covid 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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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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Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults

Affiliations.

1 Thibodaux Regional Health System, Thibodaux, LA, USA. Electronic address: [email protected].
2 Unit of Innovation and Organization, Navarre Health Service, Spain. Electronic address: [email protected].
3 Institute of Evidence-Based Healthcare, Bond University, Gold Coast, QLD, Australia. Electronic address: [email protected].
4 Fielding School of Public Health and College of Letters and Science, University of California, Los Angeles, CA, USA. Electronic address: [email protected].
5 Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: [email protected].
6 Clinical Excellence Research Center, School of Medicine, Stanford University, CA, USA. Electronic address: [email protected].
7 School of Pharmacy, University of Maryland, Baltimore, MD, USA. Electronic address: [email protected].
PMID: 36055877
PMCID: PMC9428332
DOI: 10.1016/j.vaccine.2022.08.036

Introduction: In 2020, prior to COVID-19 vaccine rollout, the Brighton Collaboration created a priority list, endorsed by the World Health Organization, of potential adverse events relevant to COVID-19 vaccines. We adapted the Brighton Collaboration list to evaluate serious adverse events of special interest observed in mRNA COVID-19 vaccine trials.

Methods: Secondary analysis of serious adverse events reported in the placebo-controlled, phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 vaccines in adults ( NCT04368728 and NCT04470427 ), focusing analysis on Brighton Collaboration adverse events of special interest.

Results: Pfizer and Moderna mRNA COVID-19 vaccines were associated with an excess risk of serious adverse events of special interest of 10.1 and 15.1 per 10,000 vaccinated over placebo baselines of 17.6 and 42.2 (95 % CI -0.4 to 20.6 and -3.6 to 33.8), respectively. Combined, the mRNA vaccines were associated with an excess risk of serious adverse events of special interest of 12.5 per 10,000 vaccinated (95 % CI 2.1 to 22.9); risk ratio 1.43 (95 % CI 1.07 to 1.92). The Pfizer trial exhibited a 36 % higher risk of serious adverse events in the vaccine group; risk difference 18.0 per 10,000 vaccinated (95 % CI 1.2 to 34.9); risk ratio 1.36 (95 % CI 1.02 to 1.83). The Moderna trial exhibited a 6 % higher risk of serious adverse events in the vaccine group: risk difference 7.1 per 10,000 (95 % CI -23.2 to 37.4); risk ratio 1.06 (95 % CI 0.84 to 1.33). Combined, there was a 16 % higher risk of serious adverse events in mRNA vaccine recipients: risk difference 13.2 (95 % CI -3.2 to 29.6); risk ratio 1.16 (95 % CI 0.97 to 1.39).

Discussion: The excess risk of serious adverse events found in our study points to the need for formal harm-benefit analyses, particularly those that are stratified according to risk of serious COVID-19 outcomes. These analyses will require public release of participant level datasets.

Keywords: Adverse events of special interest; Brighton Collaboration; COVID-19; COVID-19 vaccines; Coalition for Epidemic Preparedness Innovations; Moderna COVID-19 vaccine mRNA-1273; NCT04368728 ; NCT04470427 ; Pfizer-BioNTech COVID-19 vaccine BNT162b2; SARS-CoV-2; Safety Platform for Emergency vACcines; Serious adverse events; Vaccines; mRNA vaccines.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Serious adverse events following mRNA vaccination in randomized trials in adults. Black S, Evans S. Black S, et al. Vaccine. 2023 May 26;41(23):3473-3474. doi: 10.1016/j.vaccine.2023.04.040. Epub 2023 Apr 28. Vaccine. 2023. PMID: 37121802 No abstract available.

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ORIGINAL RESEARCH article

Covid-19 vaccination hesitance and adverse effects among us adults: a longitudinal cohort study.

$\r\nM. Abdelmasseh,$

1 Department of Surgery, Marshall University School of Medicine, Huntington, WV, United States
2 Marshall Institute for Interdisciplinary Research (MIIR), Marshall University, Huntington, WV, United States
3 Department of Informatics and Biostatistics, Marshall University School of Medicine, Huntington, WV, United States

Introduction: Although Coronavirus disease 2019 (COVID-19) vaccination is critical to control its spread, vaccine hesitancy varies significantly among the United States population; moreover, some vaccine recipients experienced various adverse effects. We aim to assess the impact of COVID-19 vaccine hesitancy in a university-affiliated community, the factors affecting participants’ decisions, and their adverse effects.

Methods: A pre-vaccination online Institutional Review Board IRB-approved survey was emailed in Nov/Dec 2020, 2 months before the implementation of state-policy protocols for COVID-19 vaccination. A post-vaccination survey was emailed in May/June 2021, two months after protocol execution. A third follow-up survey was sent in Nov/Dec 2021, and a fourth was sent in June/July 2022. The study population included three groups of adult participants: university students, faculty, and staff-(MS), university health system patients-(MP), and Cancer Center patients-(MCP). The study was designed as a longitudinal cohort study. Statistical analyses were performed using SPSS.

Results: With a combined response rate of 26% (40,578/157,292) among the four surveys, 15,361 participants completed the first survey (MS = 4,983, MP = 9,551, and MCP = 827). 2/3 of participants (63.5%) were willing to get vaccinated, with a significant difference in acceptance among groups, MS:56.6%, MP:66.2%, and MCP:71.6% ( p < 0.05). Vaccine acceptance rates reached 89% in the second survey after the vaccine's approval, with a lower acceptance rate of MS:84.6% than with MP:90.74% and MCP:92.47% participants ( p < 0.05). Safety and effectiveness concerns were the main factors affecting participants’ decisions in all the first three surveys; however, participants reported these concerns decreased between pre-vaccination, post-vaccination, and follow-up surveys with 87%, 56%, and 46%, respectively( p < 0.05). More than two-thirds of the participants (70%) reported having either minor/moderate symptoms (61.6%) or major symptoms (8.6%) after getting some of the vaccine doses ( p < 0.05).

Conclusion: The hesitance of COVID-19 vaccination was associated with concerns regarding its safety and efficacy. Vaccine acceptance rose higher than expected after protocol execution, likely due to continuous education, whereas safety and efficacy remain factors hindering vaccine acceptance. Continuous education focusing on safety and efficacy of the vaccine can reduce vaccine hesitancy and raise the rates of vaccination.

Introduction

The COVID-19 (Coronavirus disease 2019) pandemic has impacted nearly every country, infected around 775 million people, and has surpassed 7 million deaths worldwide ( 1 ). The Global and United States (US) economies have been heavily affected by a viral disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV2), overwhelming healthcare facilities ( 2 , 3 ). Despite the Centers for Disease Control and Prevention (CDC) guidelines from medical experts and healthcare advisors, the preventive measures of wearing face masks, washing hands frequently, and keeping social distancing ( 4 ) have not rescinded the spread of SARS-COV2 throughout the world. With the emergence of new and more contagious variants such as Delta and Omicron, the spread of infection was reaching unprecedented rates worldwide ( 5 – 9 ). The need to raise the vaccination acceptance rates is always important to control infections and relieve the pandemic's burden.

From the initial reported infection of COVID-19 in early December 2019, it took a full year for the world to develop the first vaccine, which was achieved in December 2020 ( 10 ). The United Kingdom was the first country to grant emergency authorization for the public administration of the mRNA-based vaccine, followed by the United States ( 11 , 12 ). The United States Food and Drug Administration (US FDA) authorized the Pfizer-BioNTech COVID-19 vaccine for children aged 12–15 by May 2021. In addition, the US FDA gave the vaccine full authorization in August 2021 ( 13 ). Moreover, in October 2021, the US FDA approved vaccinations for children five years or older ( 14 ). More than 14 billion doses of the vaccine were administered worldwide; however, only 70.6% of the world population has received at least one dose of a COVID-19 vaccine. In the US, more than 712 million doses were administered, and nearly 70% of the population were vaccinated with a complete primary series of COVID-19 vaccination ( 10 , 15 ). Governments and industries have come together to overcome the unprecedented challenges of massive distribution logistics. Nevertheless, health policymakers, scientists, and providers are still facing an uphill battle with strategies to increase acceptance of the COVID-19 vaccine, mainly when some vaccine recipients reported experiencing adverse effects post-vaccination. However, adverse event rates were reported more in their phase 3 trials ( 16 ), increasing the challenges that improving vaccination rates may face.

Since the conception of the world's first vaccine for smallpox in 1798 ( 17 , 18 ), an evolution in the movement of acceptance vs. hesitancy has grown based on vaccine safety and efficacy and its inherent adverse effects ( 19 , 20 ). In 2015, a group of experts from the World Health Organization (WHO) defined “vaccine hesitancy” as the delay in acceptance or refusal of vaccination despite vaccination services’ availability ( 21 ). In 2019, vaccine hesitancy was ranked as one of the top ten threats to global health ( 22 ). Vaccine hesitancy and uncertainty have become significant hurdles for reaching desirable societal immunity against targeted diseases in many countries ( 23 , 24 ). In cooperation with policymakers and other stakeholders, governments and health societies are required to improve the process of providing the necessary information about the vaccine and enhance the understanding and importance of immunization to reach the immunity of the community. The present study aimed to assess the COVID-19 vaccination acceptance and hesitance rates and the factors impacting people's decisions regarding vaccination, besides evaluating the adverse effects participants might have experienced post-vaccination.

Materials and methods

Study design.

The study was designed as a longitudinal cohort study over two years. A pre-vaccination online survey was developed by (Qualtrics® Services), linked to the participants’ emails, and sent upon Institutional Review Board (IRB) approval. The survey was emailed ( Supplementary Appendix 1 ) in Nov/Dec 2020, 2-months before state-policy protocols implementation for COVID-19 vaccine administration. It intended to determine the participants’ acceptance of vaccination. A second post-vaccination survey was emailed ( Supplementary Appendix 2 ) in May/June 2021, 2-months after protocols were executed. The post-vaccination survey was sent weekly with a one-month enrollment period to determine the actual vaccination rates. A third follow-up survey was emailed ( Supplementary Appendix 3 ) in Nov/Dec 2021, 5-months after the second survey. It aimed to determine the reasons affecting participants’ decisions on whether they changed their minds before and after vaccine approval. A fourth and final survey ( Supplementary Appendix 4 ) was sent in June/July 2022 to define adverse events participants may have experienced.

Study population

Individual emails were gathered from a central University and Health System warehouse and divided into three groups: (i) University faculty, students, and staff (University Students and Staff/MS); (ii) University School of Medicine affiliated Health System registered patients (General Patients/MP), and (iii) University School of Medicine affiliated Comprehensive Cancer Center registered cancer patients (Cancer Patients/MCP). An individual survey was sent weekly for three weeks with a one-month enrollment period. The software identified duplicates in each survey, which were deleted so that one individual had only one response to each of the four surveys.

The surveys were anonymous to the study team but had a unique IP address. The number of questions ranged from six questions in the first survey, seven to nine questions in the second, eight to ten in the third survey, and fourteen to twenty-three in the fourth (see Supplementary Appendix 1–S4 ). Each survey contained demographic questions about gender/sex, ethnicity/race, education level, and age category. Tacit consent was given by moving forward from the introductory survey page.

Statistical analysis

All variables were categorical and described as frequencies and percentages. For predictor variables, we generally used gender, age category, ethnicity, and education and occasionally included trusted sources of information or vaccine type. Outcome variables varied for each survey (i.e., Survey 1—the outcome is whether the respondent will get vaccinated, Survey 2—the outcome is whether the respondent received at least one dose of a vaccine, Survey 3—the outcome is whether the respondent changed their mind about getting vaccinated, Survey 4—the outcome is whether the respondent experienced side effects/symptoms following any of the vaccine doses they received).

Univariate and Multivariate analyses were performed using ordinal and binomial logistic regressions. Area under the curve (AUC) analyses of receiver operating characteristic (ROC) curves were examined for the logistic regression models to determine prediction accuracy. Results were expressed in terms of probability ( p < 0.05) and odds ratio estimates with 95% confidence intervals. For logistic regressions, the p -value measures the statistical significance of the estimated coefficients for the predictor variables and tests the null hypothesis that there is no relationship between that predictor and the outcome variables (i.e., the parameter coefficient is equal to 0). Statistical analyses were performed using SPSS version 28 (SPSS-IBM Inc., Chicago, IL, USA).

Out of the 157,292 surveys distributed to all participants, the response rate exhibited considerable variations across the four surveys. The first survey achieved a response rate of 10% ( n = 15,361), the second survey 7.3% ( n = 11,539), and both the third and fourth surveys 4.3% ( n = 6,902 and n = 6,776, respectively). Notably, significant differences in response rates among participant groups were observed for each survey ( Supplementary Table S1 ). While the response rate was higher in the MS group (27.4% and 10.5% for the first and fourth surveys, respectively), the MP group showed lower response rates (7.5% and 2.7%). As expected, participants’ demographics differed among groups and by survey ( Table 1 ). The MS group was younger when compared to the MP and the MCP groups ( p < 0.05). The education degree was lower in the MS group compared to the MP and MCP groups ( p < 0.05). In contrast, the sex distribution at a ratio of 3♀:2♂ among groups was similar for the four surveys. Most of the responders were white, with some diversity in the MS group ( p < 0.05).

Table 1 Participants’ demographic distribution from survey 1(Pre-vaccination), Survey 2 (post-vaccination), Survey 3 (follow-up), and Survey 4 (Side effects).

The participant proportion willing to get vaccinated upon the vaccine's approval was 63.5%, ranging from 56.6% in the MS group to 66.2% and 71.6% in the MP and MCP groups, respectively (MS vs. MP and MCP, p < 0.05). Vaccine acceptance rates for each group were higher, reaching 88.6% (85%, 90.3%%, and 92.5% for MS, MP, and MCP groups, respectively) after the vaccine's approval by the FDA. The follow-up survey (survey 3) indicated that 17.2% of the participants accepted vaccination after initially refusing it. Participants reported health workers, family, and friends as the main trusted sources influencing their decisions ( Supplementary Figure S1 ). Safety and efficacy concerns were the main factors affecting participants’ decisions in all three surveys: pre-vaccination (survey 1, 87%), post-vaccination (survey 2, 56%), and follow-up (survey 3, 46%, Figure 1 , p < 0.05).

Figure 1 Factors affecting COVID-19 vaccination hesitance in survey 1 (Pre-vaccination), survey 2 (post-vaccination), and survey 3 (follow-up). Safety and efficacy concerns were the main factors affecting participants’ decisions in all three surveys: pre-vaccination (87%), post-vaccination (56%), and follow-up surveys (46%, p < 0.05).

Most participants (70%) reported an adverse event from vaccination, and one out of 10 sought medical evaluation. Minor/moderate symptoms (61.6%) consisted of tiredness/fatigue and pain at the site of injection, observed more frequently after the second dose (36.1% and 28.8% for the tiredness/fatigue and pain at the site of injection, respectively). Major symptoms (8.6%) included anxiety and high-grade fever, which were the most reported after vaccination, mainly also after the second dose (3.9% and 3.7% for anxiety and high-grade fever, respectively, Table 2 ).

Table 2 Participants’ adverse events after any dose of an approved COVID-19 vaccine.

Univariate and multivariate analyses were performed to determine the factors associated with vaccine hesitance before and after vaccination ( Figure 2 ). On multivariate analyses, age (>44 years old), race (white), gender, and education (bachelor's degree or higher) were factors that statistically held a significant association with participants’ vaccine acceptance prior to vaccination ( p < 0.05). After vaccination, age (> 34 years old) and level of education (bachelor's degree or higher) remained significant ( p < 0.01). In contrast, age and trusted source were the only factors significantly associated with the change of mind for vaccine hesitance ( p < 0.05). Both univariate and multivariate analyses showed that age, gender, level of education, and the type of the vaccine were statistically significant in predicting the adverse events that the participants experienced after any dose ( Supplementary Table S2 , p < 0.01).

Figure 2 The odds ratio using multivariate analyses for the variables affecting the COVID-19 vaccination hesitance and side effects in the four consecutive surveys: survey 1 (Pre-vaccination), Survey 2 (post-vaccination), Survey 3 (follow-up), and Survey 4 (adverse events).

The need for an effective and safe vaccine to relieve the pandemic's burden of COVID-19 infection has proven to be persistent, especially with frequent virus mutations. The present study focuses on the status of vaccine acceptance among US adults, factors associated with hesitancy and their decisions, and vaccine adverse events. To the best of our knowledge, this study represents one of the largest of its kind to assess COVID-19 vaccination hesitancy. Overall, two-thirds of the study population were willing to get vaccinated, and their main concerns were the safety and efficacy of the vaccine; the percentage increased from 64% to 89% after the vaccine's approval. Moreover, around 17% of the participants eventually changed their minds and accepted the vaccines. Nevertheless, 70% of the participants reported, mainly after the second dose, either minor to moderate symptoms (61.6%) or major symptoms (8.6%) after getting vaccinated.

Prior studies showed the COVID-19 vaccine hesitance as a real impediment to achieving the immunity required to reach herd immunity ( 25 – 27 ). A global survey from 19 countries ( n = 13,426) showed a pre-vaccination acceptance rate of 71.5% ( 28 ). Nonetheless, the study was skewed from outlier higher rates from two Asian countries (in the range of 85%), which also recorded very high trust in government health recommendations. A study of American US adults ( n = 1,056) showed a lower acceptance rate (49%) ( 29 ). The hesitance to vaccination varied significantly depending on the other populations surveyed (50%–73%) ( 30 – 32 ).

Concerns with the vaccines pre- and post-approval were similar: safety and efficacy. Although the safety and efficacy profiles were proved to be favorable for most of the vaccines ( 33 – 35 ) and against recent variants ( 36 , 37 ), adverse events varied in rate and severity among different populations ( 38 – 40 ). Most of the adverse events reported were mild to moderate (the most common were pain at the injection site, fatigue, and headache) ( 41 , 42 ). Our study concurred with the published literature. Previous studies also showed that healthcare workers were the most trusted source of information regarding COVID-19 vaccines. People tend to trust their healthcare providers rather than the media. Our study proved similar results where nearly half of the participants reported trusting the health workers as their primary source of information.

Although studies have shown a solid scientific base for the needed increase in vaccination rate, substantial efforts are essential by governments and public health officials to enhance vaccine acceptance. Approaching some of the factors that play into the individual decision may pave the way for a paucity of vaccine hesitance. The present study found a significant association between COVID-19 vaccine acceptance and age, gender, race, and education level. While age, gender, and race were variables with no room for modification, general education on public media may dissipate community concerns about the safety and efficacy of the COVID-19 vaccine. Processes and results shown in an easily interpretable and transparent manner may go a long way in trust. A clear and logical approach to actual, theoretical, and fictional implications of an RNA-based vaccine will mitigate differences between those who accept and those who refuse vaccination, avoiding confusion from contradictory facts, especially in the presence of an intense media-originated by anti-vaccination activists ( 43 ).

The present study represents the largest in the US to assess COVID-19 vaccination acceptance, with a combined 40,578 responses. Even though there was a low response rate, the study had an adequate sample size; however, race predominance is a limitation to the interpretation and extrapolation of the findings. Moreover, our surveys were sent electronically through email to the participants, which excluded those who didn't have access to emails. In addition, self-reported data are subject to a potential lack of validity and reliability as they may be affected by different biases.

The present study is intended to provide a comprehensive image of the COVID-19 vaccines, assess their acceptance, identify factors that are associated with the individual decisions in the US, and assess their safety outcomes. A low vaccine acceptance rate was associated with a high degree of concern (89%) regarding its efficacy and safety before the vaccines’ approval. Nevertheless, vaccine acceptance rose higher than expected after protocol execution, likely due to continuous education. Safety and efficacy remain factors hindering vaccine acceptance. Most of the reported vaccine adverse events were mild to moderate, with minimal need for medical consulting. Continuous education concerning the importance of vaccination, along with discussing and proving the vaccine's safety and efficacy, can be the main tools to decrease the rates of vaccine hesitancy.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Marshall University Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. Tacit consent was given online by moving forward from the introductory survey page.

Author contributions

MA: Visualization, Validation, Software, Resources, Project administration, Methodology, Formal Analysis, Data curation, Writing – review & editing, Writing – original draft, Investigation, Conceptualization. AC: Writing – review & editing, Writing – original draft, Validation, Software, Methodology, Data curation. AI: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Conceptualization. VK: Writing – review & editing, Writing – original draft, Validation, Resources, Methodology, Data curation, Conceptualization. JW: Writing – review & editing, Writing – original draft, Validation, Resources, Methodology, Investigation, Data curation, Conceptualization. AG: Writing – review & editing, Writing – original draft, Validation, Methodology, Formal Analysis, Data curation. ET: Writing – review & editing, Writing – original draft, Visualization, Resources, Methodology, Investigation, Conceptualization. RF: Writing – review & editing, Writing – original draft, Visualization, Resources, Methodology, Investigation, Conceptualization. BP: Writing – review & editing, Writing – original draft, Visualization, Resources, Methodology, Investigation, Conceptualization. JS: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Data curation, Conceptualization.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

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

Publisher's note

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

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fepid.2024.1365090/full#supplementary-material

Abbreviations

COVID-19, Coronavirus disease 2019; SARS-COV2, severe acute respiratory syndrome coronavirus 2; CDC, Centers for Disease Control and Prevention; RNA, Ribonucleic acid; mRNA, Messenger Ribonucleic acid; WHO, World Health Organization; IRB, Institutional Review Board; MS, University faculty, students, and staff study group; MP, University School of Medicine affiliated Health System registered patients study group; MCP, University School of Medicine affiliated Comprehensive Cancer Center registered cancer patients study group; FDA, US Food and Drug Administration.

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Keywords: COVID-19, SARS-COV2, vaccine, survey, hesitancy, pandemic, adverse events

Citation: Abdelmasseh M, Cuaranta A, Iqbal A, Kadiyala V, Willis J, Gorka A, Thompson E, Finley R, Payne B and Sanabria J (2024) COVID-19 vaccination hesitance and adverse effects among US adults: a longitudinal cohort study. Front. Epidemiol. 4 : 1365090. doi: 10.3389/fepid.2024.1365090

Received: 3 January 2024; Accepted: 1 July 2024; Published: 16 July 2024.

Reviewed by:

© 2024 Abdelmasseh, Cuaranta, Iqbal, Kadiyala, Willis, Gorka, Thompson, Finley, Payne and Sanabria. 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: J. Sanabria, [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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Safety, immunogenicity, and effectiveness of chinese-made covid-19 vaccines in the real world: an interim report of a living systematic review.

1. Introduction

2. materials and methods, 2.1. search strategy and selection criteria, 2.2. review strategy, 2.3. data extraction and analytical strategy, 2.4. statistical analysis, 4.1. selection and characteristics of the studies, 4.2. safety, 4.3. immunogenicity, 4.4. effectiveness, 5. discussion, 6. limitations, 7. conclusions, supplementary materials, author contributions, acknowledgments, conflicts of interest.

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Click here to enlarge figure

Characteristics	Number of Studies (%) (n = 213)

2021	83 (39.0)
2022	130 (61.0)

Peer-reviewed, Chinese	2 (0.9)
Peer-reviewed, English	189 (88.7)
Preprint	22 (10.4)

Case report	71 (33.3)
Case serials	14 (6.6)
Cross-sectional study	52 (24.4)
Case–control study	15 (7.0)
Cohort study	52 (24.4)
Clinical trials	9 (4.2)

Safety	170 (79.8)
Neutralization titers	21 (9.7)
Effectiveness	33 (15.5)

Africa	0 (0)
Americas	40 (18.8)
Eastern Mediterranean	39 (18.4)
Europe	48 (22.5)
Southeast Asia	26 (12.2)
Western Pacific	60 (28.1)

High	121 (56.8)
Medium	56 (26.3)
lLw	36 (16.9)

Potential Impact Factor	OR (%, 95% CI)	p Value
Death as the endpoint (9 studies, 16 estimates)
	1.34 (0.08, 22.89)	0.8402
	9.70 (0.44, 212.51)	0.1491
<3 weeks (Ref.)
≥3 weeks	0.66 (0.11, 4.09)	0.6586
	1.05 (0.03, 35.98)	0.9771

Primary vaccination (Ref.)	-	-
Homologous booster vaccination	0.08 (0.01, 0.48)	0.0054
	2.32 (0.27, 19.89)	0.4412

Before delta (Ref.)	-	-
Delta contained	1.58 (0.01, 191.25)	0.8522
Omicron	1.35 (0.04, 40.85)	0.8633
Severe disease as the endpoint (12 studies, 21 estimates)
	1.44 (0.71, 2.91)	0.3123

<3 weeks (Ref.)	NA
≥3 weeks	NA
	NA	NA

Primary vaccination (Ref.)	-	-
Homologous booster vaccination	0.26 (0.07, 0.95)	0.0417
	1.62 (0.34, 7.73)	0.5437

Before delta (Ref.)	-	-
Delta contained	0.65 (0.11, 3.62)	0.6186
Omicron	0.53 (0.1, 2.96)	0.4706

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Share and Cite

Qi, Y.; Zheng, H.; Wang, J.; Chen, Y.; Guo, X.; Li, Z.; Zhang, W.; Zhou, J.; Wang, S.; Lin, B.; et al. Safety, Immunogenicity, and Effectiveness of Chinese-Made COVID-19 Vaccines in the Real World: An Interim Report of a Living Systematic Review. Vaccines 2024 , 12 , 781. https://doi.org/10.3390/vaccines12070781

Qi Y, Zheng H, Wang J, Chen Y, Guo X, Li Z, Zhang W, Zhou J, Wang S, Lin B, et al. Safety, Immunogenicity, and Effectiveness of Chinese-Made COVID-19 Vaccines in the Real World: An Interim Report of a Living Systematic Review. Vaccines . 2024; 12(7):781. https://doi.org/10.3390/vaccines12070781

Qi, Yangyang, Hui Zheng, Jinxia Wang, Yani Chen, Xu Guo, Zheng Li, Wei Zhang, Jiajia Zhou, Songmei Wang, Boyi Lin, and et al. 2024. "Safety, Immunogenicity, and Effectiveness of Chinese-Made COVID-19 Vaccines in the Real World: An Interim Report of a Living Systematic Review" Vaccines 12, no. 7: 781. https://doi.org/10.3390/vaccines12070781

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Efficacy of COVID-19 vaccines: From clinical trials to real life

Dominique deplanque.

a Université de Lille, Inserm, CHU Lille, CIC 1403 – Clinical Investigation Center, 59000 Lille, France.

b F-CRIN IREIVAC/COVIREIVAC, 75679 Paris, France

Odile Launay

c Université de Paris, Inserm CIC 1417, Assistance publique – Hôpitaux de Paris, hôpital Cochin, 75679 Paris, France

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the globe leading to the COVID-19 pandemic. To mitigate the effects of the virus on public health and the global economy, vaccines were rapidly developed. In less than one year, with respect to usual clinical development rules, several vaccines have been put on the market and mass vaccination campaigns have been deployed. During the phase I to phase III clinical trials, most of these vaccines have demonstrated both their safety and efficacy. Despite questions remain about the impact of virus variants and the duration of the immune response, messenger RNA (mRNA)-based and adenoviral vectored vaccines have demonstrated an overall efficacy from 70 to 95% in both phase III trials and real life. In addition, all these vaccines also reduce the severe forms of the disease and might strongly impact the mortality which could change the course of the pandemic.

Abbreviations

Introduction.

Since December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread around the globe leading to the Coronavirus Disease 2019 (COVID-19) pandemic. From January 2020 to the beginning of second quarter of 2021, the intensity and rapidity of SARS-CoV-2 transmission have led to about 150,000,000 cases and more than 3,000,000 deaths in the world putting considerable pressure on public health systems and the global economy. In the context of extraordinary scientific and technical mobilization, the genetic sequence of SARS-CoV-2 was published on January 11 th 2020, triggering intense global Research and Development (R&D) activity to develop a vaccine against this disease. To date, World Health Organization (WHO) lists about 200 vaccine candidates in preclinical development, 100 in clinical evaluation and 13 received authorization [1] .

In Europe, 4 vaccines have already been authorized by the European Medicines Agency (EMA) and several mass vaccination campaigns are also underway worldwide. These rapid developments have been made possible by the important contribution of both public and private funding, high level of volunteers’ participation in clinical trials as well as by changes in the review process of regulatory agencies [2] . On the other hand, the success of messenger RNA (mRNA) vaccine platform is probably the consequence of previous researches for more than 15 years and their previous identification as vaccine platform of choice for emerging infectious diseases [3] . Since the mechanisms of action and undesirable effects of these vaccines are addressed in other articles of this special issue, we will focus on the efficacy of coronavirus disease 2019 (COVID-19) vaccines, more particularly on the four vaccines already available in Europe.

COVID-19 vaccine development: an unprecedented timeframe

In the last decade, there was a marked evolution of vaccine platforms including the development of nucleic acid-based vaccine candidates and vectored vaccines, a number of approaches that have been used to accelerate COVID-19 vaccines elaboration. Moreover, previous preclinical data from vaccine candidates for SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) enabled the initial step of exploratory vaccine design to be largely overlooked, saving a considerable amount of time. In most cases, production processes were also adapted from those of existing vaccines [2] .

As a result, a first phase I clinical trial of a vaccine candidate for SARS-CoV-2 began in March 2020 testing the mRNA 1273 (Moderna) [4] . In April 2020, another phase I trial testing different sequences of the mRNA BNT 162 (BioNTech/Pfizer) has also begun [5] then followed by adenovirus vectored vaccines, in June and July 2020, respectively ChAdOx1nCov-19 (AstraZeneca/Oxford) and Ad26COVS1 (Janssen) [6] , [7] . One important particularity of this period was that clinical phases were overlapping and trial starts were staggered, with initial phase I/II trials followed by fast progression to phase III trials mainly considering interim analysis of the phase I/II data. Most of the manufacturers had also rapidly started the large-scale commercial production of vaccines despite the absence of any result from phase III trials [2] .

Finally, both Food and Drug Administration (FDA) and EMA implemented a rolling review process, which means that a drug company can submit completed sections of its new drug application for review, rather than waiting until every section of the application is completed before the entire application can be reviewed. Beyond these exceptional adaptations, one of the key factors of the accelerated development of COVID-19 vaccines was financial risk-taking that was greatly sustained by public funds, namely in Germany, UK and USA. Nonetheless, it should be underlined that despite these financial considerations but also the pandemic-associated emergency, no concession was made on safety.

Phase I/II clinical trials: safety and immunogenicity analysis

While phase I trials are usually designed to determine the safety profile at several dosages of a drug candidate, in the field of vaccines, the immunogenicity as a marker of drug-response is also evaluated. Indeed, this evaluation constitutes an essential step in the construction of future trials. In this context, phase II trials are intended to more precisely evaluate immunogenicity in relation to dose regimen in the way to determine the final dose to use in phase III trials. Here, most of the published studies were combined phase I/II trials aiming to determine safety and immunogenicity including the effect of a second vaccine dose according to different dosages and intervals [4] , [5] , [6] , [7] , [8] .

Phase I studies usually recruited a low number of subjects but during the early development of COVID-19 vaccines at least one study reported here included about 200 volunteers [5] and according to a phase II design, another study included more than 500 subjects [6] . Such an important recruitment clearly helped to provide stronger results and has probably facilitated the design of phase III studies. This large number of subjects also allowed to strengthen the excellent results about safety profile of these vaccine candidates whatever the platform used namely mRNA or adenoviral vector [4] , [5] , [6] , [7] , [8] .

As summarized in Table 1 , all the vaccine candidates reported here were able to induce an immune response against the spike protein of the SARS-CoV-2. Thus, there was a clear dose- or time-dependent increased in both specific Ig-G and neutralizing antibody titers ( Table 1 ) which are enhanced by the second dose of vaccine [4] , [5] , [6] , [7] , [8] . Some differences regarding Ig-G and neutralizing antibody titers may be discussed between these vaccines but it is important to point out that the assays used to perform these measures vary greatly and then comparisons must be made with caution. Nevertheless, an increase in specific Ig-G and neutralizing antibody titers has been shown in 90 to 100% of subjects while cellular responses were also observed. The phase I study on Ad26COVS1 vaccine also brings more details about immune response by analyzing the binding and functional profiles of vaccine-elicited antibodies by systems serology analyses. It was then showed the induction of S- and RBD-specific IgA1, IgA2, IgG1, IgG2, IgG3, IgG4, and IgM subclasses; FcγR2a, FcγR2b, FcγR3a, and FcγR3b binding; antibody-dependent complement deposition, antibody-dependent neutrophil phagocytosis, antibody-dependent cellular phagocytosis, and antibody-dependent NK cell activation functional antiviral responses [7] .

Main data from phases I/II clinical trials of the 4 vaccines available in Europe.

	mRNA 1273 Moderna	mRNA 1273 Moderna	BNT 162 b2 BioNTech/Pfizer	ChAdOx1nCov-19 AstraZeneca/Oxford	Ad26COVS1 Janssen
Platform	mRNA	mRNA	mRNA	Adenoviral vector Chimpanzee Ad26	Adenoviral vector Human Ad26
Study design	Phase I Non-randomized	Phase I Non-randomized	Phase I Randomized	Phase II Randomized	Phase I Non-randomized
Participants	45	40	195	560	25
Age range	18–55 y	56–70 y and ≥71 y	18–55 y and 65–85 y	18–55 y; 56–69 y; ≥70 y	18–55 y
Number of doses	2 (days 1/29)	2 (days 1/29)	2 (days 1/22)	1 or 2 (1/29)	1 or 2 (days 1/57)
Vaccine groups	25, 100, 250 μg	25, 100 μg	10, 20, 30 μg 18-55 y 10, 20, 30 μg 65-85 y Placebo	10 subgroups with low (2.2.10 vp) or full dose (3.5–6.5 10 vp) Placebo (MenACWY)	5 subgroups with 5.10 or 1.10 vp or placebo
Specific Ig-G titers	782 719 GMT	1 183 066 GMT	8147 GMT	639 GMT	478 GMT
Neutralizing antibody titers	654 GMT	878 GMT	163 GMT	136 MT	224 GMT
Cellular responses	CD4+ and CD8+	Strong CD4+ (low CD8+)	ND	413 SFCs	> 400 SFCs

Ad26: adenovirus type-26; GMT: geometric mean titer; MNA: microneutralization assay; MT: microneutralization titer; ND: not determined; PRNT: plaque reduction neutralization testing; SFCs: spot-forming cells; VNA: virus neutralizing antibody; VP: viral particles; Y: years.

Another important information provided by these phase I/II studies was related to the effect of age. Among studies shown in Table 1 , only studies on BNT 162 b2 and ChAdOx1nCov-19 vaccines included subjects over 65 years of age [5] , [6] , [8] . These studies demonstrated both antigen-binding Ig-G and virus-neutralizing responses in older adults but also a possible decrease in such responses with increasing age [5] , [6] . Nevertheless, an elderly-dedicated phase I study showed that mRNA 1273 vaccine induces a good Ig-G response against the spike-protein as well as significative neutralizing antibody titers in adults older than 70 years of age [8] . Taken as a whole, these results suggested the possibility to demonstrate COVID-19 vaccines’ efficacy in phase III trials.

Phase III studies: evidence about a high level of efficacy

One of the main issues of phase III trials, particularly in the case of a new pathology, is to define the primary criterion to be used as efficacy markers as well as to define the level of efficacy that will be considered as pertinent. Undeniably, the definition of the primary criterion strongly impacts both the conduct of the trial and the future modalities of prescription of the vaccine. On June 2020, the FDA has released a guidance document for the development and licensure of COVID-19 vaccines [9] . This document stated that symptomatic laboratory-confirmed COVID-19 might be an acceptable primary endpoint for a COVID-19 vaccine efficacy trial with an efficacy level of at least 50% required. Moreover, other secondary criteria might be used to determine the possible efficacy on asymptomatic or severe infections. As a consequence, study sample sizes and timing of interim analyses had to be based on the statistical success criteria for primary and secondary efficacy analyses and realistic, data-driven estimates of vaccine efficacy and incidence of COVID-19 for the populations and locales in which the trials are conducted [9] .

According to these conditions, phase III studies have been conducted in countries where the virus spread was extremely high and have included in a few months several tens of thousands of subjects [10] , [11] , [12] , [13] . According to these studies and except unwanted effects related to usual reactogenicity, these vaccines appear safe. As summarized in Table 2 , among the four vaccines already authorized in Europe the overall efficacy defined as reduction of symptomatic COVID-19 varies from 67% to 95% [10] , [11] , [12] , [13] . These results are largely greater than the minimum efficacy level of 50% required by the FDA [9] . Furthermore, these levels of efficacy are also similar or even higher than that the mean 60% observed with the influenza vaccines [14] . It should be underlined that mRNA vaccines [10] , [11] appear to have a higher efficacy than that of adenoviral vectored vaccines [12] , [13] . Nevertheless, a definitive conclusion about any comparisons should be done with caution. The complexity of the design of ChAdOx1nCov-19 vaccine phase III study does not facilitate neither the interpretation nor any comparisons of data. On the other hand, regarding interim analyses of trials reported in the Table 2 , the protection against severe infection appears to be close to 100% for all vaccines but not for Ad26COVS1 vaccine where data recently published show protection against severe infection with one dose of vaccine of only 77% [13] . It remains to determine how this result is only representative of this vaccine rather than may be finally observed with all other COVID-19 vaccines when long-term follow-up data will be available.

Clinical efficacy observed in phase III studies of the 4 vaccines available in Europe.

	BNT 162 b2 BioNTech/Pfizer	mRNA 1273 Moderna	ChAdOx1nCov-19 AstraZeneca/Oxford	Ad26COVS1 Janssen
Number included in the analysis	37,706	30,351	17,178	43,783
Age	≥16 y	≥18 y	≥18 y	≥18 y
Elderly (%)	> 55 y (42.2%)	> 65 y (24.8%)	56–69 y (10.4%) ≥70 y (5.7%)	≥60 y (33.5%)
Doses	30 μg (days 1/22)	100 μg (days 1/29)	Several combinations of low and full doses at different times	5.10 vp (single dose)
Primary end-point	Symptomatic COVID-19	Symptomatic COVID-19	Symptomatic COVID-19	Symptomatic COVID-19
Overall efficacy (95% CI)	95% (90.3–97.6)	94.1% (89.3–96.8)	66.7% [63.1 or 80.7% ] (57.4–74.0)	66.9% (59.1–73.4)
Clinical efficacy on variants	ND	ND	B.1.1.7: 70.4% B.1.351: 10.4%	B.1.351: 52%
Neutralization activity on variants	B.1.1.7 preserved B.1.351 reduced	B.1.1.7 preserved B.1.351 reduced	B.1.1.7 preserved B.1.351 reduced	B.1.1.7 preserved B.1.351 preserved
Protection against severe infection	100%	100%	100%	76.7 to 85.4 %

ND: not determined; VP: viral particles; Y: years.

Some other elements remain to be clarified in real life conditions, namely the effect on mortality, the level of efficacy in the elderly and the clinical efficacy of vaccines according to emerging variants and the duration of protection. Concerning mortality, the studies have not been designed to answer this question, it may then be difficult to bring clear and conclusive result. Moreover, according to the drastic reduction of severe infections observed in vaccinated-people, these studies are probably under-powered to clearly demonstrate the effect of vaccines on mortality.

Regarding elderly, not all published phase III studies had included many elderly people but in studies with a significant number of elderly participants ( Table 2 ), the efficacy level remains relatively close to the one observed in younger subjects (86.4% and 94.7% in people of 65 or over, for mRNA 1273 and BNT 162 b2 respectively) [10] , [11] . Clinical efficacy of vaccines on emerging variants remains also to be more precisely evaluated. Due to the relatively recent emergence of different virus variants’, only few clinical data are available but they show the preservation of ChAdOx1nCov-19 vaccine efficacy on B.1.1.7 variant [15] and a possible decrease in efficacy of both Ad26COVS1 and ChAdOx1nCov-19 vaccines on B.1.351 variant ( Table 2 ) [13] , [16] .

COVID-19 vaccines effectiveness in real life

When a new drug comes on the market, it takes usually several years before it could be demonstrated the reproducibility of the phase III clinical trial results’ in real life. Here, according the pandemic situation and the rapid development of mass vaccination campaigns in Israel, USA and UK, we already have many data demonstrating this achievement and also providing supplementary informations. Indeed, as summarized in Table 3 , at least 4 studies that had included 20,000 to more than 1,300,000 vaccinated people provide us impressive results on symptomatic or asymptomatic infections, severe infections as well as on mortality [17] , [18] , [19] , [20] .

Effectiveness of SARS-CoV-2 vaccination in real life.

Settings	Vaccinated population	Vaccine	Symptomatic and asymptomatic infections (95% CI)	Severe infections (95% CI)	Mortality (95% CI)
Clalit Health Services Israel	596,618	BNT 162 b2	92% (88–95)	92% (75–100)	84% (44–100)
Mayo Clinic Health System USA	31,069	BNT 162 b2 or mRNA 1273	89% (68–97)	60% (14–79)	None
Mass vaccination Scotland	1,331,993	BNT 162 b2 or ChAdOx1nCov-19	ND	91% (95% CI 85–94) 88% (95% CI 75–94)	ND
Health Care Workers England	20,641	BNT 162 b2 or ChAdOx1nCov-19	85% (74–96)	None	None

CI: confidence interval; ND: not determined; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

Israel was probably the country which developed the most rapid and extensive mass vaccination campaign in the world by using the BNT 162 b2 vaccine. All people recorded on the Clalit Health Services (53% of Israeli population) who were newly vaccinated during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls according to demographic and clinical characteristics leading to 2 study groups of 596,618 persons each [17] . Looking on results 7 days or more after the second dose of vaccine, symptomatic and asymptomatic as well as severe COVID-19 infections are reduced by 92%. Mortality was also reduced by 84% when regarding 21 to 27 days after the first dose [17] . Even if such results have to be strengthened by a longer-term follow-up, the present study also provides informations about a similar vaccine effectiveness across different age groups and a slightly lower effectiveness among patients with multiple coexisting pathological conditions [17] .

In another paper under review, similar results are provided with the Mayo Clinic Health Database showing a 90% decrease in the development of a symptomatic or asymptomatic COVID-19 infection after BNT 162 b2 or mRNA 1273 vaccination in 31 609 persons [18] . Same kind of results are also provided by both Scotland and England data where both BNT 162 b2 and ChAdOx1nCov-19 vaccines were largely used with evidence of 85% decrease in symptomatic and asymptomatic infections and about 90% decrease in severe infections ( Table 3 ) [19] , [20] . Interestingly, in the Scottish study, such results were observed while the vaccines were administered at only one dose to extend the number of subjects receiving at least one dose of vaccine. Besides the fact that all these data confirm the results of phase III clinical trials, they also help to discuss the question of the effect of vaccine on virus transmission. Because asymptomatic infections are also reduced, it may be that virus transmission is decreased. Moreover, a recently published paper brings supplemental arguments about an effect of vaccines on transmission. Indeed, people who develop a COVID-19 despite vaccination with the BNT 162 b2 vaccine have a clear reduction of viral load that might help to break the spread of the virus [21] . Complementary strategies, such as vaccines able to develop mucosal immunity are also under development [22] .

Several questions remain on hold

One of the first questions on hold is the duration of the protection afforded by the vaccination. According to studies follow-up duration, it might be supposed that this protection is as at least 6 to 12 months. This duration will determine the need of a new vaccine boost and possibly the need of annual boost. Some large population-based studies using test-negative designs might help to evaluate these different issues particularly the situations of vaccine failure [23] .

The question of using different vaccines than the one use initially is also crucial. New studies should be designed including studies for the evaluation of the impact of immunogenicity against adenoviral vector if such a vaccine is used for a third injection. Because phase III clinical studies provide no or only few data about immunogenicity, it remains important to also designed studies able to determine more precisely the immune response according to real life administration scheme namely regarding the role of both cellular and innate immunity. Actually, in France, 2 studies are in course to answer such questions by using BNT 162 b2 or mRNA 1273 vaccines in adults including a sub-population of elderly people over 75 years of age.

Besides older people, the question of the efficacy of vaccines in particular populations is also crucial. Several recently published studies bring some answers. To date, there is only few data about the efficacy of vaccine in young people under 18 years of age [10] . Studies evaluating COVID-19 mRNA vaccines in young people aged 12 to 16 years are actually in course but both FDA and EMA have already beenquestioned to provide an authorization of use. On the other hand, COVID-19 mRNA vaccines seem to generate robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women [24] . In this study, vaccine-induced immune responses were also significantly greater than the response to natural infection and immune transfer to neonates occurred via placenta and breastmilk [24] . Other data also suggest that a single dose of mRNA vaccine elicits rapid immune responses in SARS-CoV-2 seropositive participants, with post-vaccination antibody titers similar to or exceeding titers found in seronegative participants who received two vaccinations [25] . On the other hand, the immunization rate among kidney transplant recipients who received 2 doses of an mRNA vaccine can be as low as 48% [26] . Very low immune response is evidenced also in others immunocompromised populations. The issue of a third vaccine dose in these non-responsive patients is an intriguing one that will be usefully explored in further research. In this context, a large cohort has been opened in France (COV-POPART) to evaluate the immune response in a number of particular populations including patients with cancer, transplant recipients as well as patients with auto-immune disease receiving immune-modulator treatments.

Last, an important challenge also concerns the efficacy of vaccines regarding the emergence of viral variants [27] . We have previously described some data from clinical trials regarding the decrease or the absence of efficacy of the ChAdOx1nCov-19 namely on B.1.351 variant ( Table 2 ) [12] . Some similar concerns are discussed with the other vaccines but most of the data come from in vitro studies that are not able to consider the possible role of cellular immune response [27] , [28] . Besides to evaluate the effect of a boost particularly with new mRNA sequences, future trials should also explore more precisely the whole immune response against viral variants.

In less than one year, face to a worldwide pandemic due to an unknown virus, several vaccines have been put on the market and have been already used in several tens of millions of people. These vaccines are importantly effective and relatively safe according to the severity of the disease they prevent. Beyond this impressive efficacy of COVID-19 vaccines, notably those based on mRNA, such a technology may first contribute to modify the course of the pandemic but also could bring the world in a new era of specific treatments for numerous pathologies [3] .

Disclosure of interest

The authors declare that they have no competing interest.

Supported by

Vaccines Significantly Reduce the Risk of Long Covid, Study Finds

In the first two years of the pandemic, the rate of long Covid was starkly lower among people who were vaccinated, researchers reported.

Share full article

Gloved hands holding a syringe preparing a vaccine.

By Pam Belluck

A large new study provides some of the strongest evidence yet that vaccines reduce the risk of developing long Covid.

Scientists looked at people in the United States infected during the first two years of the pandemic and found that the percentage of vaccinated people who developed long Covid was much lower than the percentage of unvaccinated people who did.

Medical experts have previously said that vaccines can lower the risk of long Covid , largely because they help prevent severe illness during the infection period and people with severe infections are more likely to have long-term symptoms.

But many individuals with mild infections also develop long Covid, and the study, published Wednesday in The New England Journal of Medicine, found that vaccination did not eliminate all risk of developing the condition, which continues to affect millions in the United States.

“There was a residual risk of long Covid among vaccinated persons,” Dr. Clifford Rosen, a senior scientist at the MaineHealth Institute for Research, who was not involved in the study, wrote in an accompanying editorial . Because of that, Dr. Rosen added, new cases of long Covid “may continue unabated.”

The study evaluated medical records of millions of patients in the Department of Veterans Affairs health system. It involved nearly 450,000 people who had Covid between March 1, 2020, and Jan. 31, 2022, and about 4.7 million people who were not infected during that time.

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For up-to-date information on topics related to COVID-19, visit these U.S. government resources.

COVID-19 Treatments and Medications , Centers for Disease Control and Prevention (CDC)
Know Your Treatment Options for COVID-19 , U.S. Food and Drug Administration (FDA)
COVID-19 Treatments and Therapeutics , U.S. Department of Health and Human Services (HHS)
COVID-19 Treatment Information for Patients , Administration for Strategic Preparedness and Response (ASPR), HHS
COVID-19 Therapeutics Prioritized for Testing in Clinical Trials , NIH
Volunteer for COVID-19 Clinical Trials , National Institute of Allergy and Infectious Disease (NIAID)
COVID-19 Therapeutics: Resources for Health Care Professionals and Public Health Officials , ASPR, HHS
COVID-19 Treatments , NIH (archived)
Researching COVID to Enhance Recovery (RECOVER) Initiative , NIH
RECOVER Clinical Trials , NIH
RECOVER Studies , NIH
Long COVID or Post-COVID Conditions , CDC
Long COVID , HHS
Patient Tips: Healthcare Provider Appointments for Long COVID , CDC
Long COVID Resources , National Heart, Lung, and Blood Institute (NHLBI)
Office of Long COVID Research and Practice , Office of the Assistant Secretary for Health (OASH), HHS
Guidance on “Long COVID” as a Disability , HHS
Long COVID , NIH (archived)
Coronavirus Vaccines and Prevention , NIAID
Stay Up to Date with COVID-19 Vaccines , CDC
COVID-19 Vaccines , FDA
COVID-19 Vaccines , HHS
Benefits of Getting a COVID-19 Vaccine , CDC
Frequently Asked Questions about COVID-19 Vaccination , CDC
Vaccines.gov , CDC
Vaccine Adverse Event Reporting System , HHS
COVID-19 Vaccines , NIH (archived)
COVID-19 and Mental Health , National Institute of Mental Health (NIMH)
Taking Care of Your Mental Health , CDC
Science News About COVID-19 , NIMH
Caring for Your Mental Health , NIMH
Messages About COVID-19 , NIMH
COVID-19 Stigma , NIMH
COVID-19 and Mental Health , NIH (archived)
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Clinical Research: Benefits, Risks, and Safety , National Institute on Aging (NIA)
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Home Test to Treat Program Expands Nationwide

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Shining a Light on Long COVID Brain Fog

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Understanding Sleep Problems and Long COVID

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More Evidence That COVID-19 Vaccination While Pregnant Likely Protects Children

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Measuring the Psychological Distress of COVID-19

People from many racial and ethnic minority groups reported experiencing less distress than White adults

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09 July 2024

Vaccines save lives: how can uptake be increased?

You have full access to this article via your institution.

A man covers his face in fear while receiving a vaccine from a nurse wearing a face mask

Many people are reluctant to get vaccinations, often owing to a fear of needles or misinformation about the jabs. Credit: Genaro Molina/ Los Angeles Times /Getty

Vaccines save lives. The measles vaccine alone is estimated to have averted 23 million deaths between 2000 and 2018, according to the World Health Organization (WHO). Data from a subset of countries where girls are vaccinated against the human papillomavirus show that precancerous cervical lesions in girls aged 15–19 plummeted by 51% within a few years of vaccine rollout 1 . Globally, vaccination rates are increasing for many diseases. However, in 2022 (the latest year for which data are available), there were still 14.3 million ‘zero-dose’ children — those who had not received any routine immunizations.

A lack of access to vaccines and the high costs of producing and purchasing them are among the main reasons for low uptake, especially in low- and middle-income countries. In high-income countries, vaccine hesitancy is a significant factor 2 . This is fuelled, in part, by misinformation, which is a problem worldwide 3 .

Countries already have a range of strategies for boosting uptake. All should study the work of researchers who have been evaluating the effectiveness of different interventions. The burgeoning science of vaccine-uptake effectiveness is throwing up some unexpected results that could help public-health authorities to sharpen their policies — and save more lives.

Bird flu in US cows: where will it end?

Take the United States. By October 2022, almost two years after the first COVID-19 vaccines were rolled out, 80% of people in the country aged six months and older had received at least one dose. However, only 33% had received a follow-up booster, which offers the highest possible level of protection against the SARS-CoV-2 virus.

The low booster numbers drove some states to investigate how uptake might be increased. Researchers and health authorities have highlighted ‘last-mile vaccination delivery’ as a major barrier to uptake. In 2021, the White House came up with the idea of encouraging people to get their boosters by offering them free transport to clinics through the ride-hailing companies Lyft and Uber. But a study published in Nature last month 4 shows that this might have done little to increase booster uptake.

Economist Katherine Milkman at the University of Pennsylvania (UPenn) in Philadelphia and her colleagues compared the offer of a free ride with other interventions in a study involving 3.66 million patients of CVS Pharmacy, a retailer that provides vaccination services. The patients, who had all previously been vaccinated against COVID-19, were split into eight groups. One group received a text message offering free transport to the pharmacy; the other seven were sent different text-message reminders to get their boosters.

A global pandemic treaty is in sight: don’t scupper it

People offered free transport were not more likely to get vaccinated than were those who received the other kinds of text message. Messages that had a more positive effect included one proposing an appointment for a day of the week and time of day similar to that of a patient’s previous vaccination, and one informing the recipient that infection rates were high in their county.

“Our article really highlights the importance of testing policy,” says study co-author Sean Ellis, also at UPenn. “Whatever policy we’re putting into place, we should be robustly evaluating whether it actually works, so that if it does work, we can scale it up or continue to do it. And if it doesn’t, we can move on from it and try something else.” In other words, studies are needed to evaluate whether ‘common sense’ interventions actually work in practice.

Researchers are also helping to evaluate the overall effectiveness of text messaging on vaccine uptake. In a study published in May, Hongyu Guan at Shaanxi Normal University in Xi’an, China, and colleagues used the 2021 Chinese General Social Survey, a periodic national survey of households, to examine the actions of 7,281 people. They found that those who received notifications from their local government or community residents’ committees advising them to get vaccinated were twice as likely to get a COVID-19 vaccine than were those who did not 5 .

Half a million children die of malaria every year – finally we can change that

The same study showed that the practice also increased influenza vaccine uptake, albeit from a much lower base. Uptake was more than 40% higher for those notified compared with those who did not receive a text message. This finding builds on the work of earlier studies 6 . However, researchers are less certain whether these approaches are effective for people who are reluctant to be vaccinated 7 .

In low-income countries, research shows that uptake increases when vaccines are taken into communities. In Sierra Leone, for example, the average person lives 3.5 hours away from a vaccination centre and the cost to travel there exceeds their weekly wage. A study published in March 8 found that significantly more people in the country received their COVID-19 vaccines when mobile teams of vaccinators were deployed to 150 rural communities.

Increasing vaccine access and accessibility saves lives, but is only part of the equation. Other interventions are needed to maximize uptake, and these must undergo rigorous testing in different regions and contexts to help health authorities to determine what works. The obvious answer is not always the right one, and the vagaries of human behaviour can thwart seemingly logical solutions.

Nature 631 , 255 (2024)

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On June 27, 2024, the CDC Director adopted the ACIP’s recommendations for use of 2024–2025 COVID-19 vaccines in people ages 6 months and older as approved or authorized by FDA. The 2024–2025 vaccines are expected to be available in fall 2024. This page will be updated at that time to align with the new recommendations. Learn more: www.cdc.gov/media/releases/2024/s-t0627-vaccine-recommendations.html

COVID-19 Vaccine Basics

What to know.

COVID-19 vaccines help our bodies develop immunity to the virus that causes COVID-19 without us having to get the illness.
Different COVID-19 vaccines may work in our bodies differently but all provide protection against the virus that causes COVID-19.

Woman flexing her arm to show off vaccination bandage.

Did you know?‎

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

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

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

Types of vaccines

Available vaccines.

There are different types of vaccines.

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

None of these vaccines can give you COVID-19.

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

COVID-19 vaccines do not affect or interact with our DNA.

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

mRNA vaccines (Pfizer-BioNTech or Moderna)

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

How mRNA COVID-19 vaccines work

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

How mRNA COVID-19 Vaccines Work PDF infographic

English [128 KB, 1 page]
Other Languages

Research for mRNA technology

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

In fact, mRNA vaccines have been studied before for flu, Zika, rabies, and cytomegalovirus (CMV).
Beyond vaccines,  cancer research  has also used mRNA to trigger the immune system to target specific cancer cells.

Protein subunit vaccines (Novavax)

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

How protein subunit COVID-19 vaccines work

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

How Protein Subunit COVID-19 Vaccines Work PDF infographic

English [953 KB, 1 page]

Research for protein subunit technology

Protein subunit vaccines have been used for years.

More than 30 years ago, a hepatitis B vaccine became the  first protein subunit vaccine   to be approved for use in people in the United States.
Another example of protein subunit vaccines used today include whooping cough vaccines.

About developing COVID-19 vaccines

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

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

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

Initial Development

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

Clinical Trials

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

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

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

Authorization or Approval

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

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

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

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

Vaccine Recommendations

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

Understanding ACIP and How Vaccine Recommendations are Made‎

Learn more about the Advisory Committee on Immunization Practices (ACIP) and its role in developing vaccine recommendations.

Tracking Safety Using Vaccine Monitoring Systems

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

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

Reports of serious adverse events after vaccination are rare .

Getting Your COVID-19 Vaccine
Vaccine Effectiveness

COVID-19 (coronavirus disease 2019) is a disease caused by a virus named SARS-CoV-2. It can be very contagious and spreads quickly.

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Vaccination slashes risk of long Covid, says large study tracing cases through Delta and Omicron variants

By Elizabeth Cooney July 17, 2024

A person gets vaccinated on their left arm behind a curtain as two people wait in line, sitting outside the room — health coverage from STAT

V accination lowers the chance of developing long Covid, according to a large new study that also found that the risk of serious complications has diminished but not disappeared as new coronavirus variants emerged.

The study, published Wednesday in the New England Journal of Medicine , compared the health records of more than 440,000 Veterans Affairs patients who were infected with Covid-19 with records of more than 4 million uninfected people. The analysis found that cases of long Covid — also called PASC (post-acute sequelae of severe acute respiratory syndrome coronavirus 2) — fell among all participants during the Delta and Omicron eras of the pandemic, but dropped almost twice as much for vaccinated people when the Omicron variant dominated cases.

The new data about vaccination’s benefits come during a summer resurgence in Covid cases around the country, and as health officials prepare to roll out a vaccine updated against newer strains that Pfizer and Moderna said they could deliver in August .

Related: ‘Visionary’ study finds inflammation, evidence of Covid virus years after infection

“The study is helpful in validating the suspicion that the incidence of PASC decreased over time and in relationship to new variants (this question came up in my clinic just yesterday),” Hilary Goldberg, clinical director of pulmonary and critical care medicine at Brigham and Women’s Hospital in Boston, told STAT in an email. She was not involved in the study. “It is also helpful in validating that vaccination is protective in preventing the development of PASC, a question that has remained somewhat unsettled,” Goldberg said.

In the unvaccinated group, 10.42 out of 100 people early in the pandemic (before vaccines were available) had developed long Covid one year after being infected. In the Delta variant era (defined as June 19 through Dec. 18, 2021), 9.51 out of 100 unvaccinated people were diagnosed with long Covid, compared to 5.34 out of 100 vaccinated people. When the current Omicron era began (Dec. 19, 2021), the gap widened: 7.76 out of 100 unvaccinated people but only 3.5 out of 100 vaccinated people acquired long Covid.

“Vaccines very clearly work, but also clearly, they don’t totally wipe it out,” the study’s senior author, Ziyad Al-Aly, said in an interview. Chief of research at the VA St. Louis Health Care System, he is also a clinical epidemiologist at Washington University in St. Louis. “What we think is really important here is yes, long Covid has declined. But it’s not something that we can completely ignore.”

Earlier studies, including other research from the VA , have hinted at a protective effect for vaccination as well as the harmful impact of severe Covid infections and pre-existing medical conditions on chances of later long Covid. Jai Marathe, an assistant professor of infectious diseases at Boston University and director of the ReCOVer/ long COVID clinic at Boston Medical Center, points out that the new paper says the type or number of comorbidities did not seem to impact PASC.

“From a research perspective, there’s a strong impetus to understand the pathogenesis of PASC, given its constellation of symptoms,” she wrote to STAT. She did not participate in the NEJM paper. “If vaccination alters the immune response, we need to study this further to understand the interplay between viral infection and the immunological changes that contribute to PASC development.”

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Al-Aly hesitates to call this the final word on the full extent to which vaccine coverage better protects people, urging more research. The observational study also describes how symptoms changed with the variants for unvaccinated people.

While debilitating fatigue was once a hallmark of long Covid, more recently gastrointestinal, metabolic, and to a lesser degree, musculoskeletal problems have overtaken fatigue among the unvaccinated, with GI and metabolic issues double the risk of the pre-Delta and Delta periods combined. The study, conducted from March 2020 through January 2022, measured how long Covid does its damage in 10 disease categories: cardiovascular, blood disorders, fatigue, gastrointestinal, kidney, mental health, metabolic, musculoskeletal, neurologic, and pulmonary.

Long Covid risk changed not just with the variants, but also with better hospital treatment, including antivirals, Al-Aly said. Vaccination may have lowered the amount of virus circulating and therefore the risk of long Covid compared to 2020, but that’s only a hypothesis. “Quantitatively, the risk changed dynamically over time, but also qualitatively. It suggests that each strain has its own fingerprints,” he said. “Long Covid is not monolithic.”

Michael Peluso, an infectious disease physician and an assistant professor of medicine at University of California, San Francisco, said he and other doctors may be seeing hints of the changing symptom mix. “It will make me more cognizant of GI and musculoskeletal symptoms in my assessment of long Covid,” Peluso, who was not part of the study, said in an email to STAT. “We certainly see these symptoms, but I would not say that they are the most prominent.

Goldberg wasn’t surprised by the symptom shift. “I find this reassuring in that we would expect the nature of the disease to evolve over time. If we did not see this, we could potentially question the robustness of the data in this analysis.”

To tease out the influence of vaccination versus variant, the study authors used a statistical method called decomposition analysis to conclude that 28% of the lower long Covid incidence in vaccinated people was due to changes in the variants and improved medical care, while attributing 72% of the improvement to the vaccines.

Related: ‘Concern is real’ about long Covid’s impact on Americans and disability claims, report says

The study did not say how many vaccinations a subject received, Goldberg noted. “Gaps in the data remain — a common question from patients is what is the risk of reactivation or worsening of PASC symptoms from vaccination as compared to from infection,” she said. “We do not have sufficient information to address this question yet, and this question often informs patient decision-making.”

The study’s estimate of long Covid’s cumulative incidence is lower than a June report from the Agency for Healthcare Research and Quality published in JAMA last month that pegged long Covid’s reach at 7% of people who’ve ever had Covid-19. That’s higher than the NEJM paper’s 3% to 4% of adults in the Omicron era, but reflects the agency’s survey results as opposed to the NEJM study’s reliance on health records, Al-Aly said. Estimates of long Covid have swung wildly from early in the pandemic, before agreement was reached on just how to define the condition.

On Tuesday the Centers for Disease Control and Prevention said that people with disabilities face a higher risk of long Covid than people without disabilities. The data said 11% of people with disabilities had long Covid while only 7% of people without disabilities reported symptoms.

In other long Covid research this week, a study published Wednesday in Science Translational Medicine offered an explanation for damage to the lungs that leads to exhausting coughs, lung disease, and shortness of breath. Researchers from the University of Virginia showed that a signaling molecule named interferon-gamma stimulated an abnormal immune response, provoking inflammation and scarring in the lungs after Covid-19 infection. In mice, anti-interferon-gamma antibody treatment reduced inflammation and fibrosis after recovery from their acute infections. Drugs called JAK inhibitors, including one named baricitinib that was granted emergency use for acute Covid-19, “may merit consideration” for treating long Covid, the authors wrote.

Despite progress in research and declines in long Covid cases, the risk is still substantial, Al-Aly and others emphasized.

“Despite the risk of long Covid decreasing, it has not decreased to zero and we will still continue to see many cases of long Covid as SARS-CoV-2 continues to spread,” Peluso said. “This observation is really helpful for clinicians, researchers, and advocates to make the argument that more investment in clinical care and research for long Covid is going to be needed to meet the scope of the clinical need and to ultimately solve the problem.”

Declining uptake of vaccination is concerning, likely due to “Covid burnout,” Marathe said. “Living with a chronic condition like PASC can be debilitating. Therefore, educating and counseling patients and physicians to increase vaccine acceptance is a crucial public health task.”

Goldberg said patients with long Covid often ask her about the risks and benefits of updating their vaccination status. “This study will help to guide those of us caring for patients with PASC,” she said.

Peluso praised the paper’s value for answering questions patients ask “all the time” in clinic. “The risk with Omicron variants may be lower than it was with earlier variants, but it is still significant,” he said. “And being vaccinated is still the best thing someone can do, beyond avoiding Covid, to protect themselves against developing long Covid.”

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies . Our financial supporters are not involved in any decisions about our journalism.

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Elizabeth cooney.

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Elizabeth Cooney is a cardiovascular disease reporter at STAT, covering heart, stroke, and metabolic conditions.

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IMAGES

Journal retracts paper claiming COVID-19 vaccines kill
Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta
Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
mRNA Covid-19 vaccines: Facts vs Fiction

COMMENTS

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be safe and 95% effective against Covid-19. The vaccine met both primary efficacy end points, with more than a 99 ...
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
The Coronavirus Efficacy (COVE) phase 3 trial was launched in late July 2020 to assess the safety and efficacy of the mRNA-1273 vaccine in preventing SARS-CoV-2 infection. An independent data and ...
Long-term effectiveness of COVID-19 vaccines against infections
Our analyses indicate that vaccine effectiveness generally decreases over time against SARS-CoV-2 infections, hospitalisations, and mortality. The baseline vaccine effectiveness levels for the omicron variant were notably lower than for other variants. Therefore, other preventive measures (eg, face-mask wearing and physical distancing) might be necessary to manage the pandemic in the long term.
Safety & effectiveness of COVID-19 vaccines: A narrative review
Safety and adverse effects of current COVID-19 vaccines. As shown in Table I, current vaccines have demonstrated considerable efficacy in diminishing mild, moderate and severe cases with a low risk of adverse events 21.For some of these vaccines [such as Convidicea (AD5-nCoV), Janssen (Ad26.COV2.S), Sinopharm (BBIBP-CorV), Covaxin (BBV152) and Sinovac (CoronaVac)], there is the information ...
Comprehensive literature review on COVID-19 vaccines and role of SARS
Introduction. The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 192 million cases and 4.1 million deaths as of July 22, 2021. 1 This pandemic has brought along a massive burden in morbidity and mortality in the healthcare systems. Despite the implementation of stringent public health measures, there ...
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New Coronavirus Disease 2019 (COVID-19) vaccines are available to prevent the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We compared the efficacy of new COVID ...
Evaluating COVID-19 vaccines in the real world
The effectiveness of the mRNA vaccines in preventing COVID-19 disease progression in 2021 set new expectations about the role of prevention interventions for the disease. Efficacy observed in the trials was more than 90%.1,2 The efficacy of other vaccines evaluated in large randomised trials, such as the Oxford-AstraZeneca (70%) and Sputnik V (91%) vaccines, have been criticised for elements ...
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2020 has been a difficult year for all, but has seen 58 vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) be developed and in clinical trials,1 with some vaccines reportedly having more than 90% efficacy against COVID-19 in clinical trials. This remarkable achievement is much-needed good news as COVID-19 cases are currently at their highest daily levels globally.2 ...
Efficacy and safety of COVID-19 vaccines
Authors' conclusions: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events.
Review Real-world effectiveness of COVID-19 vaccines: a literature
2.1. Search and inclusion criteria. For this literature review and meta-analysis, a systematic search of PubMed was performed using the terms "COVID-19" or "SARS-CoV-2" and "vacc*" and "eff*" to identify articles published between August 6, 2020 ( Deplanque and Launay, 2021) and October 6, 2021, from any country, reporting VE in ...
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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 ...
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Development of an effective vaccine against Covid-19 is crucial to reducing infection. mRNA BNT162b2, developed and manufactured by Pfizer-BioNTech, was one of the first FDA-approved vaccinations reporting high efficacy (95%) and minimal side effects. ... 1 Dept. Health Evaluation & Research, Division of Data & Digital Health, Maccabi ...
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Introduction. The COVID-19 (Coronavirus disease 2019) pandemic has impacted nearly every country, infected around 775 million people, and has surpassed 7 million deaths worldwide ().The Global and United States (US) economies have been heavily affected by a viral disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV2), overwhelming healthcare facilities (2, 3).
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Background: Several COVID-19 vaccines were developed and approved in China. Of these, the BIBB-CorV and CoronaVac inactivated whole-virion vaccines were widely distributed in China and developing countries. However, the performance of the two vaccines in the real world has not been summarized. Methods: A living systematic review based on findings from ongoing post-licensure studies was ...
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About developing COVID-19 vaccines Overview: While COVID-19 vaccines were developed rapidly, all steps have been taken to ensure their safety and effectiveness. Bringing a new vaccine to the public involves many steps including: vaccine development, clinical trials, U.S. Food and Drug Administration (FDA) authorization or approval, and
An mRNA Vaccine against SARS-CoV-2
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate ...
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Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis

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Vaccine effectiveness for different clinical outcomes of COVID-19

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

Safety of SARS-CoV-2 vaccines

Sensitivity analysis and publication bias

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Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults

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Efficacy of COVID-19 vaccines: From clinical trials to real life

Odile Launay

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COVID-19 vaccine development: an unprecedented timeframe

Phase I/II clinical trials: safety and immunogenicity analysis

Phase III studies: evidence about a high level of efficacy

COVID-19 vaccines effectiveness in real life

Several questions remain on hold

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Vaccines Significantly Reduce the Risk of Long Covid, Study Finds

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Vaccines save lives: how can uptake be increased?

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