coronavirus disease 2019 (COVID-19) vaccines, especially for booster campaigns targeting vulnerable populations, prompted the development of the AVX/COVID-12 vaccine candidate. AVX/COVD-12 is based in a Newcastle disease virus La Sota (NDV-LaSota) recombinant viral vector. This vaccine expresses a stabilized version of the spike ...

  18. COVID-19 vaccines and adverse events of special interest: A

    1.Introduction. Since declaration of the COVID-19 pandemic by the World Health Organization (WHO) on March 11, 2020 [1] more than 13.5 billion doses of COVID-19 vaccines have been administered worldwide [2].As of November 2023, at least 70.5 % of the world's population had received at least one dose of a COVID-19 vaccine [2].This unparalleled scenario underscores the pressing need for ...

  19. Safety Information for Covid-19 Vaccines

    There are currently two mRNA COVID-19 vaccines available in the United States that have full approval from the United States Food and Drug Administration (FDA) for use in people ages 12 and older (Pfizer-BioNTech [Comirnaty ®] and Moderna [Spikevax ®]).These vaccines are authorized for emergency use in children ages 6 months through 11 years.

  20. Real-world effectiveness of COVID-19 vaccines: a literature review and

    For those fully vaccinated against infection, the observed effectiveness of the Pfizer-BioNTech vaccine was 91.2% and of the Moderna vaccine was 98.1%, while the effectiveness of the CoronaVac vaccine was found to be 65.7%. Conclusions: The COVID-19 vaccines are highly protective against SARS-CoV-2-related diseases in real-world settings.

  21. Adjuvants in COVID-19 vaccines: innocent bystanders or culpable

    Clinical researchers were not certain about the underlying reason for the upsurge of cardiovascular disorders with some blaming them on COVID-19 infections while others blaming them on COVID-19 vaccines. Based on the literature review, we hypothesize that adjuvants included in the COVID-19 vaccines are the real culprits for causation of ...

  22. The Role of the European Medicines Agency in the Safety ...

    The European Union (EU) regulatory network was at the forefront of the safety monitoring of COVID-19 vaccines during the pandemic. An unprecedented number of case reports of suspected adverse reactions after vaccination called for huge efforts for the assessment of this safety information, to ensure that any possible risks were detected and managed as early as possible, while ruling out ...

  23. Review Article By Misinformation Spreaders Misleads About mRNA COVID-19

    Full Story. The safety of the mRNA COVID-19 vaccines from Pfizer/BioNTech and Moderna is supported by the rigorous clinical trials run prior to their release and numerous studies conducted since ...

  24. Efficacy, safety, and public attitude toward COVID-19 vaccines: A

    Background: This paper reviews some of the literature on the safety and efficacy of different COVID-19 vaccines, the attitudes, and perceptions of people towards the vaccines, and the factor underlying such perceptions and behavior. Methods: Two major databases (PubMed and Epistemonikos) were checked using search expansion mechanisms and several search strings.