importance of covid 19 vaccine research paper

• Scoping Review
• Open access
• Published: 14 November 2021

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

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.

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 ).

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

Institute for Global Health and Development, Peking University, Beijing, 100871, China

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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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Correspondence to Min Liu or Jue Liu .

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Supplementary Information

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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Research Article

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

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

* E-mail: [email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Introduction

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

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

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

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

Materials and methods

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Supporting information

S1 file. qualtrics survey questionnaire..

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

S1 Data. Inclusion criteria.

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

Acknowledgments

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

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• Published: 16 June 2020

COVID-19 impact on research, lessons learned from COVID-19 research, implications for pediatric research

• Debra L. Weiner 1 , 2 ,
• Vivek Balasubramaniam 3 ,
• Shetal I. Shah 4 &
• Joyce R. Javier 5 , 6

on behalf of the Pediatric Policy Council

Pediatric Research volume  88 ,  pages 148–150 ( 2020 ) Cite this article

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The COVID-19 pandemic has resulted in unprecedented research worldwide. The impact on research in progress at the time of the pandemic, the importance and challenges of real-time pandemic research, and the importance of a pediatrician-scientist workforce are all highlighted by this epic pandemic. As we navigate through and beyond this pandemic, which will have a long-lasting impact on our world, including research and the biomedical research enterprise, it is important to recognize and address opportunities and strategies for, and challenges of research and strengthening the pediatrician-scientist workforce.

The first cases of what is now recognized as SARS-CoV-2 infection, termed COVID-19, were reported in Wuhan, China in December 2019 as cases of fatal pneumonia. By February 26, 2020, COVID-19 had been reported on all continents except Antarctica. As of May 4, 2020, 3.53 million cases and 248,169 deaths have been reported from 210 countries. 1

Impact of COVID-19 on ongoing research

The impact on research in progress prior to COVID-19 was rapid, dramatic, and no doubt will be long term. The pandemic curtailed most academic, industry, and government basic science and clinical research, or redirected research to COVID-19. Most clinical trials, except those testing life-saving therapies, have been paused, and most continuing trials are now closed to new enrollment. Ongoing clinical trials have been modified to enable home administration of treatment and virtual monitoring to minimize participant risk of COVID-19 infection, and to avoid diverting healthcare resources from pandemic response. In addition to short- and long-term patient impact, these research disruptions threaten the careers of physician-scientists, many of whom have had to shift efforts from research to patient care. To protect research in progress, as well as physician-scientist careers and the research workforce, ongoing support is critical. NIH ( https://grants.nih.gov/policy/natural-disasters/corona-virus.htm ), PCORI ( https://www.pcori.org/funding-opportunities/applicant-and-awardee-faqs-related-covid-19 ), and other funders acted swiftly to provide guidance on proposal submission and award management, and implement allowances that enable grant personnel to be paid and time lines to be relaxed. Research institutions have also implemented strategies to mitigate the long-term impact of research disruptions. Support throughout and beyond the pandemic to retain currently well-trained research personnel and research support teams, and to accommodate loss of research assets, including laboratory supplies and study participants, will be required to complete disrupted research and ultimately enable new research.

In the long term, it is likely that the pandemic will force reallocation of research dollars at the expense of research areas funded prior to the pandemic. It will be more important than ever for the pediatric research community to engage in discussion and decisions regarding prioritization of funding goals for dedicated pediatric research and meaningful inclusion of children in studies. The recently released 2020 National Institute of Child Health and Development (NICHD) strategic plan that engaged stakeholders, including scientists and patients, to shape the goals of the Institute, will require modification to best chart a path toward restoring normalcy within pediatric science.

COVID-19 research

This global pandemic once again highlights the importance of research, stable research infrastructure, and funding for public health emergency (PHE)/disaster preparedness, response, and resiliency. The stakes in this worldwide pandemic have never been higher as lives are lost, economies falter, and life has radically changed. Ultimate COVID-19 mitigation and crisis resolution is dependent on high-quality research aligned with top priority societal goals that yields trustworthy data and actionable information. While the highest priority goals are treatment and prevention, biomedical research also provides data critical to manage and restore economic and social welfare.

Scientific and technological knowledge and resources have never been greater and have been leveraged globally to perform COVID-19 research at warp speed. The number of studies related to COVID-19 increases daily, the scope and magnitude of engagement is stunning, and the extent of global collaboration unprecedented. On January 5, 2020, just weeks after the first cases of illness were reported, the genetic sequence, which identified the pathogen as a novel coronavirus, SARS-CoV-2, was released, providing information essential for identifying and developing treatments, vaccines, and diagnostics. As of May 3, 2020 1133 COVID-19 studies, including 148 related to hydroxychloroquine, 13 to remdesivir, 50 to vaccines, and 100 to diagnostic testing, were registered on ClinicalTrials.gov, and 980 different studies on the World Health Organization’s International Clinical Trials Registry Platform (WHO ICTRP), made possible, at least in part, by use of data libraries to inform development of antivirals, immunomodulators, antibody-based biologics, and vaccines. On April 7, 2020, the FDA launched the Coronavirus Treatment Acceleration Program (CTAP) ( https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap ). On April 17, 2020, NIH announced a partnership with industry to expedite vaccine development ( https://www.nih.gov/news-events/news-releases/nih-launch-public-private-partnership-speed-covid-19-vaccine-treatment-options ). As of May 1, 2020, remdesivir (Gilead), granted FDA emergency use authorization, is the only approved therapeutic for COVID-19. 2

The pandemic has intensified research challenges. In a rush for data already thousands of manuscripts, news reports, and blogs have been published, but to date, there is limited scientifically robust data. Some studies do not meet published clinical trial standards, which now include FDA’s COVID-19-specific standards, 3 , 4 , 5 and/or are published without peer review. Misinformation from studies diverts resources from development and testing of more promising therapeutic candidates and has endangered lives. Ibuprofen, initially reported as unsafe for patients with COVID-19, resulted in a shortage of acetaminophen, endangering individuals for whom ibuprofen is contraindicated. Hydroxychloroquine initially reported as potentially effective for treatment of COVID-19 resulted in shortages for patients with autoimmune diseases. Remdesivir, in rigorous trials, showed decrease in duration of COVID-19, with greater effect given early. 6 Given the limited availability and safety data, the use outside clinical trials is currently approved only for severe disease. Vaccines typically take 10–15 years to develop. As of May 3, 2020, of nearly 100 vaccines in development, 8 are in trial. Several vaccines are projected to have emergency approval within 12–18 months, possibly as early as the end of the year, 7 still an eternity for this pandemic, yet too soon for long-term effectiveness and safety data. Antibody testing, necessary for diagnosis, therapeutics, and vaccine testing, has presented some of the greatest research challenges, including validation, timing, availability and prioritization of testing, interpretation of test results, and appropriate patient and societal actions based on results. 8 Relaxing physical distancing without data regarding test validity, duration, and strength of immunity to different strains of COVID-19 could have catastrophic results. Understanding population differences and disparities, which have been further exposed during this pandemic, is critical for response and long-term pandemic recovery. The “Equitable Data Collection and Disclosure on COVID-19 Act” calls for the CDC (Centers for Disease Control and Prevention) and other HHS (United States Department of Health & Human Services) agencies to publicly release racial and demographic information ( https://bass.house.gov/sites/bass.house.gov/files/Equitable%20Data%20Collection%20and%20Dislosure%20on%20COVID19%20Act_FINAL.pdf )

Trusted sources of up-to-date, easily accessible information must be identified (e.g., WHO https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov , CDC https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html , and for children AAP (American Academy of Pediatrics) https://www.aappublications.org/cc/covid-19 ) and should comment on quality of data and provide strategies and crisis standards to guide clinical practice.

Long-term, lessons learned from research during this pandemic could benefit the research enterprise worldwide beyond the pandemic and during other PHE/disasters with strategies for balancing multiple novel approaches and high-quality, time-efficient, cost-effective research. This challenge, at least in part, can be met by appropriate study design, collaboration, patient registries, automated data collection, artificial intelligence, data sharing, and ongoing consideration of appropriate regulatory approval processes. In addition, research to develop and evaluate innovative strategies and technologies to improve access to care, management of health and disease, and quality, safety, and cost effectiveness of care could revolutionize healthcare and healthcare systems. During PHE/disasters, crisis standards for research should be considered along with ongoing and just-in-time PHE/disaster training for researchers willing to share information that could be leveraged at time of crisis. A dedicated funded core workforce of PHE/disaster researchers and funded infrastructure should be considered, potentially as a consortium of networks, that includes physician-scientists, basic scientists, social scientists, mental health providers, global health experts, epidemiologists, public health experts, engineers, information technology experts, economists and educators to strategize, consult, review, monitor, interpret studies, guide appropriate clinical use of data, and inform decisions regarding effective use of resources for PHE/disaster research.

Differences between adult and pediatric COVID-19, the need for pediatric research

As reported by the CDC, from February 12 to April 2, 2020, of 149,760 cases of confirmed COVID-19 in the United States, 2572 (1.7%) were children aged <18 years, similar to published rates in China. 9 Severe illness has been rare. Of 749 children for whom hospitalization data is available, 147 (20%) required hospitalization (5.7% of total children), and 15 of 147 required ICU care (2.0%, 0.58% of total). Of the 95 children aged <1 year, 59 (62%) were hospitalized, and 5 (5.3%) required ICU admission. Among children there were three deaths. Despite children being relatively spared by COVID-19, spread of disease by children, and consequences for their health and pediatric healthcare are potentially profound with immediate and long-term impact on all of society.

We have long been aware of the importance and value of pediatric research on children, and society. COVID-19 is no exception and highlights the imperative need for a pediatrician-scientist workforce. Understanding differences in epidemiology, susceptibility, manifestations, and treatment of COVID-19 in children can provide insights into this pathogen, pathogen–host interactions, pathophysiology, and host response for the entire population. Pediatric clinical registries of COVID-infected, COVID-exposed children can provide data and specimens for immediate and long-term research. Of the 1133 COVID-19 studies on ClinicalTrials.gov, 202 include children aged ≤17 years. Sixty-one of the 681 interventional trials include children. With less diagnostic testing and less pediatric research, we not only endanger children, but also adults by not identifying infected children and limiting spread by children.

Pediatric considerations and challenges related to treatment and vaccine research for COVID-19 include appropriate dosing, pediatric formulation, and pediatric specific short- and long-term effectiveness and safety. Typically, initial clinical trials exclude children until safety has been established in adults. But with time of the essence, deferring pediatric research risks the health of children, particularly those with special needs. Considerations specific to pregnant women, fetuses, and neonates must also be addressed. Childhood mental health in this demographic, already struggling with a mental health pandemic prior to COVID-19, is now further challenged by social disruption, food and housing insecurity, loss of loved ones, isolation from friends and family, and exposure to an infodemic of pandemic-related information. Interestingly, at present mental health visits along with all visits to pediatric emergency departments across the United States are dramatically decreased. Understanding factors that mitigate and worsen psychiatric symptoms should be a focus of research, and ideally will result in strategies for prevention and management in the long term, including beyond this pandemic. Social well-being of children must also be studied. Experts note that the pandemic is a perfect storm for child maltreatment given that vulnerable families are now socially isolated, facing unemployment, and stressed, and that children are not under the watch of mandated reporters in schools, daycare, and primary care. 10 Many states have observed a decrease in child abuse reports and an increase in severity of emergency department abuse cases. In the short term and long term, it will be important to study the impact of access to care, missed care, and disrupted education during COVID-19 on physical and cognitive development.

Training and supporting pediatrician-scientists, such as through NIH physician-scientist research training and career development programs ( https://researchtraining.nih.gov/infographics/physician-scientist ) at all stages of career, as well as fostering research for fellows, residents, and medical students willing to dedicate their research career to, or at least understand implications of their research for, PHE/disasters is important for having an ongoing, as well as a just-in-time surge pediatric-focused PHE/disaster workforce. In addition to including pediatric experts in collaborations and consortiums with broader population focus, consideration should be given to pediatric-focused multi-institutional, academic, industry, and/or government consortiums with infrastructure and ongoing funding for virtual training programs, research teams, and multidisciplinary oversight.

The impact of the COVID-19 pandemic on research and research in response to the pandemic once again highlights the importance of research, challenges of research particularly during PHE/disasters, and opportunities and resources for making research more efficient and cost effective. New paradigms and models for research will hopefully emerge from this pandemic. The importance of building sustained PHE/disaster research infrastructure and a research workforce that includes training and funding for pediatrician-scientists and integrates the pediatrician research workforce into high-quality research across demographics, supports the pediatrician-scientist workforce and pipeline, and benefits society.

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Department of Pediatrics, Division of Emergency Medicine, Boston Children’s Hospital, Boston, MA, USA

Debra L. Weiner

Harvard Medical School, Boston, MA, USA

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Vivek Balasubramaniam

Department of Pediatrics and Division of Neonatology, Maria Fareri Children’s Hospital at Westchester Medical Center, New York Medical College, Valhalla, NY, USA

Shetal I. Shah

Division of General Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Joyce R. Javier

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

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All authors made substantial contributions to conception and design, data acquisition and interpretation, drafting the manuscript, and providing critical revisions. All authors approve this final version of the manuscript.

Pediatric Policy Council

Scott C. Denne, MD, Chair, Pediatric Policy Council; Mona Patel, MD, Representative to the PPC from the Academic Pediatric Association; Jean L. Raphael, MD, MPH, Representative to the PPC from the Academic Pediatric Association; Jonathan Davis, MD, Representative to the PPC from the American Pediatric Society; DeWayne Pursley, MD, MPH, Representative to the PPC from the American Pediatric Society; Tina Cheng, MD, MPH, Representative to the PPC from the Association of Medical School Pediatric Department Chairs; Michael Artman, MD, Representative to the PPC from the Association of Medical School Pediatric Department Chairs; Shetal Shah, MD, Representative to the PPC from the Society for Pediatric Research; Joyce Javier, MD, MPH, MS, Representative to the PPC from the Society for Pediatric Research.

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Weiner, D.L., Balasubramaniam, V., Shah, S.I. et al. COVID-19 impact on research, lessons learned from COVID-19 research, implications for pediatric research. Pediatr Res 88 , 148–150 (2020). https://doi.org/10.1038/s41390-020-1006-3

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REVIEW article

Impact of vaccines; health, economic and social perspectives.

• 1 Department of Zoology, University of Oxford, Oxford, United Kingdom
• 2 Department of Paediatric Infectious Diseases, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
• 3 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States

In the 20th century, the development, licensing and implementation of vaccines as part of large, systematic immunization programs started to address health inequities that existed globally. However, at the time of writing, access to vaccines that prevent life-threatening infectious diseases remains unequal to all infants, children and adults in the world. This is a problem that many individuals and agencies are working hard to address globally. As clinicians and biomedical scientists we often focus on the health benefits that vaccines provide, in the prevention of ill-health and death from infectious pathogens. Here we discuss the health, economic and social benefits of vaccines that have been identified and studied in recent years, impacting all regions and all age groups. After learning of the emergence of SARS-CoV-2 virus in December 2019, and its potential for global dissemination to cause COVID-19 disease was realized, there was an urgent need to develop vaccines at an unprecedented rate and scale. As we appreciate and quantify the health, economic and social benefits of vaccines and immunization programs to individuals and society, we should endeavor to communicate this to the public and policy makers, for the benefit of endemic, epidemic, and pandemic diseases.

Introduction

“The impact of vaccination on the health of the world’s peoples is hard to exaggerate. With the exception of safe water, no other modality has had such a major effect on mortality reduction and population growth” ( Plotkin and Mortimer, 1988 ).

The development of safe and efficacious vaccination against diseases that cause substantial morbidity and mortality has been one of the foremost scientific advances of the 21st century. Vaccination, along with sanitation and clean drinking water, are public health interventions that are undeniably responsible for improved health outcomes globally. It is estimated that vaccines have prevented 6 million deaths from vaccine-preventable diseases annually ( Ehreth, 2003 ). By 2055, the earth’s population is estimated to reach almost 10 billion ( United Nations Department of Economic and Social Affairs, 2019 ), a feat that in part is due to effective vaccines that prevent disease and prolong life expectancy across all continents. That said, there is still much to be done to ensure the financing, provision, distribution, and administration of vaccines to all populations, in particular those which are difficult to reach, including those skeptical about their protective value and those living in civil disruption. Agencies including the World Health Organization (WHO), United Nations Children’s Fund (UNICEF), Gavi, the Vaccine Alliance, The Bill & Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Initiative (CEPI), with their multiple funding streams have been instrumental in expanding vaccine benefits to all. These importance of these organizations in global co-operation and participation was essential in the setting of the 2019 global pandemic of SARS-CoV-2, in light of the health and economic impact of COVID-19 on societies in high-, middle- and low-income countries. This review will highlight the benefits of vaccinations to society from the perspectives of health, economy, and social fabric ( Figure 1 ), which need to be considered in the overall assessment of impact to ensure that vaccines are prioritized by those making funding decisions.

Figure 1. The impact of vaccines according to their health, economic or social benefit.

Brief History of Vaccine Development

Human use of preparations to prevent specific infections have been described since 1500 AD, beginning in China ( Needham, 2000 ) where smallpox was prevented by variolation, which is the introduction of material from scabs into the skin. In 1796 in the United Kingdom, Edward Jenner observed the immunity to smallpox of milkmaids having previously had natural infection with cowpox ( Jenner, 1798 ). He determined that inoculating small amounts of pus from the lesions of cowpox, presumably containing a virus related to vaccinia, into susceptible hosts rendered them immune to smallpox. The vaccine against smallpox was developed in 1798. The next phase of scientific developments involving the manipulation of infectious agents to extract suitable vaccine antigens took almost a century of research. Louis Pasteur’s work with attenuation by oxygen or heat led to live-attenuated chicken cholera, inactivated anthrax and live-attenuated rabies vaccines at the turn of the 20th century ( Pasteur, 1880 , 1881 , 1885 ). Alternative methods of attenuation using serial passage of Mycobacterium bovis led to the live Bacille Calmette-Guerin (BCG) ( Calmette, 1927 ) vaccine, still in use today for the prevention of tuberculosis. Serial passage was also used in the development of yellow fever vaccines ( Theiler and Smith, 1937a ) which are grown in chicken embryo tissues ( Theiler and Smith, 1937b ). Whole cell killed bacterial vaccines were developed when methods to treat and kill bacteria through heat or chemicals were established and whole cell typhoid, cholera and pertussis vaccines resulted at the end of the 19th Century. In 1923, Alexander Glenny and Barbara Hopkins developed methods to inactivate bacterial toxins with formaldehyde, leading to the diphtheria and tetanus toxoid vaccines ( Glenny and Hopkins, 1923 ).

Advances in virus culture in vitro allowed viral pathogens to be studied in greater detail and attenuation methods due to cultivation in artificial conditions led to the live oral polio, measles, rubella, mumps and varicella virus vaccines. In the 1960’s at the Walter Reed Army Institute of Research, vaccines were developed using capsular polysaccharides ( Gold and Artenstein, 1971 ; Artenstein, 1975 ), of encapsulated organisms including meningococci and later pneumococci ( Austrian, 1989 ) and Haemophilus influenzae type b (Hib) ( Anderson et al., 1972 ). To protect against multiple serotype variants of polysaccharide capsules, polyvalent vaccines were developed and later conjugated to carrier proteins to enhance their efficacy in infants in particular by recruiting T-cell mediated help to induce memory B-cells ( Schneerson et al., 1980 ). Vaccines made solely from proteins were rare, with the exception of the toxoid vaccines, but the acellular pertussis vaccine containing five protein antigens, was developed to mitigate the unwanted effects of the whole cell vaccine ( Sato and Sato, 1999 ).

The end of the 20th century marked a revolution in molecular biology and provided insights into microbiology and immunology allowing a greater understanding of pathogen epitopes and host responses to vaccination. Molecular genetics and genome sequencing has enabled the development of vaccines against RNA viruses possessing multiple variants of epitopes, such as the live and inactivated influenza vaccines ( Maassab and DeBorde, 1985 ) and live rotavirus vaccines ( Clark et al., 2006 ). DNA manipulation and excision allowed the use of surface antigen for hepatitis B viral vectors ( Plotkin, 2014 ). The human papilloma virus (HPV) vaccine benefits from enhanced immunogenicity due to the formation of virus-like particles by the L1 antigen of each virus contained in the vaccine ( Kirnbauer et al., 1992 ). Bacterial genome sequencing has provided in depth analysis of meningococcal antigens, to identify potential proteins for meningococcal B vaccines ( Serruto et al., 2012 ).

Vaccine development was tested in 2020 when a novel coronavirus, SARS-CoV-2, emerged from China causing a severe acute respiratory illness, which subsequently spread globally. Within 5 months of the discovery of this virus (7th January 2020) ( Zhu et al., 2020 ) and person-person transmission ( Chan et al., 2020 ), 5,697,334 cases had been identified, with orders of magnitude likely not measured and almost no country escaped the pandemic. Owing to the previous advances in vaccinology, by 8th April 2020, there were 73 vaccine candidates under pre-clinical investigation ( Thanh Le et al., 2020 ). Of these, six were in Phase 1 or 1/2 trials and one was in Phase 2/3 trials by 28th May 2020. The rapidity of this response demonstrated the ability to harness existing technologies including: RNA vaccine platforms (NCT04283461), DNA vaccine platforms (NCT04336410), recombinant vector vaccines (NCT04313127, NCT04324606) and adjuvants. The regulation, manufacturer and distribution of these vaccines will require expedition given the global public health need, from a period of many years to a matter of months. The efficacy and health impact of these vaccines is yet to be established, but if they are effective, then vaccines need to be made available for all global regions affected by SARS-CoV-2. The funding of this endeavor will prove challenging in a global context of national social and economic lockdown and massive government borrowing, but the justification for this provision will be through the multiple benefits to society that will need healthy citizens to rebuild economies in the decades post-COVID-19.

The history of vaccination is not complete without describing the public health intervention that led to the routine use of these vaccines for children globally. The Expanded Program of Immunization (EPI) was founded by WHO in 1974 with the aim of providing routine vaccines to all children by 1990 ( World Health Assembly, 1974 ). In 1977, global policies for immunization against diphtheria, pertussis, tetanus, measles, polio, and tuberculosis were set out. The EPI includes hepatitis B, Hib, and pneumococcal vaccines in many areas and by 2017, 85% of the world’s children (12–23 months of age) received diphtheria, pertussis, tetanus, and measles vaccines ( World Bank, 2019 ).

Health Benefits of Vaccination

Reduction in infectious diseases morbidity and mortality.

The most significant impact of vaccines has been to prevent morbidity and mortality from serious infections that disproportionately affect children. Vaccines are estimated to prevent almost six million deaths/year and to save 386 million life years and 96 million disability-adjusted life years (DALYs) globally ( Ehreth, 2003 ). The traditional measures of vaccine impact include: vaccine efficacy, the direct protection offered to a vaccinated group under optimal conditions e.g., trial settings; or vaccine effectiveness, the direct and indirect effect of vaccines on the population in a real-life setting ( Wilder-Smith et al., 2017 ). Providing a numerical measure of vaccine impact therefore involves estimating the extent of morbidity and mortality prevented. In the United States in 2009, amongst an annual birth cohort vaccinated against 13 diseases it was estimated that nearly 20 million cases of disease and ∼42,000 deaths were prevented ( Zhou et al., 2009 ). Infectious diseases that accounted for major mortality and morbidity in the early 20th century in the United States all showed over a 90% decline in incidence by 2017 from the pre-vaccine peak incidence ( Roush and Murphy, 2007 ), due to high vaccine uptake of over 90% for the DTaP (diphtheria, tetanus, and acellular pertussis), MMR (measles, mumps, and rubella) and polio vaccines ( World Health Organisation, 2019a ; Table 1 ). A similar pattern of infectious diseases reduction was seen across other high-income countries, demonstrating the efficacy of vaccines when available and accessible.

Table 1. Vaccine impact in United States comparing the incidence of diseases prior to the implementation of vaccine ( Roush and Murphy, 2007 ), described as the pre-vaccine era and the vaccine coverage ( Hill et al., 2017 ) and disease incidence ( Centers for Disease Control and Prevention, 2017 ) in 2017, as reported by the Centers for Disease Control and Prevention.

Globally, the provision of vaccines is more challenging in many low- and middle- income countries (LMIC), as evidenced by the failure to make the EPI vaccines available to every child by 1990, irrespective of setting ( Keja et al., 1988 ). Central to this is limited financial resources, but other barriers to vaccine introduction include: underappreciation of the value of vaccines locally/regionally though insufficient relevant data on disease burden, vaccine efficacy, or cost-effectiveness; inadequate healthcare infrastructure for vaccine handling, storage, programmatic management, and disease surveillance; and lack of global, regional or local policy-making and leadership ( Munira and Fritzen, 2007 ; Hajjeh, 2011 ). In 2018, the global uptake of three doses of DTaP reached 86% which corresponded to 116,300,000 infants ( World Health Organisation, 2019a ). The vaccine coverage is, however, variable between low-, middle- and high-income countries because of a combination of economic and political circumstances as well as variable access to non-governmental support from Gavi, the Vaccine Alliance ( Turner et al., 2018 ; Figure 2 ). Nevertheless, there has been a decrease in the global burden of diseases caused by vaccine-preventable pathogens ( Figure 3 ) enabling healthier lives for many millions of children. A further benefit following vaccination, is the evidence that although vaccines may not always prevent an infection, for example VZV or pertussis, a milder disease course may follow ( Andre et al., 2008 ; Bonanni et al., 2015 ).

Figure 2. Vaccine uptake across different regions defined by economic status by the World Bank into high- (solid line), middle- (dashed line), and low-income countries (dotted line) for the past 20 years. Data from the World Health Organization and UNICEF dataset “Coverage Estimates Series” ( World Health Organization [WHO] and United Nations Children’s Fund [UNICEF], 2019 ).

Figure 3. Reduction in infectious diseases globally. Across all world regions, data from the WHO, for the last 20 years showing the control of diphtheria and tetanus and the decline in rubella and congenital rubella syndrome (data not shown). Data from the World Health Organization dataset “Reported cases of vaccine-preventable diseases” ( World Health Organisation, 2019c ).

Eradication of Infectious Diseases

Global disease eradication can be achieved for pathogens that are restricted to human reservoirs. For eradication of infectious diseases, high levels of population immunity are required globally, to ensure no ongoing transmission in our well-connected world ( Andre et al., 2008 ). Furthermore, surveillance systems must be in place to monitor the decline in disease, with accurate and reliable diagnostic testing to monitor ongoing cases. At the time of writing, the only infectious disease that has been eradicated in humans by vaccination is smallpox. This disease had afflicted humans for millenia, with the earliest evidence found in Egyptian mummies from 1000 BC ( Geddes, 2006 ). Jenner’s successful development of the smallpox vaccine using vaccinia virus ( Jenner, 1798 ) led to the ultimate eradication of the disease through ring vaccination as announced by the World Health Assembly in 1980 ( Strassburg, 1982 ), which was an historic public health achievement. The second example of eradication was of the rinderpest virus in livestock, an infection that indirectly led to human loss of life through loss of agriculture leading to humanitarian crises through famine and poverty. Rinderpest virus infects cattle, buffalo and numerous other domestic species, with widespread disease affecting large parts of Africa and Europe in the 19th century ( Roeder et al., 2013 ). The Plowright tissue culture rinderpest vaccine, developed during the 1950s, was used for mass vaccination campaigns, alongside other public health measures, leading to eradication in 2011 ( Morens et al., 2011 ).

The next infection targeted for eradication is wild polio virus. This devastating paralytic disease routinely afflicted children and adults in both industrialized and developing settings, prior to the development of vaccines. Two polio vaccines, the inactivated polio vaccine (IPV) and the live-attenuated oral polio vaccine (OPV) became available in 1955 and 1963, respectively ( Plotkin, 2014 ), both able to protect against all three wild types of polio virus. Both vaccines have been used globally, with live-attenuated OPV much cheaper and easier to administer but carrying the risk of causing circulating vaccine-derived poliovirus (cVDPV) owing to back-mutation and re-acquisition of neurovirulence. Hence, due to its safety IPV was preferred in industrialized regions and those where the polio incidence was low. In 1998, the Global Polio Eradication Initiative, the largest public-private partnership led by national governments in partnership with the WHO, Rotary International, United States Centers for Disease Control and Prevention (CDC), and UNICEF was launched with the aim of global polio eradication by 2000. Although this target was not met due to lack of funding, political will, and competing health initiatives, there was a 99% reduction in polio incidence by 2000 ( Lien and Heymann, 2013 ). By 2003, there were only six endemic countries with new cases: Egypt, Niger, India, Nigeria, Afghanistan, and Pakistan, of which only the latter four had new cases by 2005. Eradication in India was problematic due to the high birth rates and poor sanitation amongst densely populated regions with marginalized communities and high population mobility ( Thacker et al., 2016 ). India was declared polio free in 2014. Wild polio virus type 2 was eradicated in 2015, the last case of wild type 3 was in 2012 and eradication announced in 2019, with wild type 1 virus remaining in two countries, Pakistan and Afghanistan ( World Health Organisation, 2019b ). In 2019, Nigeria was declared 3 years free of wild polio, the last country in Africa to declare any cases. In the first 6 months of 2020, there were 51 and 17 cases of wild type 1 polio reported in Pakistan and Afghanistan respectively ( Global Polio Eradication Initiative, 2019 ). Ongoing programs to roll out universal vaccination in both countries remain hindered by armed conflict, political instability, remote communities and underdeveloped infrastructure. The risk of the OPV recipients developing cVDPV disease, with transmission through the faeco-oral route to cause outbreaks of vaccine-derived paralytic poliomyelitis remains a concerning obstacle in the eradication process, requiring intensive surveillance.

Herd Immunity

The overriding health benefit perceived by most vaccine recipients is their personal, direct, protection. The added value of vaccination, on a population level, is the potential to generate herd immunity. Where a sufficiently high proportion of the population are vaccinated, transmission of the infecting agent is halted thereby protecting the unvaccinated, who may be those too young, too vulnerable, or too immunosuppressed to receive vaccines. Highly successful vaccination programs have been in place as part of the routine EPI, against encapsulated bacteria that are carried asymptomatically in the oropharynx but that can invade and cause septicemia and meningitis in all age groups. Vaccines against Neisseria meningitidis ( Gold and Artenstein, 1971 ), Streptococcus pneumoniae ( Austrian, 1989 ), and Hib ( Anderson et al., 1972 ) were developed in the 1960s, 1970s, and 1980s, respectively, using their polysaccharide capsules as vaccine antigens, which successfully induced protective immunity (direct protection). Conjugation of these polysaccharides to carrier proteins in the 1990s improved their efficacy by not only ensuring a T cell response and immune memory, but by reducing acquisition of pharyngeal carriage of these organisms, thus providing indirect protection and thereby preventing ongoing transmission ( Pollard et al., 2009 ). This was first observed in national carriage studies in the United Kingdom in 1999–2001 during a mass vaccination campaign against serogroup C N. meningitidis ( Maiden et al., 2008 ) and was a major contributing factor to the declining disease thereafter.

Herd (population) immunity requires high levels of vaccine uptake, to limit the number of unvaccinated people and the opportunity for pathogen transmission between them. The proportion of a given population required to induce herd immunity through vaccination is lower for the bacterial infections and conjugate polysaccharide vaccines, as their basic reproductive number (R 0 ) is lower than viral infections like measles, varicella or polio ( Table 2 ). Measles virus can cause devastating disease ranging from acute presentations with pneumonia or encephalitis, to immune amnesia and long-term complications such as subacute sclerosing panencephalitis ( Mina et al., 2015 , 2019 ; Moss, 2017 ; Petrova et al., 2019 ). The live-attenuated measles vaccine is highly efficacious and the first dose is recommended at 9–12 months of age. To protect those who cannot receive live vaccines (younger infants, pregnant women, the immunosuppressed) from acquiring measles in the community, at least 93–95% of the population is required to be vaccinated with two doses in order to interrupt measles virus transmission. In many countries in Europe and in the United States, this level of vaccination uptake is falling ( Wise, 2018 ), due to a combination of reduced accessibility to health services and vaccine misinformation. As a result, some countries, including the United Kingdom and United States, where elimination of measles had been declared have had a resurgence of disease ( Wise, 2019 ). For high-risk individuals who are unable to be vaccinated, herd immunity represents a life-saving protection strategy against many infections. An alternative strategy, cocooning, has been employed with limited success for pertussis and influenza ( Grizas et al., 2012 ), where their close/household contacts are vaccinated to prevent transmission.

Table 2. Vaccines with the potential to induce herd immunity, with the infectious agent, vaccine type, and thresholds of population vaccination needed for herd immunity ( Peltola et al., 1999 ; Whitney et al., 2003 ; Donaghy et al., 2006 ; Fine and Griffiths, 2007 ; Maiden et al., 2008 ; Curns et al., 2010 ; Paulke-Korinek et al., 2011 ; Plans-Rubio, 2012 ; Daugla et al., 2014 ; Tabrizi et al., 2014 ; Funk et al., 2019 ; Palmer et al., 2019 ).

Herd immunity has been observed for gastrointestinal infections with vaccines against cholera (oral cholera vaccine) and rotavirus (oral rotavirus vaccines). Early adopters of rotavirus vaccines included the United States (2006) and Austria (2007) where there were dramatic reductions in disease observed in the vaccinated infant cohort, and also in the older age groups of children and adults ( Curns et al., 2010 ; Paulke-Korinek et al., 2011 ), suggesting that the reduction in disease and shedding of virus in the stool stopped transmission to healthy household contacts. For the OPV, herd protection may also be induced through vaccine virus shedding and spread to unvaccinated people ( Fine and Griffiths, 2007 ).

Reduction in Secondary Infections That Complicate Vaccine-Preventable Diseases

Vaccines can prevent diseases beyond the specific infection they are designed to target. Infections with pathogens, in particular viruses, can predispose to the acquisition of other bacterial infections. For example, influenza virus infection, both seasonal and pandemic, is frequently complicated by bacterial pneumonia and acute otitis media (OM), and infrequently Aspergillus pneumonia/pneumonitis. During the influenza pandemic of 1918–19, secondary bacterial bronchopneumonia with S. pneumoniae, Streptococcus pyogenes , H. influenzae , and Staphylococcus aureus identified at autopsy, likely contributed to the excess mortality observed amongst healthy children and adults ( Morens and Fauci, 2007 ). Influenza vaccinations can be beneficial in preventing these complications and also morbidity including acute OM in children; a systematic review demonstrated influenza vaccine efficacy against OM of 51% (21–70%) ( Manzoli et al., 2007 ). Further, there is evidence that inactivated influenza vaccines administered to pregnant women can reduce the hospital admission with acute respiratory illnesses in their infants up to 6 months of age ( Regan et al., 2016 ). Amongst pregnant, HIV-negative women in South Africa, infants (<3 months) were protected against hospitalization with all-cause lower respiratory tract infections with a vaccine efficacy of 43% ( p = 0.05), including primary viral and secondary bacterial causes ( Nunes et al., 2017 ). Additionally, in children pneumococcal conjugate vaccines were observed to reduce the incidence of influenza-associated hospital admissions in United States ( Simonsen et al., 2011 ), Spain ( Dominguez et al., 2013 ), and South Africa ( Madhi et al., 2004 ; Abadom et al., 2016 ), through the prevention of secondary bacterial infections following primary influenza infection.

The introduction of the live-attenuated measles vaccine in the 1970s was observed to reduce both measles and non-measles mortality in children ( Aaby et al., 2003 ). Measles causes severe pneumonia, encephalitis, and the long-term sequel of subacute sclerosing panencephalitis ( Moss, 2017 ), but the decline in mortality was not limited to preventing these alone ( Aaby et al., 2003 ). Mathematical modeling of vaccination and immunological research demonstrated that measles causes an immunological amnesia, eliminating B cell populations and thus immune memory, leaving measles survivors susceptible to all the infective agents they had previously developed immunity against; it is estimated to take 3 years for immune recovery to occur ( Mina et al., 2015 ).

Prevention of Cancer

Historically, vaccines were developed against very severe infections with major morbidity and mortality from acute disease. As non-communicable diseases, including cancer, become the most frequent causes of death in industrialized countries and some developing countries, vaccines are being used to prevent these too, when the infectious agents are involved in carcinogenesis. Hepatitis B prevalence is high in regions of East Asia, sub-Saharan Africa, and the Pacific Islands. Chronic hepatitis B infection can lead to liver cirrhosis and hepatocellular carcinoma ( Bogler et al., 2018 ). Vertical transmission of hepatitis B is problematic as 70–90% of babies born to HbsAg and HbeAg positive mothers will become infected without prophylaxis administered to babies; with ∼90% of infants developing chronic hepatitis ( Borgia et al., 2012 ; Gentile and Borgia, 2014 ). The chronic hepatitis B carriage status of mothers is routinely checked at the start of pregnancy, in order to assess the need to vaccinate the infant after birth. The use of both hepatitis B vaccine, containing hepatitis B surface antigen, and immunoglobulin containing hepatitis B antibody can be used to minimize vertical transmission, with evidence from a 20-year-long study in Thailand demonstrating 100% prevention of transmission ( Poovorawan et al., 2011 ).

The sexually transmitted HPV is responsible for genital tract and oropharyngeal infections as a precursor to causing oncological disease affecting the cervix, vagina, vulva, penis, anal tract, and pharynx in both men and women. Cervical cancer is the fourth most common cancer globally, with 528,000 new cases annually and peak incidence in young women aged 25–34 years ( Ferlay et al., 2012 ). The HPV serotypes 16 and 18 carry a high-risk for cervical cancer ( Wang et al., 2018 ) and vaccination against these specific serotypes has been available since 2006 through bivalent (16 and 18), quadrivalent (6, 11, 16, and 18), and nonavalent (6, 11, 16, 18, 31, 33, 45, 52, 58) vaccines, which are now available to individuals from the age of 9 years ( Gupta et al., 2017 ). A vaccination program started in the United Kingdom in 2008, and at the time of writing over 10.5 million doses had been given to girls ( Public Health England, 2018 ), with the aim of preventing primary infection with HPV. The vaccine coverage was 83.8% for 13–14 year old girls in England in 2017/18 ( Public Health England, 2019 ). In July 2018, the vaccine was approved for use in boys ( Public Health England, 2019 ). After a decade of use, there has been an observed decline in the genital infections caused by serotypes 16 and 18 ( Public Health England, 2018 ), with further time needed to observe the fall in cervical cancer incidence. However, the incidence of pre-invasive cervical diseases has been reduced by 79–89% in Scottish women over 20 who were vaccinated with bivalent HPV vaccine when aged 12–13 years, with evidence of herd protection ( Palmer et al., 2019 ), offering a promising outlook for the reduction of cervical cancer in the future. An additional benefit of HPV vaccines, is their impact on neonatal morbidity and mortality, through the reduction in surgical treatment of cervical neoplasias, and the related preterm births and complications ( Soergel et al., 2012 ).

Preventing Antibiotic Resistance

The rise in antimicrobial resistance (AMR) is a universal threat. The use of antibiotics in humans, exposes the bacteria that reside in our microbiota to selection pressures resulting in the development of AMR. As the bacteria constituting the host microbiota are frequently responsible for invasive diseases such as: meningitis, pneumonia, urinary tract, or abdominal infections, the risk of developing infections that are difficult or eventually impossible to treat is fast becoming a reality ( Brinkac et al., 2017 ). In regions where resistant pathogens are circulating at high frequency, such as India or regions of Europe ( Logan and Weinstein, 2017 ), patients will be faced with choosing between having elective surgical procedures or chemotherapy for malignancy, and the risk of acquiring potentially untreatable, multi-drug resistant bacterial infections ( Liu et al., 2016 ). Vaccination is crucial in mitigating this risk, by preventing people from developing viral and bacterial infections in the first instance, and therefore reducing the antibiotic burden to which their microbiota are exposed. The development of AMR in bacteria is a cumulative process with frequent, repeated exposure to broad spectrum antibiotics as a major driver. Children and the elderly who are at particular risk of infection can benefit from vaccines against common primary and secondary infections such as: pneumonia (prevented by PCV, PPSV, influenza, and measles vaccines), OM (PCV, Hib, and measles vaccines), cellulitis secondary to VZV (VZV vaccine), and typhoid fever (typhoid vaccine) which alleviates the need for antibiotics being prescribed or bought ( Kyaw et al., 2006 ; Palmu et al., 2014 ). The extent to which vaccination contributes to antimicrobial stewardship was highlighted by its inclusion in vaccine cost-effectiveness analyses as part of national United Kingdom policy ( Bonanni et al., 2015 ).

Economic Benefits

Cost savings.

Vaccines are highly beneficial on a population level and also cost-effective ( Shearley, 1999 ) in comparison to other public health interventions ( Bloom et al., 2005 ). Government departments are required to perform systematic economic analyses of vaccines and vaccine programs to justify their purchase in view of pressure on public and private finances globally, this was exacerbated by the 2008 financial crash. A vaccination program has clear direct costs including: vaccine purchase, infrastructure to run the program and maintain the cold chain, and healthcare/administration personnel. Governments, sometimes supported by charities and non-governmental organizations, invest in these with the intention of improving health. The reduction in morbidity and mortality associated with successful vaccine programs, through a combination of direct and indirect protection, has led to reduced incidence of diseases and their associated treatments and healthcare costs ( Deogaonkar et al., 2012 ). This potentially leads to economic growth, with less money spent owing to the costs averted through fewer medical tests, procedures, treatments and less time off work by patients/parents. Additionally, the use of combination vaccines e.g., DTaP/IPV/Hib/HepB provides protection against an increased number of diseases, with no additional infrastructure costs i.e. the same number of injections per child within existing immunization programs.

The cost-effectiveness analyses of vaccination programs demonstrate that they are overwhelmingly worth the investment, with most programs costing less than $50 per life gained, orders of magnitude less than prevention of diseases like hypertension ( Ehreth, 2003 ; Bloom et al., 2005 ). The returns on investment in vaccines, given their increasing provision through Gavi, have been estimated at 12–18% ( Bloom et al., 2005 ), but this is likely an underestimate. The monetary advantages of vaccination programs are important both to industrialized nations, such as the United States which obtains a net economic benefit of $69 billion, but also in 94 LMIC where investment of $34 billion, resulted in savings of $586 billion from the direct illness costs ( Ozawa et al., 2016 ; Orenstein and Ahmed, 2017 ). The net economic impact of eradication of disease has been estimated for both smallpox and polio. For smallpox, the eradication costs were over 100 million USD, but there are cost savings of 1.35 billion USD annually, with elimination of polio estimated to save 1.5 billion USD annually ( Barrett, 2004 ; Bloom et al., 2005 ). A less well-considered economic saving, not captured in cost-effectiveness or cost-benefit analyses, is from the prevention of long-term morbidity following acute infections ( Bloom et al., 2005 ), for example hearing impairment following pneumococcal meningitis or limb amputation following meningococcal disease, along with broader productivity gains ( Deogaonkar et al., 2012 ), which could have a major impact on LMIC adoption of vaccine programs.

Productivity Gains

The relationship between health and the economy is bidirectional, whereby economic growth enables funding in investments that improve health; and a healthy population contributes to and enhances an economy. These benefits of vaccinations and other public health interventions including sanitation, clean water, and antibiotics, are important for social as well as economic reasons. It has been suggested that the economic impact of vaccines should be considered more broadly than just the averted healthcare costs from prevented illness episodes and associated carer costs ( Deogaonkar et al., 2012 ; Barnighausen et al., 2014 ; Bonanni et al., 2015 ; Gessner et al., 2017 ; Wilder-Smith et al., 2017 ). Bärnighausen et al. (2011) , set out a framework to consider productivity gains measured by: outcome and behavior; community health and economic externalities; risk reduction; and health gains. Healthy children demonstrate improved educational attainment at school through better attendance and better cognitive performance ( Barham and Calimeria, 2008 ; Bloom et al., 2011 ; Deogaonkar et al., 2012 ). The impact of hearing loss from mumps, rubella or pneumococcal infections, or visual impairment from measles may require specific educational support, whereas the cognitive deficits from those childhood infections may require substantial remedial input. As more children survive to adulthood, a larger adult workforce is available, who when healthy can work for longer and more productively both physically and mentally ( Bloom and Canning, 2000 ; Bloom et al., 2005 ); though to date this has been observed largely following other health improvements, not vaccination specifically ( Jit et al., 2015 ). As a result of vaccination healthy and economically successful populations have lower fertility rates and smaller families ( Sah, 1991 ; Andre et al., 2008 ). With improved health and therefore life expectancy, there is a wider effect on families who may choose to invest more money in their future, for example to enhance their education or through savings ( Jit et al., 2015 ). Overall, vaccine programs should be viewed as an investment in human capital, providing enduring impact on economies worldwide.

Minimizing the Impact on Family

The economic impact of adult illness is evident from loss of productivity and pay for the duration of the illness and recovery period. The impact of childhood illness falls primarily on their adult carers, generally parents. In most industrialized regions, two-parent families are reliant on both parents undertaking at least part-time or full-time work. Therefore, when a child is unwell with childhood illnesses, which may or may not necessitate admission to hospital, the parent will invariably have to forego their paid employment to care for the child. In seven European countries one parent or carer required time off work in 39–91% of rotavirus gastroenteritis cases ( Van der Wielen et al., 2010 ). This loss of productivity in the parental workforce tends to disproportionately affect women, but loss of either parental attendance at work reduces overall employer productivity and in the short-term is rarely replaced. This argument was made for the impact of chicken pox on children, whereby the exclusion from school mandates parental caring at home for a period until the lesions are crusted over. VZV vaccines are estimated to have had a similar impact as rotavirus vaccine in United States studies ( Lieu et al., 1994 ). In many regions, mothers are still the primary carers, spending their days at home caring for children and maintaining the household; in these settings, the impact on this unpaid work is harder to determine.

It is of paramount importance to quantify and include productivity gains and the wider effects in analyses of impact for vaccines with only moderate efficacy, as calculated using traditional metrics. Vaccines such as the RTS,S/AS01 malaria vaccine, CYD-TDV dengue vaccine and rotavirus vaccine used in LMIC all have limited ability to broadly protect populations over a long duration but the public health benefits were important in vaccine implementation decisions in those countries ( Wilder-Smith et al., 2017 ). This suggests a paradigm for alternative regulatory requirements with a focus on public health outcomes ( Gessner et al., 2017 ).

Cost-Effective Preparedness for Outbreaks

As human populations grow and their use of the finite land resources increases, we are in increasingly close association with other living creatures, voluntarily or involuntarily. This interaction with natural reservoirs of potential infectious diseases increases the risk of zoonotic transmission of new infectious pathogens e.g., SARS, MERS-CoV, or known infectious pathogens with increased virulence e.g., influenza. Emerging infectious diseases disproportionately affect developing regions, where health infrastructure and surveillance are likely to be less well-established and robust. There were 1,307 epidemics of infectious diseases between 2011 and 2017, which cumulatively cost $60 billion annually to manage ( GHRF Commission, 2016 ). The unpredictability of outbreaks was highlighted by the Ebola epidemic in Western African countries of Liberia, Sierra Leone, and Guinea in 2014, which occurred in a period when public health was supposedly at its most advanced in recent history. However, a catalog of areas including: outbreak planning infrastructure; disease surveillance; local health services; escalation to international agencies were found to be lacking ( GHRF Commission, 2016 ). Although the WHO received criticism for its lack of escalation, in reality the global and interconnected infrastructure to prevent such epidemics taking lives and devastating societies is insufficient at the present time. The Zika virus epidemic in Latin America in 2015, first observed through an unexpectedly high incidence of microcephaly amongst newborns in Brazil’s northern regions ( Heukelbach et al., 2016 ), provide another example of how epidemics can have lasting impact, with the virus causing significant neurological damage to surviving infants ( Russo et al., 2017 ). The SARS-CoV-2 pandemic which began in 2019, was, at the time of writing, the largest infectious disease pandemic since the influenza pandemic of 1918/9. This global public health crisis highlighted stark societal inequalities persistent in many high-, middle- and low-income countries with direct and indirect impact on health outcomes from this infection. The cost-effectiveness of a vaccine in this setting was unquestionable, with economies and societies shut down for months in early 2020 and likely again in future. As it is not feasible or practical to be able to predict the location or nature of the next emerging threat, investment of an estimated $4.5 billion/year in healthcare systems could help speed up responses to infectious epidemics by prompt identification of the agent and effective control measures to limit the spread and consequences of disease ( GHRF Commission, 2016 ). The importance of this planning within the political landscape and the ongoing threat that infectious disease pose, may be appreciated more widely after 2020.

Establishing Programs for Vaccine Development

One effective infection control method is the use of vaccines in the course of an epidemic to halt transmission and to induce immunity to those as yet unaffected. The cost of vaccine development is a major challenge as there is little incentive for industry to invest in the design, testing and manufacture of vaccines that may never be needed, have a limited market, and, as previously eluded to, may be required in LMIC which cannot afford the upfront costs as an epidemic unfolds. The estimated costs for funding the development of infectious diseases vaccines for epidemics through phase 2a clinical trials are a minimum of $2.8-3.7 billion ( Gouglas et al., 2018 ). The CEPI alliance was established at the Davos World Economic Forum in 2017 as a global partnership between public, private and philanthropic organizations. In response to the conclusion that “a coordinated, international, and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemics,” CEPI have identified the most important known global infectious threats and invested in the development of vaccines, stockpiling, and policies to allow equitable access to these ( Plotkin, 2017 ). Further, the establishment of research and development infrastructure pipelines will allow production of suitable vaccine candidates within 16 weeks of identification of a new pathogen antigen. The broader aims including: improving global epidemic responses; capacity building; and global regulation of outbreak management strategies are also within the remit of CEPI’s work. It is these types of preparedness plans that assisted vaccine development and global health collaborations to address the COVID-19 pandemic, though many regions of high-, middle-, and low-income countries alike were slow or resistant to pre-empt and prepare for this type of infectious disease threat.

Social Benefits

Equity of healthcare.

As a result of the combined effects of poverty, malnutrition, poor hygiene and sanitation, overcrowding, discrimination and poorer access to health-care, the underprivileged in society are disproportionately afflicted by infectious diseases. Over the 20th century, it has become a moral standpoint and a human right for every individual to be provided with access to safe vaccines. The provision of vaccination as part of the EPI on a national and international scale ( World Health Assembly, 1974 ) acted as a great leveler to start reducing the impact of infectious diseases to all, regardless of other disadvantages. Over the 15 years of the EPI, the vaccine coverage in developing countries increased from 5% to ∼80% ( Levine and Robins-Browne, 2009 ). The EPI was revolutionary for its time, an ambitious public health program that aimed to improve children’s life chances despite the country and situation in which they were born. The administration of vaccines by UNICEF was deemed so important that there have been at least seven ceasefires in civil conflicts to allow this to happen ( Hotez, 2001 ).

The impact of vaccines on the inequity of those living in poverty is marked. A study of over 16,000 children during the phased introduction of the measles vaccine in Bangladesh in 1982, demonstrated improved health outcome equity when measured by under-5 mortality ( Bishai et al., 2003 ). Further, modeling of the impact of the rotavirus vaccine in India across social strata, which are closely aligned to wealth, suggested that the vaccine program would provide the poor with both health and financial benefits ( Verguet et al., 2013 ). Including such equity impact in the health economic modeling of vaccines would allow policy decisions to be targeted to the most vulnerable in society ( Riumallo-Herl et al., 2018 ). Additional cost-effective benefits observed after the implementation of combined public health initiatives ( Deogaonkar et al., 2012 ; Gessner et al., 2017 ) include provision of vaccines, facilitation of healthcare, reduction of indoor air pollution and improvement of nutrition to prevent childhood pneumonia ( Niessen et al., 2009 ).

Strengthening Health and Social Care Infrastructure

To provide the EPI universally to infants and children, a significant degree of healthcare infrastructure is required ranging from primary care to public health. An example of the multiple facets of a successful vaccine program were outlined in the Mission Indradhanush in India, which planned to make life-saving vaccines available to all children and pregnant women by 2020 through programs with (i) national, (ii) state, (iii) district, and (iv) block/urban level input ( Hinman and McKinlay, 2015 ). National programs require governments to provide financial resources and set out policy for implementation. States needed to obtain the vaccines and to store them appropriately whilst eligible children were identified through public health messaging and outreach. Districts and urban areas recruited staff trained in vaccine delivery and communication to administer vaccines and to provide the aftercare where required. Establishing this degree of nationwide infrastructure to reach those in urban and rural areas, provides the basis for the provision of other health and social care services for all members of the community, in particular improving maternal and infant mortality in developing regions and in the elderly in industrialized regions ( Shearley, 1999 ). Public health infrastructure and personnel could be used to promote other important messages and health education ( Shearley, 1999 ), relating to malnutrition, hygiene and sanitation and preventable diseases such as malaria and HIV infection. Global drivers are also key, as demonstrated by the establishment of the EPI in 1974, when all countries were directed to provide these vaccines, thereby developing their primary- and public health-care infrastructure, with benefit beyond the vaccine program. Vaccination contributes to the UN Millennium Development Goals and later Sustainable Development Goals for achievement by 2030. Gavi, the Vaccine Alliance, has been an important provider of funds, vaccines and support for countries whose gross national income per capita was <£1000/year ( Hinman and McKinlay, 2015 ). The partnerships forged through the development of vaccine programs in LMIC, can be long-lasting and beneficial through other health and social care endeavors ( Shearley, 1999 ).

Impact of Life Expectancy and Opportunity

Vaccination programs provide a degree of social mobility, as poverty and the associated ill-health and mortality from infectious diseases are no longer the determinants of one’s life chances. Vaccine recipients have the potential for improved life-expectancy largely demonstrated by, but not confined to, infants and children ( Andre et al., 2008 ). It has become increasingly recognized that an aging population goes through the process of immunosenescence ( Fulop et al., 2017 ), and increased incidence and severity of infectious diseases. In many countries, therefore, older people are offered vaccines to prevent infections with high mortality and morbidity, including the influenza, pneumococcal, herpes zoster, and pertussis vaccines ( Bonanni et al., 2015 ). These prevent the development of pneumonia, admission to hospital and the subsequent associated risks of death from cardiac failure, as observed in Sweden ( Christenson et al., 2004 ).

The global and interconnected world of the 21st century provides opportunity to discover new cultures, new environments and their resident microbes. The safety of global travel has been greatly enhanced by the availability of vaccines that provide protection against organisms that are different to those in a person’s home setting. Movement of people may be through necessity when fleeing war and conflict, in the search of better life opportunities, or for leisure purposes. For mass movements of refugees vaccines are crucial to the aid and relief efforts to support these individuals ( Hermans et al., 2017 ), as measles and cholera can be highly problematic in refugee camps. Global mass cultural or religious gatherings, such as the Hajj pilgrimage ( Yezli et al., 2018 ) or the Chinese New Year ( Chen et al., 2018 ) have been implicated in the spread of meningococcal disease outbreaks. Pre-travel vaccines offer the optimal level of protection for those with scheduled travel plans and include protection against: yellow fever, hepatitis A and B, rabies, Japanese encephalitis, tick-borne encephalitis, typhoid, and cholera.

Empowerment of Women

The empowerment of women is both a driver and effect of vaccination programs. The degree of education, literacy and independence of girls and women varies considerably across the world and within countries. Where women have the information and autonomy to make health-related decision for their children, childhood immunization rates improve. In a study in Bihar State in rural India involving an empowerment program, where participating women were educated about health and hygiene, there was a higher rate of DTP, measles and BCG vaccination in their children compared to the non-participants in the villages running the program ( Janssens, 2011 ). Further, this information and autonomy served to improve the rates of vaccination in children of non-participants in the villages running the program compared to control villages not running the education program, through social or formal ongoing dialogue within the village community. A separate public health initiative in Haryana, India conducted between 2005 and 2012 to reduce maternal and child health inequalities, involved improving access and provision of health resources to rural areas, the poor in society, women and children. One significant outcome of this initiative was the equitable provision of immunizations to girls and boys, despite the male-favored disparity prior to starting the public health initiative ( Gupta et al., 2016 ).

By improving infant and childhood mortality from infection, more children will survive to adulthood with the potential to have productive and healthy lives. This has led to healthy and economically secure women having fewer children and less peripartum morbidity and mortality ( Sah, 1991 ; Shearley, 1999 ). Thus, women are able to spend more time with their children and on their development ( Shearley, 1999 ) as well as their own education and contribution to the workforce. The strategy of maternal vaccination has demonstrated great success at preventing diseases that afflict infants too young to be vaccinated against pertussis, influenza and tetanus ( Marchant et al., 2017 ). Factors influencing the uptake of maternal vaccination include women’s previous experiences with healthcare and vaccines, so it is crucial to provide the access and support required to enable them to make informed choices during their pregnancy ( Wilson et al., 2019 ).

The impact of vaccines is broad and far-reaching, though not consistently quantifiable, analyzed or communicated. Traditionally, the perceived benefits of vaccination were to reduce morbidity and mortality from infections, and those remain the drivers for the innovation of new vaccines, in particular in preparation for outbreaks or against infections that afflict the most disadvantaged in society. However, an increasing appreciation for the economic and social effects of vaccines is being included in the development and assessment of vaccine programs, potentially realizing a greater benefit to society and resulting in wider implementation. There remain challenges to delivering vaccines to all children and vulnerable people worldwide, in particular those in communities that are difficult to reach geographically, politically and culturally and these challenges can only be overcome with the continued commitment and dedication to this endeavor on an international, national and individual scale.

Author Contributions

SP conceptualized and designed the study. CR prepared the manuscript and figures. CR and SP contributed to literature search and revision and review of the final manuscript. Both authors contributed to the article and approved the submitted version.

Conflict of Interest

SP consults for many major vaccine manufacturers and biotechnology companies but this article was unfunded.

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

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Keywords : immunization, vaccines, infectious diseases, infection, children, health economics

Citation: Rodrigues CMC and Plotkin SA (2020) Impact of Vaccines; Health, Economic and Social Perspectives. Front. Microbiol. 11:1526. doi: 10.3389/fmicb.2020.01526

Received: 09 April 2020; Accepted: 12 June 2020; Published: 14 July 2020.

Reviewed by:

Copyright © 2020 Rodrigues and Plotkin. 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: Stanley A. Plotkin, [email protected]

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.

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Importance of the COVID-19 Vaccine Booster Dose in Protection and Immunity

Alireza abdollahi.

1 Department of Pathology, School of Medicine, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran 1416634793, Iran

Yeganeh Afsharyzad

2 Department of Microbiology, Faculty of Modern Sciences, The Islamic Azad University of Tehran Medical Sciences, Tehran 1416634793, Iran

Atefeh Vaezi

3 Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran

Alipasha Meysamie

4 Department of Community Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran 1416634793, Iran

5 Community-Based Participatory Research Center, Iranian Institute for Reduction of High Risk Behaviors, Tehran University of Medical Sciences, Tehran 1416634793, Iran

Associated Data

All relevant data are available in the article.

Background: There is debate on the necessity of booster doses of COVID-19 vaccination, especially in countries with limited resources. Methods: This cross-sectional study was conducted in a referral laboratory in Tehran, Iran. The level of COVID-19 antibodies was measured and compared between individuals regarding the number of COVID-19 vaccine shots. Results: In this study, 176 individuals with a mean age of 36.3 (±11.7) years participated. A total of 112 individuals received two doses of the COVID-19 vaccine, and 64 individuals received three doses. Level of all antibodies was higher in those who received three doses than in those who received two doses of the COVID-19 vaccine. Considering the SARS-CoV-2 Spike IgG, the difference was not statistically significant but for the SARS-CoV-2 RBD IgG and SARS-CoV-2 NAB the difference was statistically significant. Regarding to the background variables, receiving influenza vaccine in the past year, history of autoimmune diseases and past medical history of chicken pox showed a significant association with the number of vaccine doses received. Their effects on the outcome variables assessed with multivariate logistic regression analysis. Conclusion: The results of our study show that a booster dose of the COVID-19 vaccine enhances the antibody response.

1. Introduction

The emergence of SARS-COV-2 in 2019 resulted in the COVID-19 pandemic and still involves countries [ 1 ]. About 30 months after the first case of COVID-19, about 551 million cases and 6.3 million deaths were reported globally [ 2 ]. Vaccination is the main promising strategy to return to everyday life in the fight against COVID-19. The level of vaccination varies in different countries. Some countries have begun to implement third and fourth doses, while others are still lagging behind. In Iran, 150 million doses of COVID-19 vaccines were administered by July 2022; about 77% of the population had at least one shot, 68.8% of the population was fully vaccinated, and only 32.7% received their booster dose [ 3 ].

COVID-19 vaccines have different platforms with different mechanisms of action, including nucleic acid, protein-based, viral-vector-based, inactivated virus, and live-attenuated virus platforms [ 4 ]. Vaccine-induced immunity against viral infections mainly relies upon neutralizing antibodies (NABs) along with cellular immunity induced by T-lymphocytes [ 5 ]. The fusion of the virus to the host cell is caused by the receptor binding protein (RBD), which is a part of the structure of the virus spike glycoprotein and is a good target for improving NABs [ 6 ].

All the approved COVID-19 vaccines reported to have an acceptable increase in the level of RBD-binding IgG and neutralizing antibodies in their phase I/II trials. In the trial of BNT162b1, geometric mean of NAB titer increased by 1.9–4.6-fold compared to COVID-19-infected patients; for RBD-binding IgG, the same increase was also documented [ 7 ]. ChAdOx1-S enhances the spike-specific T cell response and this enhancement is boosted after the second dose [ 8 ]. Anti-spike antibody increased after the first dose of mRNA-1273 and improved after the second dose; two months after the second dose, NAB was detected in all participants [ 9 ]. Seroconversion and elevated antibody levels were reported in more than 95% of participants in phases I and II of the BBIBP-CorV vaccine [ 10 ]. Regarding the rAd5-S/rAd26-S vaccine, seroconversion and cell-mediated response were detected in 100% of the participants [ 11 ].

From the public health perspective, herd immunity is the ultimate goal [ 12 ]. Still, there are some challenges, including the antigenic evolution of SARS-CoV-2 to escape immunity [ 13 ], the decrease in the level of infection/vaccine-induced protective antibodies over time [ 14 , 15 , 16 ], and also the necessity of booster doses regarding populations with limited access even to the first dose [ 17 , 18 ]. Hence, governments need to decide whether to mobilize the population to get booster shots or not. In this study, we tried to investigate the humoral response induced by the COVID-19 booster dose (regardless of the vaccine type) to help policymakers make evidence-informed decisions.

2. Materials and Methods

2.1. study design and participants.

This cross-sectional study was conducted in January 2022 in the laboratory of Imam Khomeini hospital, which is a referral hospital affiliated with the Tehran University of Medical Sciences, Tehran, Iran. Among those who were referred to the laboratory for any reason, COVID-19-vaccinated adults were enrolled using a convenience sampling method. This study was approved by the Ethics Committee of the Tehran University of Medical Sciences (IR.TUMS.Medicine.REC.1400.1297). Participants were informed about the aims of the study, and all voluntarily accepted the participation. All data were managed, analyzed, and reported anonymously, and all COVID-19 Ab tests were performed free of charge for the participants. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline was used to report the study results [ 19 ].

2.2. Demographics

Data on demographic variables such as age, gender (female, male), height, weight, body mass index (BMI), type of received vaccine for the first, second, and booster dose (BBIBP-CorV, rAd26-S/rAd5-S, Bharat Covaxin, ChAdOx1-S, BNT162b2, and CoVIran Barekat), comorbidities (mental health problems, cardiovascular diseases, respiratory disorders, autoimmune diseases, anemia, and diabetes), medications, history of previous infections (measles, influenza, and chicken pox), history of COVID-19 infection, and administration of influenza vaccine during the last year were gathered. Two groups were formed based on the number of COVID-19 vaccines doses received: the first group included individuals who had received two doses, and the second group who had received three doses.

2.3. Measurement of Antibodies

A venous blood sample of 5 mL was collected into an ethylenediaminetetraacetic acid-coated microtainer from all participants. Samples were centrifuged, and the serum was separated. The serum levels of SARS-CoV-2 spike IgG, SARS-CoV-2 RBD IgG, and SARS-CoV-2 NAB were evaluated using Pishtaz Teb-specific ELISA kits. The results were interpreted according to the references provided by the Pishtaz Teb company.

Pishtaz Teb ELISA kit (product code: PT-SARS-CoV-2 Spike IgG-96) was used to measure the level of SARS-CoV-2 spike IgG in the serum. The specificity and sensitivity of the kit are 99.01% and 98.16%, respectively. A concentration of ≥8 relative units per milliliter (RU/mL) is assumed as positive.

To measure the concentration of SARS-CoV-2 RBD IgG in blood samples, we used the Pishtaz Teb ELISA kit (product code: PT-SARS-CoV-2-RBD-IgG-96) with a specificity of 100% and a sensitivity of 97.1%. The concentration of ≥5 RU/mL is assumed to be positive.

For SARS-CoV-2 NAB, the level of NAB assessed using the Pishtaz Teb ELISA kit (product code: PT-SARS-CoV-2-Neutralizing-Ab-96). Based on the product brochure, antibody levels ≥ 2.5µg/mL are supposed to be a positive result.

2.4. Data Analysis

Data were analyzed using SPSS version 25 (IBM Corp., Armonk, NY, USA). A mean and standard deviation were used to describe continuous variables. A frequency table was used to present categorical variables. To compare continuous and categorical variables between groups, independent sample t -tests and chi-squared tests were used, respectively. Variables with statistically significant associations in univariate analysis were included in logistic regression analysis to control the confounding effects of background variables. The level of significance was set below 0.05.

In this cross-sectional study, 176 individuals (119(67.6%) female, 57(32.4%) male) who were referred to the laboratory of Imam Khomeini hospital were assessed. The mean (±SD) age of the study population was 36.3 (±11.7) years. The frequency of comorbidities was almost low in the study sample. Only four (2.3%) and two (1.1%) individuals reported cardiovascular and respiratory diseases, respectively and no one had a history of diabetes mellitus. Any history of an autoimmune disease was documented in three (1.7%) individuals. A history of COVID-19 infection was documented in 57.2% of the study population.

Considering COVID-19 vaccination, 112 individuals (63.6%) received two doses of the COVID-19 vaccine of any kind, and 64 individuals (36.4%) received three doses. Most of the study population (107(60.8%)) received BBIBP-CorV for the first dose. Other vaccines include BNT162b2 (1(0.6%)), ChAdOx1-S (12(6.8%)), rAd26-S/rAd5-S (25(14.2%)), CoVIran Barekat (10(5.7%)), and Bharat Covaxin (21(11.9%)). For the second dose, 108(62.4%) received BBIBP-CorV, 1(0.6%) received BNT162b2, 11(6.4%) received ChAdOx1-S, 24(13.9%) received rAd26-S/rAd5-S, 10(5.8%) received CoVIran Barekat, and 19(11.0%) received Bharat Covaxin. For the third dose, ten individuals (16.4%) received BBIBP-CorV, 51(83.6%) received ChAdOx1-S. Details are presented in Supplementary Table S1 .

Based on the number of the COVID-19 vaccine doses received, the sample population was categorized into two groups of two or three doses. The mean±SD of age was not statistically different between the two groups (36.8 ± 12.1 vs. 35.6 ± 11.0, p -value, 0.504). The frequency of the female gender was 64.3% and 73.4% in the groups that received two and three doses, respectively ( p -value, 0.212). There was no statistically significant difference in the distribution of comorbidities between the two groups except for autoimmune diseases. All three individuals with an autoimmune disease received three doses of the COVID-19 vaccine. Past medical history of COVID-19 infection was reported in 59 (52.6%) individuals with two doses and 40 (62.5%) individuals who received three doses ( p -value, 0.207). Past medical history of chicken pox and history of influenza vaccination in the past year differed between the two groups ( p -value, 0.004 and <0.001, respectively). Other variables are presented in Table 1 .

Baseline variables of the study population regarding the number of vaccine doses received.

Data is presented in number (percent) unless otherwise stated. BMI: body mass index; SD: standard deviation.

The serum levels of SARS-CoV-2 spike IgG, SARS-CoV-2 RBD IgG, and SARS-CoV-2 NAB were evaluated ( Table 2 and Table 3 ). More than 90% of the study population had positive levels of SARS-CoV-2 spike IgG (mean± SD, 68.5 ± 32.5). The frequency of positive spike IgG was higher in individuals who received three doses than in individuals with two doses, but it was not statistically significant (96.9% vs. 90.2%, respectively; OR, 3.4, 95% CI, 0.7–15.6; p -value, 0.137). Meanwhile, the level of spike IgG was higher in those who received three doses than in those who received two doses (82.8 ± 24.2 vs. 60.4 ± 33.8, respectively; p -value < 0.001).

Frequency of immune level of antibodies in groups of 2 and 3 doses of COVID-19 vaccine.

Data are presented in numbers (percentage). IgG: immunoglobulin G; NAB: neutralizing antibody; RBD: receptor binding domain.

The level of anti-SARS-CoV-2 antibodies regarding the number of received vaccine doses.

Data are presented as mean ± SD. IgG: immunoglobulin G; NAB: neutralizing antibody; RBD: receptor binding domain; RU/mL: relative units per milliliter; µg/mL: micrograms per milliliter.

The frequency of positive levels of RBD IgG and NAB was 81.3% and 75.0% in the whole sample, respectively. Administration of the third dose increased the frequency of the protective rate considering RBD IgG (OR, 7.5; 95% CI, 2.1–25.6; p -value < 0.001) and NAB (OR, 8.3; 95% CI, 2.8–24.3; p -value < 0.001). RBD AB increased significantly with the third dose of the COVID-19 vaccine (from 28.2 ± 25.6 to 51.0 ± 29.7, p -value < 0.001). The increase in NAB was also notable, from 23.9 ± 27.5 to 51.3 ± 24.1 ( p -value < 0.001). The serum level of SARS-CoV-2 Spike IgG, SARS-CoV-2 RBD IgG, and SARS-CoV-2 NAB are presented in Figure 1 .

Comparison of the serum level of antibodies in twice- and triple-vaccinated individuals.

To control the confounding variables in the prediction of positive levels of antibodies, age, gender, BMI, past medical history of autoimmune disease, past medical history of chicken pox, and past medical history of influenza vaccination, along with the number of COVID-19 vaccine dosages, have been entered into three separate logistic regression models. The result of the logistic regression for each antibody is presented in Table 4 .

Logistic regression analysis predicting the positivity of antibodies.

* The reference is receiving two doses of COVID-19 vaccine. ** The reference is a negative history. *** The reference is BMI < 25. IgG: immunoglobulin G; RBD: receptor binding domain; NAB: neutralizing antibody; BMI: body mass index.

In the logistic regression for the prediction of positive anti-spike antibody (Cox and Snell R squared, 0.1), as in the univariate analysis, the number of vaccine dosages was not associated with positive anti-spike antibody levels in the study population ( p -value, 0.066). Moreover, the association between age (OR, 1.08; 95% CI, 1.02–1.14; p -value, 0.005) and BMI (OR, 0.15; 95% CI, 0.02–0.84; p -value, 0.031) with the positive level of SARS-CoV-2 Spike IgG was statistically significant.

The positive level of SARS-CoV-2 RBD IgG showed a positive association with the number of COVID-19 vaccine dosages (OR, 2.27; 95%CI, 2.95–166.66; p -value, 0.003) and a negative association with a medical history of autoimmune disease (OR, 0.03; 95% CI, 0.00–0.77; p -value, 0.034) (Cox and Snell R squared, 0.134).

The association between the number of dosages with the frequency of protective SARS-CoV-2 NAB levels remained statistically significant (OR, 16.66; 95% CI, 3.84–100.00; p -value < 0.001) in multiple logistic regression analysis. Other variables showed no significant association (Cox and Snell R squared, 0.16).

4. Discussion

Although we are in the third year of the COVID-19 pandemic, there are still unanswered questions, especially regarding the COVID-19 vaccines. The level of protective antibodies, the role of heterologous vaccine regimens, and optimum dose intervals are still under question. A higher titer of antibodies is supposed to be associated with more extended and higher protection, especially against emerging COVID-19 variants [ 20 , 21 ]. No matter the type of COVID-19 vaccine administered, the waning of humoral responses is observed, especially in older adults, immunosuppressed individuals, and males [ 22 , 23 ]. Meanwhile, the willingness to receive a booster dose has decreased in communities, and “doubt on the necessity of further vaccination” is mentioned as the main reason [ 24 , 25 , 26 ].

The vaccine-induced immune response is strongly affected by host factors (age, gender, genetics, history of COVID-19 infection, and comorbidities) and vaccine factors (vaccine type, adjuvants, number of doses, and vaccination schedule) [ 27 , 28 , 29 ]. We examined the relationships of different factors as determinants of vaccine response, including age, gender, BMI, comorbidities, medications, history of measles, influenza, and chicken pox, history of COVID-19, administration of influenza vaccine in the past year, and the number of vaccine doses.

The results of our study, in line with other studies, showed that the number of doses is a significant determinant of antibody concentration [ 30 , 31 , 32 ]. Our study indicated that the level of SARS-CoV-2 spike IgG, SARS-CoV-2 RBD IgG, and SARS-CoV-2 NAB were significantly higher after the booster dose with about a 1.5–2-fold increase in their titer.

Age is a determinant of immunity response, as the production of antibodies decreases with age due to impairment in T-cells and maturation of B-cells [ 33 ]. However, the only antibody associated with age in our study was the SARS-CoV-2 Spike IgG. In contrast to our study, in a survey by Uysal et al., age had no statistically significant relationship with the titer of RBD antibody [ 34 ]. This contradiction could be explained by the time of antibody measurement, as the antibody level decreases over time, which could be apart from the effect of age on the antibody level. The results of a study by Levin et al. show that adults over 65 years old have lower levels of antibodies compared to younger adults [ 22 ]. In this study, the mean age of the participants was around 36 years old, and older adults did not participate, which could explain the difference in the association of age with the frequency of protective antibodies in our study with previous studies.

Immunosuppression is a determinant of antibody concentration after vaccination. The results of two studies by Boyarski et al. show an increase in immunity after the second dose in organ transplant receivers. Immunity is detected in 15% and 54% after the first and second doses, respectively [ 35 , 36 ]. The result of our study was in line with previous studies. In our study, having an autoimmune disease is negatively associated with positive levels of RBD IgG. In contrast, administering the third dose was positively associated with positive levels of RBD IgG. In organ transplant recipients and cancer patients, the levels of antibodies were boosted after the third dose [ 37 , 38 ]. In a study on a group of solid organ transplant recipients, about half of those who were seronegative after the second dose became seropositive after the third dose [ 39 ]. It has also been indicated that the odds of having a positive test and hospitalization decrease after three doses of the BNT162B2 vaccine compared to two doses [ 40 ].

Another determinant of vaccine-induced immunity is obesity, which is negatively associated with antibody concentration, and obese individuals are more at risk of breakthrough COVID-19 infection [ 41 ]. Individuals with a BMI of 25 or higher had a lower likelihood of having positive SARS-CoV-2 spike Ab.

There are some limitations to acknowledge in our study. First, we did not measure the period between the vaccine shot and antibody evaluation, so we cannot make a definite conclusion regarding the titer of antibodies. Second, due to our limited sample size, this study has no claim on the effectiveness of different vaccines. Third, we aim to investigate the level of humoral response at a particular point in time. Still, the lack of follow-up data, especially on clinical outcomes, could be mentioned as another limitation, and longitudinal studies are needed. Finally, the power of our models is not high enough. Therefore, there are other factors influencing the level of antibodies that are not included in our study.

5. Conclusions

Different variables are associated with the titer of protective antibodies induced by COVID-19 vaccines. In conclusion, the results of our study show that the booster dose of the COVID-19 vaccine is a strong determinant of positive SARS-CoV-2 RBD IgG and SARS-CoV-2 NAB, which best correlates with immunity.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/vaccines10101708/s1 , Table S1: The frequency of COVID-19 vaccine types received.

Funding Statement

This research was funded by the Tehran University of Medical Sciences.

Author Contributions

Conceptualization, A.A., Y.A. and A.M.; Data curation, A.M.; Formal analysis, Y.A., A.V. and A.M.; Investigation, Y.A., A.V. and A.M.; Methodology, A.M.; Project administration, A.M.; Software, Y.A.; Supervision, A.M.; Validation, A.A. and A.V.; Writing—original draft, Y.A. and A.V.; Writing—review & editing, A.A. and A.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Tehran University of Medical Sciences (IR.TUMS.Medicine.REC.1400.1297).

Informed Consent Statement

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COVID-19 vaccination coverage and its cognitive determinants among older adults in Shanghai, China, during the COVID-19 epidemic

Affiliations.

• 1 Department of Geriatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
• 2 Department of Global Health, School of Health, Georgetown University, Washington, DC, United States.
• 3 Department of Geriatrics, Shanghai Fourth People's Hospital Affiliated to Tongji University, Shanghai, China.
• 4 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
• PMID: 37333561
• PMCID: PMC10272832
• DOI: 10.3389/fpubh.2023.1163616

Objectives: This study aimed to examine the coverage of coronavirus disease 2019 (COVID-19) vaccination and its cognitive determinants among older adults.

Methods: A cross-sectional study was conducted using a questionnaire to conduct a survey among 725 Chinese older adults aged 60 years and above in June 2022, 2 months after the mass COVID-19 outbreak in Shanghai, China. The questionnaire covered demographic characteristics, COVID-19 vaccination status, internal risk perception, knowledge, and attitude toward the efficacy and safety of COVID-19 vaccines.

Results: The vaccination rate was 78.3% among the surveyed individuals. Self-reported reasons for unwillingness to get vaccinated (multiple selections) were "concerns about acute exacerbation of chronic diseases after vaccination (57.3%)" and "concerns regarding vaccine side effects (41.4%)." Compared to the unvaccinated group, the vaccinated group tended to have a higher score in internal risk perception ( t = 2.64, P < 0.05), better knowledge of COVID-19 vaccines ( t = 5.84, P < 0.05), and a more positive attitude toward the efficacy and safety of COVID-19 vaccines ( t = 7.92, P < 0.05). The path analysis showed that the cognitive effect on vaccination behavior is relatively large, followed by the internal risk perception, and then the attitude toward COVID-19 vaccines. The more knowledgeable the participants were about COVID-19 vaccines, the more likely they were to receive the COVID-19 vaccines. In the multivariate logistic regression, the increased coverage of COVID-19 vaccination was associated with reduced age (OR = 0.53 95% CI 0.43-0.66, P < 0.001), being a resident in other places than Shanghai (OR = 0.40, 95% CI 0.17-0.92, P < 0.05), a shorter time of lockdown (OR = 0.33, 95% CI 0.13-0.83, P < 0.05), a history of other vaccines (OR = 2.58, 95% CI 1.45-4.60, P < 0.01), a fewer number of chronic diseases (OR = 0.49, 95% CI 0.38-0.62, P < 0.001), better knowledge about COVID-19 vaccines (OR = 1.60, 95% CI 1.17-2.19, P < 0.01), and a positive attitude toward COVID-19 vaccines (OR = 9.22, 95% CI 4.69-18.09, P < 0.001).

Conclusion: Acquiring accurate knowledge and developing a positive attitude toward COVID-19 vaccines are important factors associated with COVID-19 vaccination. Disseminating informed information on COVID-19 vaccines and ensuring efficacious communication regarding their efficacy and safety would enhance awareness about COVID-19 vaccination among older adults and consequently boost their vaccination coverage.

Keywords: COVID-19; attitude; cognition; older adults; vaccine; vaccine hesitancy.

Copyright © 2023 Wei, Zeng, Huang, Ye, Chen, Yang and Cai.

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Conflict of interest statement

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.

Vaccination status among older adults…

Vaccination status among older adults (N = 725).

Reasons for willingness and unwillingness…

Reasons for willingness and unwillingness to get vaccinated.

Path analysis of vaccination with…

Path analysis of vaccination with internal risk perception, cognition, and attitude. ** P…

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