research report on covid 19 vaccine

• 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

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

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Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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

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Home > Books > Epidemic Preparedness and Control

A Review of COVID-19 Vaccines, Immunogenicity, Safety, and Efficacy toward Addressing Vaccine Hesitancy, Inequity, and Future Epidemic Preparedness

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This chapter provides an update on COVID-19 vaccines, emphasizing their immunogenicity, safety, efficacy, and potential impact on vaccine hesitancy, inequity, and future epidemic preparedness. Various vaccine types, such as mRNA-based, DNA-based, viral vector, inactivated, and protein subunit vaccines, are explored, evaluating their mechanisms and advantages in eliciting robust immune responses. Safety is thoroughly assessed using clinical trials and real-world data to address hesitancy concerns. Strategies for equitable distribution are discussed to achieve widespread coverage and overcome barriers. Lessons drawn from the pandemic serve as a roadmap for proactive measures aimed at bolstering epidemic preparedness, highlighting the critical role of global cooperation and equitable vaccine distribution in safeguarding public health worldwide.

• COVID-19 vaccine
• immunogenicity
• vaccine hesitancy
• vaccine inequity
• and future epidemic preparedness

Author Information

• Clinical Vaccine R&D Center, Chonnam National University Medical School, Hwasun-gun, Jeonnam, Republic of Korea

Vandara Loeurng

• Department of BioMedical Sciences, Chonnam National University Medical School, Hwasun-gun, Jeonnam, Republic of Korea
• Department of Veterinary Medicine, Meanchey National University, Banteay Meanchey province, Cambodia

*Address all correspondence to: [email protected]

1. Introduction

On January 30, 2020, the World Health Organization (WHO) officially declared the outbreak of novel coronavirus disease 2019 (COVID-19) as a global pandemic. This declaration was made in response to the highly transmittable and pathogenic nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus [ 1 ]. Since then, COVID-19 has caused more than 6 million deaths worldwide [ 2 ], resulting in significant economic losses globally [ 3 ]. Despite efforts to control the pandemic, it is still ongoing as China continues to report high numbers of cases. Concerns are rising that the “Zero COVID” policies implemented in China may not effectively contain the spread of COVID-19 [ 4 ]. Furthermore, scientific evidence suggests that climate changes, such as global warming, rapid population growth, urban expansion, and deforestation, are bringing human habitation closer to livestock and wildlife, potentially serving as hosts for future pandemic pathogens [ 5 ].

Since the onset of the disease, vaccines and vaccination strategies have continuously evolved, gaining particular attention in the wake of the COVID-19 outbreak. Notable advancements have been made in the development of novel vaccine technologies, resulting in the creation of effective vaccines against various diseases [ 6 , 7 ]. Specifically addressing the ongoing global pandemic caused by the SARS-CoV-2 virus, COVID-19 vaccines have been swiftly developed and distributed, serving as a crucial tool in the fight against the pandemic [ 8 , 9 , 10 ]. Clinical trials have demonstrated that these vaccines effectively prevent severe illness, hospitalization, and death. Furthermore, they possess the potential to slow down virus transmission and reduce the emergence of new variants ( Tables 1 – 3 ). The widespread administration of vaccines is vital in safeguarding vulnerable populations, including the elderly and individuals with underlying health conditions [ 10 ]. Compared to natural infection, vaccination plays a prominent role in saving humanity from various COVID-19 variants, including the recent surge of the Omicron variant and aiding in the recovery from the global economic crisis ( Tables 1 – 3 ).

A comprehensive review of the immunogenic characteristics exhibited by approved COVID-19 vaccines.

A comprehensive review of the safety profiles demonstrated by approved COVID-19 vaccines.

A comprehensive review of the effectiveness of approved COVID-19 vaccines in preventing symptomatic COVID-19.

While COVID-19 vaccines offer numerous benefits, they also have limitations regarding their immunogenicity, safety, and effectiveness. Vaccine hesitancy is a concern, as individuals may refuse vaccination due to apprehensions about the immunogenicity, safety, and efficacy of the vaccines [ 61 , 62 , 63 , 64 , 65 ]. The efficacy rates of COVID-19 vaccines vary among different types, and emerging virus variants can impact their effectiveness. For instance, mRNA vaccines have demonstrated higher efficacy rates compared to viral vector and inactivated virus vaccines ( Table 3 ). Extensive research and monitoring have been conducted to ensure the safety of COVID-19 vaccines with most reported adverse events being mild and temporary ( Table 2 ). However, rare cases of severe adverse events, such as blood clots, have been associated with some vaccines, leading to temporary suspensions in vaccine distribution and increased surveillance [ 65 , 66 ].

Overall, COVID-19 vaccines induce immunogenicity by stimulating the production of neutralizing antibodies and cellular immune responses ( Table 1 ). While the inactivated COVID-19 vaccines may exhibit slightly lower immunogenicity compared to certain other formed vaccines, they still prove effective in reducing the severity of COVID-19 and providing protection against severe outcomes ( Table 3 ). Despite the development and approval of multiple vaccines, there remains a significant challenge of inequitable access to vaccines, particularly in low- and middle-income countries (LMICs) [ 67 ]. Additionally, logistical obstacles such as cold chain storage and vaccine distribution have hindered efficient delivery in certain regions [ 68 ].

At this juncture, it is crucial for us to reflect upon the valuable lessons learned during the COVID-19 pandemic spanning the past 3 years. It is imperative that we contemplate how to prepare better and effectively respond to future challenges. In addition to implementing measures like social distancing, it is essential to have a comprehensive understanding of vaccine technologies and the immunogenicity, safety, and efficacy of vaccines. The objective of this chapter is threefold: (1) To examine and reflect upon recent advancements in vaccine technologies, focusing on the immunogenicity, safety, and efficacy of approved COVID-19 vaccines; (2) To provide critical insights aimed at addressing gaps in vaccine inequity, ensuring that access to vaccines is fair and equitable for all; (3) To provide critical insights and recommendations for preparedness and control measures in response to potential future pandemics. By addressing these aspects, we aim to enhance our preparedness and response capabilities, ultimately striving for more effective control and management of future health crises.

2. Overview of SARS-CoV-2 and its biology

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belonging to the coronavirus family, has led to outbreaks of various diseases. This family of viruses includes common viruses responsible for ailments ranging from common colds to more severe conditions like severe acute respiratory syndrome (SARS), which caused an outbreak in 2003 [ 69 ], as well as middle east respiratory syndrome (MERS), which caused an outbreak in 2012 [ 70 ]. The most recent outbreak occurred in 2019 with the emergence of SARS-CoV-2 [ 1 ], resulting in significant global health impacts [ 2 ] and economic consequences [ 3 ].

SARS-CoV-2 is an enveloped virus characterized by its positive-sense single-stranded RNA genome. The genome of SARS-CoV-2 contains instructions for the production of four primary structural proteins: spike glycoprotein (S), envelope protein (E), membrane protein (M), and nucleoprotein (N) [ 71 ]. These four structural proteins come together to encapsulate the viral genetic material (RNA), forming a complete virus capable of replication, transmission, and disease onset ( Figures 1 and 2 ).

The structural representation of SARS-CoV-2. This visual depiction was obtained from biorender ( https://www.biorender.com ).

The portrayal of SARS-CoV-2’s entry into host cells via the ACE2 receptor. This visual representation illustrates the simulated steps and mechanisms involved in the recognition and entry of host cells through ACE2-mediated pathways by the prefusion spike glycosylation (S1). This visual depiction was obtained from biorender ( https://www.biorender.com ).

The virus exhibits a spherical shape and displays spike-like projections on its surface, which gives it a crown-like appearance ( Figure 1 ). These projections are composed of the glycoprotein spike (S protein), consisting of two subunits, S1 and S2, and play a crucial role in receptor recognition and fusion with the host cell membrane [ 72 , 73 ]. Specifically, SARS-CoV-2 attaches to host cells by utilizing its spike protein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor located on the surface of human cells. Upon entering the host cell, the viral RNA genome is released and serves as a template for the synthesis of viral proteins. The viral RNA is then replicated, packaged into new virus particles, and subsequently released from the host cell to infect other cells, leading to the development of novel coronavirus disease 2019 (COVID-19) ( Figure 2 ). In the absence of prevention or treatment, SARS-CoV-2 primarily targets the respiratory tract and can cause symptoms ranging from mild to severe respiratory illness [ 74 ]. It is worth noting that the virus can also infect other organs, including the skin, kidneys, endocrine organs, and eyes [ 75 ]. The severity of COVID-19 disease can vary widely and is influenced by factors such as age, underlying health conditions, and viral load [ 76 ].

Mounting an effective immune response to SARS-CoV-2 infection plays a crucial role in controlling the virus and mitigating the development of severe disease [ 77 , 78 , 79 , 80 ]. Vaccination, in particular, elicits the production of antibodies targeting the S proteins, which have been shown to generate neutralizing antibodies capable of impeding the virus from infecting host cells. Additionally, T cells are activated, enabling them to identify and eliminate infected cells ( Table 1 ).

Like all viruses, including SARS-CoV-2, there are numerous mutations that can give rise to new variants with distinct characteristics. These characteristics can include rapid transmission, increased disease severity, or resistance to vaccines and treatments [ 81 , 82 ]. These altered versions of the virus are commonly referred to as “variants”. Some variants have shown higher transmissibility and may be linked to an elevated risk of severe illness [ 83 , 84 , 85 ]. The emergence of these variants highlights the critical need for ongoing surveillance and research to comprehend the evolution and dissemination of the virus [ 81 ]. The Omicron variant of SARS-CoV-2, initially identified in South Africa, was reported to the WHO on November 24, 2021, as a novel variant [ 84 ].

3. An update of COVID-19 vaccines

Recent advancements in vaccine technology have led to the development of various vaccines available in the market ( Figure 3 ) [ 6 , 7 ]. These vaccines consist of several crucial components. First, they contain an antigen, which can be in the form of a live-attenuated or killed virus, or a specific protein derived from the virus. The presence of the antigen enables our bodies to recognize and combat the disease if we come into contact with it in the future. Second, vaccines include an adjuvant, which assists in enhancing our immune response and improving the effectiveness of the vaccine. Additionally, vaccines are formulated with preservatives to maintain their efficacy over time, and stabilizers to prevent mechanical failures during storage and transportation. It is important to note that all the ingredients used in vaccines, as well as the vaccines themselves, undergo thorough testing and monitoring to ensure their safety and efficacy [ 7 ].

An overview of the approved COVID-19 vaccines. Fifty approved COVID-19 vaccines were obtained from the COVID-19 vaccine tracker ( https://covid19.trackvaccines.org/ ), with data updated until December 2, 2022, and accessed on June 19, 2023. The vaccine platforms are classified into four main categories, based on their vaccine technologies. Each vaccine platform as a representative example was illustrated for its immunogenic mechanisms. (A) inactivated vaccines (11 vaccines), (B) protein-based vaccines (19 protein vaccines & 1 VLP vaccine), (C) viral vector vaccines (9 vaccines), and (D) nucleic acid vaccines (9 mRNA vaccines & 1 DNA vaccine). This visual depiction was produced using a biorender ( https://www.biorender.com ).

Up until December 2, 2022, a significant milestone has been reached with the approval of 50 vaccines by at least one country. Additionally, the WHO has granted Emergency Use Listing (EUL) to 11 vaccines, benefiting a total of 201 countries [ 86 ]. This remarkable progress showcases the global efforts in combating the COVID-19 pandemic. The extensive pursuit of vaccine development is evident in the reported 821 vaccine trials. Currently, there are 242 vaccine candidates undergoing clinical trials at various stages of progress. Among them, 66 vaccines are in Phase 1 trials, indicating their initial safety and dosage assessments. Phase 2 trials involve 72 vaccines, evaluating their effectiveness in larger populations. Furthermore, 92 vaccines are in Phase 3 trials, which involve large-scale testing to determine their overall efficacy. Notably, 50 vaccines have already received authorization, indicating their successful completion of clinical trials and regulatory approval. These crucial vaccine trials are being conducted in 80 countries worldwide, highlighting the widespread collaboration and dedication in the pursuit of effective COVID-19 vaccines ( Figure 4 ).

An overview of the present scenario concerning COVID-19 vaccines available in the market. The figure was adopted from the COVID-19 vaccine tracker ( https://covid19.trackvaccines.org/ ), with data updated until December 2, 2022, and accessed on June 19, 2023. This visual depiction was produced using a biorender ( https://www.biorender.com ).

Furthermore, the authorized COVID-19 vaccines encompass a diverse array of types, showcasing advancements in medical technology. These include mRNA, DNA, viral vectors, inactivated or killed viruses, and protein-based subunit vaccines ( Figure 3 ). mRNA vaccines, such as the notable ones developed by Pfizer-BioNTech and Moderna, harness the power of genetic material to initiate an immune response within the body. Similarly, DNA vaccines like Zydus Cadila utilize genetic material to stimulate the immune system’s defenses. Viral vector vaccines, such as the well-known ones manufactured by AstraZeneca and Johnson & Johnson, take advantage of a modified virus as a delivery system to transport genetic material and activate the immune response. By utilizing this approach, these vaccines can effectively trigger the body’s defense mechanisms against the virus. Inactivated or killed virus vaccines, exemplified by the commendable efforts of Sinovac or Sinopharm, employ viruses that have been rendered inactive or killed to provoke an immune response. Through this method, the immune system becomes primed to recognize and combat the virus should an actual infection occur. Protein subunit vaccines, including the notable ones produced by Novavax or Medicago, employ specific proteins derived from the virus itself. By introducing these viral proteins into the body, an immune response is triggered, enabling the immune system to develop defenses against the virus. Collectively, these various COVID-19 vaccine platforms have demonstrated their efficacy in generating neutralizing antibodies and stimulating cell-mediated responses, as depicted in Figure 3 and referenced in Tables 1 – 3 .

4. The immunogenicity of COVID-19 vaccines

Vaccine immunogenicity refers to the capacity of a vaccine to stimulate an immune response within the body. The primary objective of vaccination is to activate the immune system, prompting it to recognize and counter specific components of a pathogen, such as a virus, while avoiding the onset of the actual disease [ 87 ]. Upon administration of the vaccine, the immune response is triggered, leading to the activation of various immune cells, including B cells. The immune system identifies the foreign components within the vaccine as antigens and initiates an immune response against them. B cells are responsible for producing antibodies that can neutralize the pathogen or mark it for elimination by other immune cells. T cells, comprising helper T cells and killer T cells, play a crucial role in coordinating and executing the immune response [ 88 ].

Vaccine immunogenicity is evaluated through clinical trials, wherein researchers measure the production of specific antibodies, such as neutralizing antibodies, in the blood of vaccinated individuals ( Table 1 ). These antibodies are designed to recognize and bind to the specific components of the targeted pathogen that the vaccine aims to address. The presence of these antibodies indicates that the vaccine has successfully stimulated an immune response. The level and quality of the immune response induced by a vaccine can vary based on several factors, including the vaccine type, the antigens it contains, the dosage, and the vaccination schedule [ 89 ]. High immunogenicity is desirable as it suggests that the vaccine effectively triggers a robust immune response and provides protection against the specific pathogen being targeted [ 90 ].

Table 1 provides a comprehensive analysis of the immunogenicity of approved COVID-19 vaccines. Overall, these vaccines have been shown to elicit strong immune responses, including the generation of neutralizing antibodies and virus-specific T cells which are effective in reducing the risk of severe disease, hospitalization, and death due to COVID-19.

5. The safety of COVID-19 vaccines

Vaccine safety encompasses the comprehensive evaluation of potential risks and adverse effects associated with the administration of a vaccine. This evaluation involves rigorous testing throughout clinical trials and ongoing monitoring following its approval and widespread use [ 2 ]. Before entering clinical trials, vaccines typically undergo preclinical testing, including laboratory studies and animal testing to assess their safety and effectiveness. This initial evaluation helps identify any potential safety concerns and informs the decision to proceed with human trials. Subsequently, vaccines progress through various phases of clinical trials involving human participants. These trials thoroughly examine the vaccine’s safety, immunogenicity, and efficacy. Throughout these trials, vaccine safety is closely monitored, and participants are carefully observed for any adverse reactions or side effects [ 91 , 92 , 93 ].

Table 2 provides a comprehensive analysis of the safety profile of approved COVID-19 vaccines, which has been extensively studied in both clinical trials and real-world settings. Most of the reported adverse events have been mild and temporary, such as localized pain at the injection site and low-grade fever [ 92 ]. Although rare, there have been reports of more severe adverse events, including anaphylaxis [ 93 ]. However, it is important to note that the occurrence of such serious adverse events is very low [ 93 ]. Overall, the risk of experiencing severe adverse events from the vaccines is significantly lower compared to the risk of severe illness resulting from COVID-19 ( Table 2 ).

6. The efficacy of COVID-19 vaccines

Vaccine efficacy is a measurement of the effectiveness of a vaccine in disease or infection prevention, determined through controlled clinical trials under controlled conditions. This measure quantifies the reduction in disease incidence among vaccinated individuals in comparison to their unvaccinated counterparts, offering insights into the vaccine’s capacity to protect against a specific pathogen. Clinical trials randomly assign participants to receive either the vaccine or a placebo, monitoring the occurrence of the targeted disease or infection in both groups [ 94 ]. By comparing the incidence rates, researchers can calculate the vaccine’s efficacy, expressed as a percentage that represents the reduced risk of developing the disease among vaccinated individuals.

Table 3 provides an efficacy review analysis of approved COVID-19 vaccines in preventing symptomatic COVID-19. Clinical trials and real-world data have demonstrated that all COVID-19 vaccines effectively protect against severe illness, hospitalization, and mortality. When it comes to preventing symptomatic COVID-19, mRNA vaccines have demonstrated notably higher efficacy rates compared to other types of vaccines ( Table 3 ) [ 94 ].

7. Opinions on immunogenicity, safety, and efficacy toward filling gaps of vaccine hesitancy

The evaluation of COVID-19 vaccines takes into account important factors such as immunogenicity, safety, and efficacy. A thorough review of these factors for authorized COVID-19 vaccines reveals that various vaccine platforms, including inactivated vaccines, viral vector vaccines, mRNA vaccines, DNA vaccines, and protein-based vaccines, demonstrate strong immunogenicity by eliciting neutralizing antibodies and cellular immune responses ( Table 1 ). Moreover, studies have demonstrated that these vaccines are both safe and effective in preventing symptomatic cases of COVID-19 ( Tables 2 and 3 ).

In terms of immunogenicity, both the recommended two-dose regimen and a single dose of the Johnson & Johnson vaccine have been shown to elicit strong immune responses in clinical trials and real-world data ( Table 1 ). These responses include the production of neutralizing antibodies and the activation of T-cell responses, which are important for combating the SARS-CoV-2 virus. While the level of immunogenicity may vary among different vaccine platforms, overall, vaccines have proven effective in reducing the severity of COVID-19 symptoms and preventing hospitalization and mortality ( Table 3 ).

When it comes to safety, robust monitoring systems have been implemented to continuously evaluate the side effects of vaccines [ 53 , 92 , 93 ]. Most adverse events have been mild and temporary, including symptoms like pain at the injection site, fatigue, or low-grade fever ( Table 2 ). These mild to moderate side effects have been observed across various vaccine platforms and generally resolve on their own within a few days. Serious adverse events are exceedingly rare [ 53 ], and the benefits of vaccination in preventing severe COVID-19 far outweigh the potential risks. However, ensuring vaccine safety remains a top priority, and ongoing surveillance plays a critical role in promptly addressing any emerging safety concerns [ 53 ].

In terms of efficacy, COVID-19 vaccines have shown remarkable effectiveness in preventing both the incidence and severity of COVID-19 [ 94 ] ( Table 3 ). Vaccination has proven to be highly successful in reducing hospitalizations and fatalities, even in the presence of emerging variants of concern. However, breakthrough infections can still occur, particularly with new variants like “Omicron,” underscoring the need for ongoing surveillance, booster doses, and the development of updated vaccines to address viral mutations. Continued vigilance and adaptation are crucial to ensure the continued effectiveness of COVID-19 vaccination efforts according to a report [ 95 ].

Furthermore, the prime-boost vaccination strategy has demonstrated its potency, safety, and effectiveness in combating COVID-19 ( Tables 2 and 3 ). In addition, studies have shown that heterologous prime-boost vaccination using combinations of an inactivated vaccine, AstraZeneca, Pfizer, and Moderna vaccines can be even more potent compared to homologous prime-boost vaccination using any single vaccine alone [ 96 , 97 ]. The implementation of homologous or heterologous prime-boost vaccination strategies has been observed. In Cambodia, for instance, a homologous or heterologous prime-boost vaccination approach has been implemented, with inactivated vaccines used as the priming vaccine and viral vector or mRNA vaccines as the boosting vaccine. Encouragingly, no adverse events have been reported, and the vaccinated population in Cambodia has experienced a significant reduction in mortality [ 98 ]. These findings further emphasize the overall convenience and benefits of COVID-19 vaccination strategies.

8. Opinions on immunogenicity, safety, and efficacy toward filling gaps of vaccine inequity

In the global context, the impact of COVID-19 vaccines is influenced by the administration of numerous approved vaccines worldwide, as illustrated in Figures 4 and 3 . A staggering 13.47 billion vaccine doses have been administered globally, with an average of 70.3% of the world population having received at least one dose and 93,683 doses being administered daily [ 8 ]. However, it is concerning that only 32.2% of individuals in low and middle-income countries (LMICs) have received at least one vaccine dose, primarily utilizing vaccines with lower prominence [ 8 ]. These statistics highlight the existence of a “vaccine inequity” gap between LMICs and developed nations.

The “vaccine inequity” observed among LMICs can be attributed to several crucial factors. These include the inability of these countries to manufacture their own vaccines, limited budgets to purchase advanced vaccines like Pfizer or Moderna [ 7 ], and concerns regarding the immunogenicity, safety, and efficacy of lower-profile vaccines, which may lead to vaccine hesitancy [ 61 , 62 , 63 , 64 , 65 ]. In light of these challenges, it is important to emphasize that the available vaccines, as outlined in Tables 2 and 3 , have demonstrated overall safety and effectiveness, particularly in reducing hospitalizations and deaths. Therefore, individuals are encouraged to receive any vaccines that are accessible and affordable to help mitigate the impact of COVID-19.

COVAX and vaccine diplomacy are crucial strategies that have significant impacts on achieving equitable distribution of vaccines. By pooling resources and coordinating with vaccine manufacturers, COVAX aims to provide vaccines to LMICs that may otherwise struggle to secure sufficient doses. This initiative helps bridge the gap between nations with ample resources and those facing financial and logistical challenges. In addition, to effectively address vaccine inequity, it is also crucial to establish comprehensive vaccine surveillance systems that monitor the immunogenicity, safety profile, and efficacy of vaccines in regional countries. Taking inspiration from the UK report released by the UK Health Security Agency on October 21, 2021 [ 95 ], implementing such surveillance systems can provide valuable insights and help ensure that vaccines are being administered effectively and safely in different regions. This approach would significantly enhance trust in vaccine uptake within these countries and serve as essential documentation for future vaccine research and development. In Cambodia, for instance, a range of vaccines, including inactivated vaccines (Sinovax & Sinopharm), mRNA vaccines (Pfizer & Moderna), and viral vector vaccines (Astrazeneca & Janssen), are being used [ 7 , 98 ]. It would be highly beneficial if Cambodia also conducts evaluation reports similar to the UK case [ 95 ]. These reports will be invaluable for future vaccine research and development in Cambodia, providing insights into which vaccine-based platforms offer long-lasting protective and therapeutic efficacy for the country’s geographic and regional populations. Additionally, the reports will bolster efforts to enhance vaccine production capabilities, enabling better preparedness for future pandemics and ensuring the availability, safety, effectiveness, and affordability of vaccines in Cambodia.

In the global context, furthermore, as the UK holds the presidency of the G7, it should also consider conducting a comprehensive study in line with the research conducted by Edward J Mills and Gilmar Reis [ 99 ]. This study would involve head-to-head clinical trials comparing vaccines such as Pfizer, Moderna, Astrazeneca, Sputnik V, and Sinopharm, among others. The aim of this study would be to accumulate data and establish trust in the immunogenicity, safety, and efficacy of these vaccines. Including lower-profile vaccines in the study would have a significant impact on many LMICs, maximizing vaccine uptake in those regions. Importantly, such a study would contribute to shaping a better global solution regarding the prioritization of vaccine production, determining who should be offered the vaccine and establishing guidelines for booster shots, both in LMICs and developed nations. Moreover, it would enhance preparedness and control measures for future pandemic threats, ensuring a more effective response.

In cases where certain lower-profile vaccines are not approved for use in the UK, conducting a head-to-head study becomes limited. However, it is crucial to consider alternative approaches such as a collective report from G7 and G20 countries, along with data from LMICs. This would provide a more comprehensive analysis of vaccines’ immunogenicity, safety, and efficacy. Additionally, the inclusion of vaccines like the DNA vaccine (Zydus Candila) from India, VLP (Medicago) from Canada, and Novavax (USA) ( Figure 3 ) should be considered. Another valuable approach would be to develop a methodology that combines data from separate studies to estimate the immunogenicity, safety, and efficacy of different vaccines. This approach would enhance the credibility and reliability of the findings.

9. Opinions on immunogenicity, safety and efficacy toward future epidemic preparedness and control

This report presents an update on the current landscape of COVID-19 vaccines, emphasizing their immunogenicity, safety, and efficacy in the context of filling gaps of vaccine hesitancy, vaccine inequity, and future epidemic preparedness and control. The development and widespread administration of vaccines have played a crucial role in mitigating the impact of the ongoing COVID-19 pandemic [ 9 , 10 ]. With numerous vaccines receiving emergency use authorization, the knowledge gained from their development and deployment can significantly contribute to future epidemic preparedness and control efforts [ 100 ]. The remarkable speed at which vaccines were developed and distributed globally highlights the potential for expediting vaccine development in response to emerging infectious diseases. Through collaborative endeavors involving governments, researchers, and pharmaceutical companies, we can further enhance vaccine production, distribution, and ensure equitable access, thus strengthening global preparedness against future epidemics [ 7 ].

Furthermore, it is crucial for LMICs to prioritize the enhancement of laboratory capacities to enable prompt and accurate diagnosis of infectious diseases [ 101 ]. This can be achieved by investing in infrastructure, equipment, and training for laboratory personnel. By strengthening laboratory capabilities, LMICs can effectively contribute to epidemic prevention, detection, and control. It is also important for LMICs to allocate resources to support research and development initiatives focused on combating epidemics [ 7 ]. This entails providing financial support to local research institutions, fostering collaborations with international partners, and conducting studies on the local epidemiology of infectious diseases, actively practice in non-pandemic times through one health concept [ 101 ]. To ensure reliable and standardized testing, it is imperative to establish well-equipped laboratories, provide comprehensive training to laboratory staff, and implement robust quality control measures [ 7 ]. Additionally, addressing vaccine hesitancy is paramount. This can be accomplished through transparent communication, accessible education, and community engagement. Public health campaigns should prioritize disseminating accurate information, dispel myths and misinformation, and address concerns in order to enhance vaccine acceptance among the population.

10. Conclusion

In summary, the utilization of COVID-19 vaccines has demonstrated their effectiveness in mitigating the impact of the pandemic, showcasing favorable immunogenicity, safety, and efficacy against the virus. These valuable insights gained from developing and deploying vaccines can be invaluable for future epidemic preparedness and control. To ensure successful vaccination strategies in future outbreaks and epidemics, it is imperative to prioritize factors such as maintaining public trust, promoting equitable access to vaccines, and continuing research and development efforts. By applying these lessons, we can strengthen our readiness to effectively address and control potential future epidemics.

Conflict of interest

The authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this chapter.

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• 94. Grana C, Ghosn L, Evrenoglou T, Jarde A, Minozzi S, Bergman H, et al. Efficacy and safety of COVID-19 vaccines. Cochrane Database of Systematic Reviews. 2022; 12 (12):CD015477. DOI: 10.1002/14651858.CD015477
• 95. UK Health Security Agency. COVID-19 Vaccine Surveillance report Week 42. 2021. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1027511/Vaccine-surveillance-report-week-42.pdf
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• Published: 27 May 2024

Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England

• Emma Copland   ORCID: orcid.org/0000-0001-9280-5241 1 ,
• Martina Patone 1 ,
• Defne Saatci   ORCID: orcid.org/0000-0002-2414-2906 1 ,
• Lahiru Handunnetthi 2 , 3 ,
• Jennifer Hirst 1 ,
• David P. J. Hunt   ORCID: orcid.org/0000-0003-4230-0207 4 ,
• Nicholas L. Mills   ORCID: orcid.org/0000-0003-0533-7991 5 , 6 ,
• Paul Moss   ORCID: orcid.org/0000-0002-6895-1967 7 ,
• Aziz Sheikh   ORCID: orcid.org/0000-0001-7022-3056 1 , 6 ,
• Carol A. C. Coupland 1 , 8 ,
• Anthony Harnden 1 ,
• Chris Robertson   ORCID: orcid.org/0000-0001-6848-5241 9 &
• Julia Hippisley-Cox   ORCID: orcid.org/0000-0002-2479-7283 1  

Nature Communications volume  15 , Article number:  3822 ( 2024 ) Cite this article

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• Epidemiology
• Public health

The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1–42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0–23) hospitalisations with epilepsy and 4 (95%CI 0–6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

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Introduction.

The United Kingdom (UK) approved COVID-19 vaccination for all children aged 12 and over in September 2021. This was extended to 5–11-year-olds in April 2022 in a one-off programme offering a primary course of COVID-19 vaccination to children who were not in a vulnerable or high-risk group 1 . Despite uptake being very high in adults, with over 80% receiving at least one dose of COVID-19 vaccine as of 11th May 2023, uptake has been lower in children, with 62% of 16–17-year-olds, 46% of 12–15-year-olds and 10% of 5–11-year-olds being vaccinated against COVID-19 2 . In the UK, the vast majority of vaccinated children received the BNT162b2 (Pfizer/BioNTech) COVID-19 vaccine, as the UK Joint Committee on Vaccination and Immunisation (JCVI) advised against using ChAdOX1 (AstraZeneca) in people under 40 or mRNA-1273 (Moderna/SpikeVax) in children under 18 during the time period that most children were vaccinated 3 .

In November 2022, the JCVI recommended that 16–49-year-olds who are not in a clinical risk group should no longer be offered a third dose of vaccine from February 2023, and that primary course vaccination in 5–49-year-olds should be targeted to groups at high risk of severe COVID-19 4 . They have advised to continue vaccinating clinically vulnerable children aged 6 months and above and to vaccinate otherwise healthy children aged 12 years and above living with immunosuppressed individuals 4 .

Although the benefits of COVID-19 vaccines in older adults clearly outweigh the risks of rare complications 5 , 6 , 7 , 8 , the balance of risks and benefits in young people remains uncertain. Whilst clinical trials have demonstrated the effectiveness of COVID-19 vaccines in reducing the risk of severe COVID-19 in children aged 5–15 years, the absolute risk of severe outcomes, including hospitalisation, intensive care unit (ICU) admission and death, following infection is low 9 , 10 , 11 , 12 . A serious consequence of SARS-CoV-2 infection in children is multisystem inflammatory syndrome (MIS-C) 13 , 14 , which can lead to coronary artery aneurysms, cardiac dysfunction, and multiorgan inflammatory manifestations 15 . Post-COVID syndrome, or long COVID, is another serious outcome of SARS-CoV-2 infection 16 . The possible impact of long COVID in children is still unclear, but it is estimated to affect 10% of those infected by SARS-CoV-2 and could potentially result in lifelong illness 16 , 17 . COVID-19 vaccines in childhood may reduce the risk of MIS-C 13 and long COVID 17 , and secondary benefits might include increasing overall population immunity, thereby minimising disruptions to education and maintaining overall well-being and health within this age group.

Concerns around vaccine safety have been identified as a barrier to COVID-19 vaccine acceptance, particularly in the context of parents and guardians giving consent for their children to be vaccinated 18 , 19 , 20 . An increased risk of myocarditis has been consistently reported after the delivery of mRNA vaccines, predominantly affecting males aged 18 to 35 years and most notably after the second dose 21 , 22 . This elevated risk of mRNA vaccination-associated myocarditis has also been reported in adolescent males, although these cases have generally been mild and the long-term prognosis is favourable 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . No serious safety concerns have yet been raised in younger children; however, population-based studies assessing the risk of adverse events following vaccination compared with an unvaccinated group are lacking 33 , 34 , 35 .

In light of the JCVI’s advice to continue vaccinating specific groups of children against COVID-19, and the potential for future mass vaccination programmes if new SARS-CoV-2 variants emerge or the number of severe COVID-19 cases increase, it remains important to quantify the overall risks and benefits of COVID-19 vaccination in this age group to inform future vaccine policy. Therefore, our primary aim was to investigate and compare the risks of pre-specified vaccine safety outcomes following vaccination with BNT162b2, mRNA-1273 and ChAdOX1 in children. We also aimed to compare the risks of these safety outcomes following SARS-CoV-2 infection in vaccinated and unvaccinated children, as a guide to inform global public health policy considerations.

We used the English National Immunisation Management Service (NIMS) database of COVID-19 vaccination, linked at the individual-level to national data for mortality, hospital admissions, and SARS-CoV-2 infection. We undertook a self-controlled case series design, originally developed to examine vaccine safety 36 , 37 , to investigate the association between COVID-19 vaccines available in the UK between 8th December 2020 and 7th August 2022 (BNT162b2, mRNA-1273 and ChAdOx1) and hospitalisation with the following pre-specified outcomes: myocarditis 21 , 22 , MIS-C 38 , immune thrombocytopenia (ITP) 39 , epilepsy 40 , acute pancreatitis 41 , acute disseminated encephalomyelitis (ADEM) 42 , Guillain-Barre syndrome 43 , appendicitis 44 , demyelinating disease 6 , myositis 45 , angioedema 46 and anaphylaxis 46 . We also investigated the association of SARS-CoV-2 infection with these outcomes in children who had been vaccinated prior to infection compared to those who were unvaccinated at time of infection. We compared the incidence of hospitalisation from each outcome in the six weeks following vaccination or SARS-CoV-2 infection relative to the baseline period, and estimated the absolute risk as the excess number of events expected per million children exposed. We also conducted a matched cohort analysis using vaccinated and unvaccinated children included the QResearch primary care database to improve the robustness of the study.

Number of children receiving COVID-19 vaccines

A total of 5,197,925 young people aged 5–17 years, comprising 1,842,159 children aged 5–11 years and 3,355,766 adolescents aged 12–17 years were included in the study. 4,347,781 young adults aged 18–24 years, were included as a comparison. The characteristics of the young people included in the study are detailed in Table  1 and Supplementary Table  1 .

In children aged 5–11 years, 32% ( n  = 581,545) received at least one dose of COVID-19 vaccine and 16% ( n  = 303,118) received a second dose within the study period. Over 99.9% of 5–11-year-olds who received at least one COVID-19 vaccine dose received the BNT162b2 vaccine (Table  2 ). 82% ( n  = 1,508,661) of children in this age group had a positive SARS-CoV-2 test recorded between 8th December 2020 and 7th August 2022, 0.4% ( n  = 5665) of whom received their first COVID-19 vaccine dose prior to their first recorded positive SARS-CoV-2 test (Table  2 ).

In adolescents aged 12–17 years, 86% ( n  = 2,882,229) received a first dose of COVID-19 vaccine, 67% ( n  = 2,254,214) received a second dose and 14% ( n  = 454,868) received a third dose (Table   2 ).

The characteristics of the population excluded from the self-controlled case series analysis (i.e. those who did not receive any COVID-19 vaccine and did not have a positive SARS-CoV-2 test recorded during the study period) are presented in Supplementary Table  2 .

Risk of pre-specified safety outcomes following COVID-19 vaccination in children aged 5–11 years

In children aged 5–11 years, we did not observe an increased risk of any of the pre-specified outcomes in the 1–42 days following any dose COVID-19 vaccine with BNT162b2, mRNA-1273 or ChAdOX1 (Table  3 ). However, given that less than 0.1% of vaccinated 5-11-year-olds received a ChAdOX1 or mRNA-1273 vaccine, the probability of type II errors was high as the sample size was too small to detect statistically significant associations for these vaccines.

The clinical characteristics of all children hospitalised with a pre-specified safety event are shown in Supplementary Table  3 . Supplementary Tables  4 – 7 show the incidence rate ratios (IRR) and 95% confidence intervals (CI) for all outcomes 1–42 days and in weekly risk periods following each vaccine dose in 5–11-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome.

Risks of pre-specified safety outcomes following COVID-19 vaccination in adolescents aged 12–17 years

In the 1–42 days after the first and second doses of BNT162b2, we observed an increased risk of myocarditis in adolescents aged 12–17 years (IRR 1.92, 95%CI 1.08–3.43 and IRR 2.96, 95%CI 1.65–5.32 for first and second dose, respectively) (Table  4 ). We estimated that an additional 3 (95%CI 0–5) cases per million exposed would be anticipated after the first dose and 5 (95%CI 3–6) after the second dose (Fig.  1 ). When we split the risk period into weekly blocks, the increased risk was restricted to 1–14 days following each dose (Supplementary Table  8 ). There was also an increased risk of hospitalisation with epilepsy (IRR 1.17, 95%CI 1.00–1.37; excess events per million: 12, 95%CI 0–23) in the 1–42 days following the second dose of BNT162b2 (Table  4 , Fig.  1 ).

Estimated number of excess events per million (95% CI) based on incidence rate ratios of each outcome in the 1–42 days following vaccination or SARS-CoV-2 positive test compared to baseline period are presented where there were at least five events during the exposure period and when number of excess events is greater than zero. Data available from 8th December 2020 and 7th August 2022. Table  4 contains the data presented in this figure. MIS-C Multisystem inflammatory syndrome; ITP Idiopathic or immune thrombocytopenic purpura, ADEM Acute disseminated encephalomyelitis.

In the sex-stratified analysis, the increased risk of myocarditis after the first dose of BNT162b2 was only observed in females (IRR 4.01, 95%CI 1.33–12.09; excess events per million: 3, 95%CI 1–4), while the increased risk following the second dose was observed in males only (IRR 2.87, 95%CI 1.50–5.51; excess events per million: 9, 95%CI 4–11) (Supplementary Figs.  1 & 2 , Supplementary Tables  4 & 5 ). We additionally observed an increased risk of demyelinating disease, restricted to females (IRR 2.41, 95%CI 1.06-5.48; excess events per million: 4, 95%CI 0–6) following the second dose of BNT162b2. Of the eight female adolescents who experienced demyelinating disease in the 1–42 days following a second dose of BNT162b2, five were coded as optic neuritis.

In a post hoc analysis investigating differences in risk between children of different ethnic backgrounds, we found that the risk of anaphylaxis following a second dose of BNT162b2 in adolescents with non-white ethnicity was higher relative to the risk in adolescents with white ethnicity (relative IRR 2.55, 95%CI 1.00–6.46) (Supplementary Table  6 ). However, when the analysis was restricted to the subgroup of adolescents from non-white ethnic backgrounds, the risk of anaphylaxis in the 1–42 days following a second dose of BNT162b2 was not significantly increased compared to the baseline period (IRR 1.69, 95%CI 0.80–3.54) (Supplementary Table  6 ). We did not identify any differences in vaccine safety between white and non-white ethnicity for any of the other pre-specified outcomes in under-18s.

We found no evidence for significantly increased risks for any of the pre-specified outcomes in the 1–42 days following a first, second or third dose of mRNA-1273 vaccine in 12–17-year-olds (Table  4 ). However, this analysis lacked power to detect statistically significant associations, except for very large effect sizes, as less than 0.1% of adolescents received a first or second dose of mRNA-1273 vaccine.

There was an increased risk of hospitalisation with epilepsy 1–42 days after a first dose of ChAdOX1 (IRR 1.93, 95%CI 1.10–3.39), with an additional 705 (95%CI 129–1033) cases expected per million exposed (Table  4 ). This increased risk was restricted to females in the sex-stratified analysis (IRR 2.26, 95%CI 1.03–4.94) with an additional 813 (95%CI 44–1164) hospitalisations with epilepsy expected per million female adolescents exposed (Supplementary Table  4 ).

We also observed an increased risk of appendicitis in the 1–42 days following the second dose of ChAdOX1 (IRR 4.64, 95%CI 1.77–12.17; excess events per million: 512, 95%CI 283–599) (Table  4 ).

The IRRs and 95% CIs for all outcomes 1–42 days and in weekly risk periods following each vaccine dose in 12–17-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome, are presented in Supplementary Figs.  1 & 2 , Supplementary Tables  4 – 6 & 8 .

Risks of pre-specified safety outcomes following COVID-19 infection in children aged 5–11 years

In children aged 5-11 years who had received at least one dose of COVID-19 vaccine before the date that their positive SARS-CoV-2 test was recorded, we did not observe increased risks of any of the pre-specified outcomes in the 1–42 days following SARS-CoV-2 infection. In children who had not been vaccinated against COVID-19 prior to infection, there was an increased risk of hospital admission with MIS-C following a SARS-CoV-2 positive test (IRR 11.52, 95%CI 9.25–14.36), with an additional 137 (95%CI 134–140) cases expected per million exposed (Table  3 , Fig.  2 ). In the sex-stratified analysis, the risk of MIS-C was slightly greater in male children (IRR 12.00, 95%CI 8.92–16.12; excess events per million: 162, 95%CI 157-166) compared to female children (IRR 11.13, 95%CI 7.96–15.57; excess events per million: 124, 95%CI 119–127) (Supplementary Figs.  3 & 4 , Supplementary Tables  4 & 5 ). The increased risk was mainly observed in the 22–42 days following the date that the positive SARS-CoV-2 test was recorded (Supplementary Table  7 ).

Estimated number of excess events per million (95% CI) based on incidence rate ratios of each outcome in the 1–42 days following SARS-CoV-2 positive test compared to baseline period are presented where there were at least five events during the exposure period and when number of excess events is greater than zero. Data available from 8th December 2020 and 7th August 2022. Table  3 contains the data presented in this figure. MIS-C Multisystem inflammatory syndrome, ITP Idiopathic or immune thrombocytopenic purpura, ADEM Acute disseminated encephalomyelitis.

We also observed increased risks of hospital admission for myositis, myocarditis, acute pancreatitis and ADEM following SARS-CoV-2 infection before vaccination (Table  3 , Fig.  2 ). In the sex-stratified analyses, we additionally identified increased risks of ITP (in both sexes) and anaphylaxis (in females only) (Supplementary Figs.  3 & 4 , Supplementary Tables  4 & 5 ).

The IRRs and 95% CIs for all outcomes 1–42 days following SARS-CoV-2 infection in 5–11-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome, are presented in Supplementary Figs.  3 & 4 , Supplementary Tables  4 , 5 , 6 & 7 .

Risks of pre-specified safety outcomes following COVID-19 infection in adolescents aged 12–17 years

In adolescents aged 12–17 years, we observed an increased risk of MIS-C (IRR 12.38, 95%CI 8.88–17.28; excess events per million: 84, 95%CI 81–86) in the 1–42 days following a SARS-CoV-2 infection in those who had not been vaccinated prior to SARS-CoV-2 infection (Table  4 , Fig.  1 ). In the sex-stratified analysis, male adolescents were at higher risk of MIS-C following infection compared to females (IRR 12.33, 95%CI 8.31–18.31 and IRR 13.11, 95%CI 6.90–24.91 in males and females, respectively), with an additional 131 (95%CI 126–135) cases expected per million males exposed compared to 48 (95%CI 44-50) in females (Supplementary Figs.  1 & 2 , Supplementary Tables  4 & 5 ).

We also observed increased risks of hospitalisation with myocarditis, ITP and epilepsy in the 1-42 days following SARS-CoV-2 infection in adolescents who had not been vaccinated against COVID-19 prior to infection as well as an increased risk of hospitalisation with epilepsy in those who had received at least one vaccine dose prior to infection (Table  4 , Fig.  1 ). In the sex-stratified analysis, the increased risks of hospitalisation with myocarditis and epilepsy were restricted to males while the increased risk of ITP following infection was only observed in females (Supplementary Figs.  1 & 2 , Supplementary Tables  4 & 5 ). We additionally identified increased risks of appendicitis (in females only) and anaphylaxis (in males only) following SARS-CoV-2 infection.

The IRRs and 95% CIs for all outcomes 1–42 days following SARS-CoV-2 infection in 12-17-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome, are presented in Supplementary Figs.  1 & 2 , Supplementary Tables  4 , 5 , 6 & 8 .

The results for all analyses in young adults aged 18-24 years are presented in Supplementary Tables  6 & 9 .

Robustness of the self-controlled case series results

The robustness of the results of the self-controlled case series analyses were assessed by (1) checking that the risk of outcomes during the pre-vaccination period (month prior to vaccination to account for potential bias of people with recent hospitalisation being less likely to get vaccinated) was lower than the baseline period and (2) checking that the risk of the positive control outcome (anaphylaxis) was higher following vaccination or SARS-CoV-2 infection than the baseline period. In the vast majority of analyses the estimates of the pre-vaccination period and the risk of anaphylaxis following vaccination or SARS-CoV-2 agreed with what was expected (Supplementary Tables  8 & 9 ).

Matched cohort study

Our matched cohort analysis included 1,580,869 children aged 5–11 years and 1,535,341 adolescents aged 12–17 years. Characteristics of the cohort are detailed in Supplementary Table  10 .

Incidence rates of vaccine safety outcomes in the 1–42 days following each vaccine dose and following SARS-CoV-2 infection in vaccinated and unvaccinated children are presented in Supplementary Table  11 . Incidence rates for all outcomes were significantly higher following SARS-CoV-2 infection compared to COVID-19 vaccination.

We matched 160,262 children aged 5–11 years and 848,186 adolescents aged 12–17 years who had received at least one dose of COVID-19 vaccine to a child of the same age and sex who had not received any COVID-19 vaccine doses by the date of the vaccinated child’s first vaccine dose (characteristics of matched cohort reported in Supplementary Table  12 ).

As in the self-controlled case series analysis, we identified an increased risk of hospitalisation with epilepsy in the 1–42 days following a second dose of COVID-19 vaccine with BNT162b2 in 12-17-year-olds (unadjusted IRR 1.77, 95%CI 1.05–2.99, adjusted IRR 3.88, 95%CI 1.27–11.86), but did not find significantly increased risks of appendicitis or myocarditis with BNT162b2 vaccination in adolescents (Supplementary Table  13 ).

We identified additional increased risks of anaphylaxis and appendicitis in 12-17-year-olds following a first dose of BNT162b2 (unadjusted IRR 3.71, 95%CI 1.23–11.14 and unadjusted IRR 1.37, 95%CI 1.05–1.80, respectively) and an increased risk of hospitalisation with epilepsy following a first dose with BNT162b2 in 5–11-year-olds, although the confidence interval was very wide reflecting the uncertainty of the estimate (unadjusted IRR 16.00, 95%CI 2.12–120.65) (Supplementary Table  13 ).

In general, the estimates from the matched cohort study were in agreement with the results from the self-controlled case series analysis in under-18s.

Unadjusted IRRs and IRRs adjusted for self-reported ethnicity (white, non-white, missing), quintile of deprivation (based on Townsend score) and presence of comorbidity (yes/no) for each outcome are reported in Supplementary Table  13 .

In our study of approximately 5.1 million young people aged 5–17 years, we have examined the risks of vaccine safety outcomes following COVID-19 vaccination and SARS-CoV-2 infection, stratified by age group (5–11 years and 12–17 years) and additionally by sex (males and females). We report several key findings that are relevant to public health policy makers. Firstly, we found no strong evidence for increased risks of any of the 12 safety outcomes investigated following COVID-19 vaccination in children aged 5–11 years. Second, in adolescents aged 12–17 years, we observed an increased risk of hospital admission for myocarditis following a first or second dose of BNT162b2, and an increased risk of hospitalisation with epilepsy and demyelinating disease (in females only) following a second dose of BNT162b2 in our primary analysis. Third, children and adolescents aged 5–17 years who had not received a COVID-19 vaccine dose prior to SARS-CoV-2 infection had an increased risk of hospitalisation from seven of the pre-specified safety outcomes including MIS-C and myocarditis. Finally, the risks of safety outcomes from SARS-CoV-2 infection were largely absent in 5–17-year-olds who received at least one COVID-19 vaccine dose prior to infection.

In our cohort of > 2.8 million vaccinated adolescents aged 12–17 years, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) excess cases of myocarditis per million exposed in the 1–42 days following a first and second dose of BNT162b2, respectively. We did not observe an increased risk of myocarditis following vaccination with mRNA-1273 in adolescent males or females as some previous studies have reported 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . However, the mRNA-1273 vaccine was only given to a relatively small number of adolescents in England, primarily for the third booster dose, therefore the study was underpowered to detect statistically significant associations, except for very large effect sizes. As expected, we observed a substantially increased risk of myocarditis in the 1–42 days following almost all doses of both mRNA vaccines in young adults aged 18–24 years compared to the baseline period, consistent with other studies reporting an increased risk of myocarditis in young adult males following a second mRNA-1273 vaccine dose 24 , 25 , 26 . Importantly, however, there were no deaths following a diagnosis of myocarditis in under-18s, and our findings are likely to reflect self-limiting disease.

We also observed a modest increased risk of hospitalisation with epilepsy in adolescents following a second dose of BNT162b2, with an additional 12 (95%CI 0-23) cases estimated per million exposed in 12–17-year-olds. However, a diagnosis of epilepsy is made over a period of time as it typically involves outpatient referral, a magnetic resonance imaging (MRI) scan and an electroencephalogram 47 . Therefore, this reported increased risk of epilepsy is highly unlikely to reflect new-onset epilepsy triggered by the vaccine. A limitation of the data was that we were only able to exclude prior hospital admissions with epilepsy (or any of the pre-specified outcomes) in the two years preceding the study start date. Therefore, the increase in admissions reported here is more likely to reflect seizures in children with an already underlying diagnosis of epilepsy or other chronic neurological condition but who hadn't been hospitalised in the previous two years, which we were unable to capture in our dataset, rather than new diagnoses.

Seizure exacerbation following COVID-19 vaccination has been reported in previous studies, but primarily in adults with epilepsy rather than children 40 . One survey of 224 children (median age 8 years) with epilepsy reported that 10% of those who had been living with epilepsy for more than two years or who had not been seizure-free in the year prior to vaccination had seizures in the month following the first and second dose of COVID-19 vaccine 48 . However, in children who were seizure-free for at least six months before they were vaccinated, the risk of seizures was decreased following vaccination 48 . Another survey of 278 people with Dravet Syndrome (with a median age 19 years) showed that there was increased seizure frequency following COVID-19 vaccination in 13% of the 120 participants who had received at least one vaccine dose 49 . Our findings suggest that the BNT162b2 vaccine is associated with a small increased risk of hospitalisation with epilepsy, but this risk is most likely restricted to children with pre-existing epilepsy and should be balanced against risks of hospitalisation through natural infection with SARS-CoV-2.

In the sex-stratified analysis, we identified a small increased risk of demyelinating disease in females following a second dose of BNT162b2, with an estimated 4 (95%CI 0-6) excess cases per million. To date there has been weak evidence linking mRNA vaccines with neuroimmunological disorders 50 , 51 , and a similar self-controlled case series in adults only identified links between the ChAdOX1 vaccine and neuroimmunological conditions 6 . The coding description demyelinating disease can refer to a spectrum of monophasic and chronic neuroinflammatory disorders, however, the majority of cases following BNT162b2 were coded as optic neuritis, which is typically monophasic and associated with good visual recovery in most childhood cases 52 . From the neurological perspective, this risk should be balanced against the protection vaccination offers against rare and more severe neuroimmunological sequelae of COVID-19 infection such as ADEM.

This study identified two strong safety signals in adolescents associated with the ChAdOX1 vaccine: appendicitis and epilepsy. A substantially increased risk of appendicitis was observed in adolescents following a second dose of ChAdOX1, with an additional 512 (95%CI 283–599) cases expected per million. This estimate is based on a small sample size as the ChAdOX1 vaccine was not approved for use in under-40s in the UK from April 2021 3 , 53 . Additionally, the increased risk was not identified in the matched cohort study, suggesting the evidence from this study for a causal association between appendicitis and ChAdOX1 vaccination is weak. Appendicitis was highlighted as an outcome of interest for vaccine safety by the US Food and Drug Administration following a clinical trial of BNT162b2, which reported a higher number of appendicitis cases in the vaccine arm compared to the placebo arm 44 . However, subsequent evidence from observational studies and adverse event reporting databases is conflicting, limited to adults and primarily focusing on mRNA vaccines 11 , 54 , 55 .

Following a first dose of ChAdOX1, we observed a substantially increased risk of hospitalisation with epilepsy, particularly in females, with 813 (95%CI 44–1164) excess cases estimated per million female adolescents vaccinated with a first dose of ChAdOX1, but as discussed above, these are not likely to reflect new diagnoses of epilepsy. The small sample size (only 0.3% of adolescents received ChAdOX1 for the first dose) and resulting wide confidence interval for this estimate should be noted. We also found that there was a higher proportion of adolescents with a hospital admission for epilepsy in the two years prior to the study start date who received ChAdOX1 for the first dose (2.7%), compared to BNT162b2 (0.2%) and mRNA-1273 (0.6%). While these individuals were excluded from the analysis, it is indicative that a higher proportion of adolescents who received a ChAdOX1 vaccine were included in a priority group, such as those with a chronic neurological disease including epilepsy 3 , compared to those who received mRNA vaccines and that the majority of hospitalisations with epilepsy following ChAdOX1 were likely in adolescents with a pre-existing condition. We did not identify an increased risk of hospitalisation with epilepsy following vaccination with ChAdOX1 in the matched cohort study. Our findings, together with a recent study that found evidence for increased risk of cardiac death in young women following a first dose of non-mRNA vaccine 56 , suggest that further work would need to be done to ensure the safety of ChAdOX1 in young people if it were to be used in future vaccination programmes.

In our cohort of > 580,000 children aged 5–11 years who were vaccinated against COVID-19, we found no evidence for increased risks of any of the pre-specified adverse events following any dose of BNT162b2, mRNA-1273 or ChAdOX1 vaccine 33 , 34 , 35 . Based on vaccine uptake rates reported by the UK Health Security Agency 2 , this analysis includes most vaccinated children in this age group in England, however, the lack of safety signals identified in this analysis could partially reflect the relatively small sample size due to the low uptake rate of COVID-19 vaccines in 5–11-year-olds. In the matched cohort study including > 160,000 vaccinated 5–11-year-olds, we additionally found an increased risk of hospital admission with epilepsy following a first dose with BNT162b2 compared to unvaccinated children. However, given that epilepsy was not identified as a safety signal in this age group in the self-controlled case series analysis and the lengthy diagnosis pathway for epilepsy as described above, this potential increased risk is most likely restricted to children with pre-existing epilepsy.

Following SARS-CoV-2 infection we observed increased risks of hospital admission from MIS-C, myocarditis, acute pancreatitis, myositis and ADEM in children aged 5–11 years who had not been vaccinated against COVID-19 prior to infection. Most notably, we estimated an additional 137 (95%CI 134–140) hospital admissions from MIS-C in the four to six weeks after the date of a positive test being reported per million children exposed. We also observed increased risks of MIS-C, myocarditis, ITP and hospitalisation with epilepsy in adolescents aged 12–17 years following SARS-CoV-2 infection in those who had not been vaccinated prior to infection. 84 (95%CI 81-86) additional cases of MIS-C per million exposed would be expected following SARS-CoV-2 infection in adolescents of this age group prior to vaccination.

However, in both children and adolescents, these increased risks of serious outcomes from SARS-CoV-2 infection were absent in those who received at least one dose of COVID-19 vaccine prior to infection. The exception was hospitalisation with epilepsy. Our analyses suggested that the risk of admission to hospital with epilepsy was increased following SARS-CoV-2 infection in adolescents aged 12–17 years who were not vaccinated against COVID-19 prior to infection, with an estimated additional 16 (95%CI 2–28) cases per million. A risk was still seen following infection in those who received at least one vaccine dose prior to infection, but at a slightly lower level, with an additional 15 (95%CI 1–24) hospital admissions with epilepsy per million. This study has shown that vaccination is associated with a significantly reduced risk of most SARS-CoV-2 complications in young people, particularly MIS-C, which can be fatal 15 .

This study has several strengths. First, this was a population-based study of prospectively recorded data not subject to recall and selection biases linked to case reports. Second, the large sample size allowed us to investigate rare outcomes, particularly following vaccination with BNT162b2, which could not be assessed through clinical trials. Third, the self-controlled case series study design removes potential confounding from fixed characteristics, and the additional breakdown of our study period into weekly blocks accounted for temporal confounding. We also assessed the robustness of our results through several sensitivity analyses, a matched cohort analysis and a parallel analysis in 18–24-year-olds to ensure that the results from our study were consistent with the current evidence base in adults.

There were also some limitations to this study. First, despite the large sample size, this study may have been under-powered to investigate rare outcomes in 5–11-year-olds due to the relatively small proportion of vaccinated children in this age group. Second, we relied on hospital admission codes and death certification to define the outcomes so our design will not have captured milder events only occurring in the community or only reported in GP records. This could have resulted in a misclassification bias. Third, we only had access to cases of SARS-CoV-2 infection confirmed with a reverse transcription polymerase chain reaction (RT-PCR) test in our database, which were more likely to happen in the early stages of the pandemic or in a hospital setting, and less likely to be used in schools and community settings where the vast majority of routine testing took place. We were also unable to account for unascertained SARS-CoV-2 infections, therefore, some of the adverse events could be misclassified as being associated with vaccination rather than a SARS-CoV-2 infection that was not recorded and the analysis of adverse outcomes following SARS-CoV-2 infection may have been biased by incomplete COVID-19 testing in the English population. Fourth, we were unable to determine the effect of SARS-CoV-2 variant on the risk of adverse events, as detailed data on the viral variant of SARS-CoV-2 underlying recorded infections was also not available in our database. Fifth, although we adjusted for seasonal effects in the self-controlled case series models, we did not explicitly investigate the effect of the wave of the pandemic during which the infection occurred on the risk of adverse events. For example, the incidence of MIS-C has been reported to be lower during the periods when Delta and Omicron variants were dominant, even before 12–15-year-olds started being vaccinated, compared to the period when the Alpha variant was dominant 57 . Given that > 98% of children in this study were vaccinated against COVID-19 during the periods that Delta and Omicron were dominant, we may expect a lower incidence of MIS-C following infection in vaccinated children, who were unlikely to have been infected with the Alpha variant, compared to unvaccinated children, who had a higher likelihood of being infected with the Alpha variant. Lastly, we were unable to assess differences in vaccine safety by level of deprivation, which should be prioritised as a future area of research.

In summary, we found no strong evidence for increased risks of 12 pre-specified vaccine safety outcomes following COVID-19 vaccination in children aged 5–11 years and no new significant safety concerns in 12–17-year-olds following vaccination with mRNA vaccines recommended for use in these age groups in the UK by the JCVI. Additionally, in unvaccinated children we found increased risks of hospitalisation from seven adverse outcomes including MIS-C and myocarditis following SARS-CoV-2 infection that were either not observed, or were reduced, following vaccination. Overall, our findings support a favourable safety profile of COVID-19 vaccination using mRNA vaccines in children and young people aged 5-17 years.

Ethics approval and consent to participate

The QResearch® ethics approval was provided by the East Midlands-Derby Research Ethics Committee [reference 18/EM/0400] and reviewed by the QResearch science committee [Project OX300]. Consent from participants was not required. The study was performed in accordance with the Declaration of Helsinki.

Data sources

We used the NIMS database of COVID-19 vaccination. We linked individual-level vaccination data to national data for mortality (Office for National Statistics), hospital admissions (Hospital Episode Statistics), and SARS-CoV-2 infection assessed by RT-PCR (Second Generation Surveillance System) using the unique NHS number. Additional analyses to assess robustness of the results made use of the QResearch database, which includes anonymised health records from ~1800 family practices across England.

Study design

We undertook a self-controlled case series design, originally developed to examine vaccine safety 36 , 37 , to explore the association between BNT162b2, mRNA-1273 and ChAdOx1 vaccines and pre-specified outcomes. Separate analyses were conducted for each outcome. The analyses were conditional on each case, thus any fixed characteristic during the study period, such as sex and ethnicity, were inherently controlled for by design. Age was considered as a fixed variable because the study period was short.

Study period and population

The cohort included all children aged 5–17 years who had received at least one dose of BNT162b2, mRNA-1273 or ChAdOx1 vaccine or who had a positive SARS-CoV-2 test between 8th December 2020 and 7th August 2022. In each self-controlled case series analysis, we only included children who were admitted to hospital or died from the outcome during the study period and excluded children with a hospitalisation for the same outcome in the two years prior to 8th December 2020 and those who received other COVID-19 vaccine types. We also undertook an analysis in young adults aged 18–24 years as a comparison.

We a priori selected severe outcomes resulting in hospital admission or death which are monitored by national medical regulatory authorities, clinical trials, post-marketing surveillance, emerging scientific literature and neurological, cardiology, paediatric and immunology/vaccine expertise available. Our pre-defined outcomes were previously reported COVID-19 infection- and COVID-19 vaccination-related adverse events with strong evidence in young people: myocarditis 21 , 22 , MIS-C 38 and myositis 45 and those in adults: Guillain-Barre syndrome 43 , demyelinating disease 6 , ITP 39 and appendicitis 44 as well as adverse events reported following any vaccination during childhood and early young adulthood: epilepsy 40 , acute pancreatitis 41 , ADEM 42 and angioedema 46 . The selected outcomes are consistent with previous studies reporting COVID-19 vaccine safety in young people 58 . Anaphylaxis was also included as a positive control outcome because it can occur shortly after vaccination 46 . Outcomes were identified using relevant International Classification of Diseases codes ( https://www.qresearch.org/data/qcode-group-library/ ). For each outcome, we used the first event recorded during the study period and did not incorporate readmissions for the same outcome into the analysis.

Our main vaccine exposures were a first, second and third dose of BNT162b2, mRNA-1273 or ChAdOx1. To account for heterologous vaccination, each vaccine type and dose was considered separately. SARS-CoV-2 infection exposure was defined as the first positive SARS-CoV-2 test (assessed by RT-PCR) within the study period and was included as a separate variable, allowing safety outcomes that occurred following vaccination and infection to be allocated to both exposures in the model and mutually adjusted. We did not include reinfections in the analysis. We distinguished between infection occurring before the first vaccine dose, or after. We defined the exposure risk period as 1–42 days after each exposure under the assumption that the adverse events under consideration were unlikely to be related to the exposures if they occurred after 42 days. In the case where two vaccine doses were given within 42 days of each other, the risk period of the earlier dose was truncated on the date prior to the day that the next vaccine dose was received. People with a recent hospital admission may delay vaccination, therefore a pre-risk period of 1–28 days before each exposure was excluded from the baseline period to account for this potential bias 36 . Since people may have SARS-CoV-2 testing on hospital admission, we allocated day zero to a risk period of its own 36 . Whilst these admissions may have been caused by SARS-CoV-2 infection, reverse causality involved in their detection could lead to overestimation of the effect of infection on the outcome. All remaining observation time was included in the baseline period.

Statistical analysis

We analysed the data with the self-controlled case series method using a conditional Poisson regression model with an offset for the length of the exposure risk period. We fixed age as the age at date of first COVID-19 vaccination or date of first positive SARS-CoV-2 test recorded in study period for those who were unvaccinated. To allow for underlying seasonal effects, we split the study observation period into two-week periods and adjusted for these as a factor variable in the statistical models. We censored follow-up at the earliest of time of death, fourth dose or study end. We estimated the additional number of events per million persons exposed following vaccination or infection 59 and assessed significance at the 5% level.

In the primary analysis, we fitted the self-controlled case series model separately in children aged 5–11 years and adolescents aged 12–17 years and stratified by sex (male and female). We additionally fitted the model in 18–24-year-olds for comparison. As sensitivity analyses, we fitted the self-controlled case series model starting the observation period at the day of first, second and third vaccine dose and without censoring for deaths due to the outcome, to ascertain the robustness of our results when the outcome increases the probability of death. We fitted the model excluding those who received a third dose, as they might be the most clinically vulnerable individuals. We also fitted the model including children who were vaccinated but did not have a record of a SARS-CoV-2 infection during the study period, to assess the effect of the vaccine alone, to account for the possibility that an adverse event could have occurred within 42 days of both a vaccine dose and a SARS-CoV-2 infection. Finally, we fitted the model including only SARS-CoV-2 positive patients who had not received any vaccine to assess the effect of SARS-CoV-2 exposure alone. We additionally tested the effect of ethnicity (white or non-white) on the risk of each outcome by including an interaction term between ethnicity and vaccine/infection exposures.

Matched cohort analysis

We also conducted a post hoc matched cohort study using the QResearch database of primary care records, linked to hospital episode statistics, COVID-19 vaccination and SARS-CoV-2 infection data. The study population included all vaccinated children aged 5–17 years with GP records in the QResearch database, and matched unvaccinated children, irrespective of SARS-CoV-2 test status during the study period. We matched vaccinated children to children of the same age and sex who were unvaccinated at the time that the vaccinated child received their first dose (rounded to the nearest 7 days) at a ratio of 1:1. Unvaccinated children were sampled from the whole cohort and included children who were vaccinated later in the study period, and these children were censored on date of their first vaccination. The same matched pairs were included in the analysis of the second and third doses for those who received these doses, and where the matched unvaccinated child remained unvaccinated at the time of the second and third doses being received by the vaccinated child.

We estimated incidence rates and fitted conditional Poisson regression models to estimate IRRs of each outcome in the 1–42 days following a first, second or third dose of BNT162b2, mRNA-1273 or ChAdOX1 COVID-19 vaccine. We estimated unadjusted IRRs and IRRs adjusted for self-reported ethnicity (white, non-white, missing), quintile of deprivation (based on Townsend score) and presence of comorbidity (yes/no) that would result in inclusion in clinical risk group (diagnosis prior to vaccine being available).

We additionally conducted a matched cohort analysis in 18–24-year-olds for comparison.

Stata v17 was used for data analysis.

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

The data that support the findings of this study—NIMS Database of COVID-19, mortality (Office of National Statistics), hospital admissions (Hospital Episode Statistics), SARS-CoV-2 infection data (SGSS) and primary care (QResearch)—are not publicly available because they are based on deidentified national clinical records. Due to national and organizational data privacy regulations, individual-level data such as those used for this study cannot be shared openly. Access to the QResearch data is according to the information on the QResearch website ( www.qresearch.org ).

Code availability

A sample of the code used for a similar study has been deposited in the public git repository of the research group, available at https://github.com/qresearchcode/COVID-19-vaccine-safety . This sample code can be used to run a self-controlled case series analysis in STATA.

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Acknowledgements

This research is funded by the NIHR School for Primary Care Research, Grant Reference Number 622. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. We acknowledge the contribution of EMIS practices who contribute to QResearch and EMIS Health and the Universities of Nottingham and Oxford for expertise in establishing, developing or supporting the QResearch database. This project involves data derived from anonymised patient-level information collected by the NHS. The SARS-CoV-2 test data were originally collated, maintained and quality assured by Public Health England (PHE) and transferred to NHS England during the study. Access to the data was therefore facilitated by NHS England. The Hospital Episode Statistics, Secondary Users Service (SUS-PLUS) datasets and civil registration data are used by permission from NHS England who retain the copyright in that data. NHS England and Public Health England bears no responsibility for the analysis or interpretation of the data. JHC is supported by an NIHR senior investigator award. NLM is supported by a British Heart Foundation Chair Award (CH/F/21/90010), Programme Grant (RG/20/10/34966) and Research Excellence Award (RE/18/5/34216). DPJH is supported by the Wellcome Trust (215621/Z/19/Z), Medical Research Foundation and UKDRI (principal funder UKRI Medical Research Council).

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Contributions

M.P., E.C., J.H.C., C.A.C.C. led the study conceptualization, development of the research question and analysis plan and interpretation of the results. M.P. and J.H.C. obtained funding, obtained data approvals, undertook the data specification and curation. M.P. and E.C. designed the analysis, contributed to interpretation of the analysis, undertook data analysis and wrote the first draft of the paper. D.S., L.H., J.H., N.L.M., P.M., A.S., A.H., C.R. and D.P.J.H. contributed to the discussion on protocol development and provided critical feedback on drafts of the manuscript. All authors approved the protocol, contributed to the critical revision of the manuscript and approved the final version of the manuscript.

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Correspondence to Julia Hippisley-Cox .

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Competing interests.

J.H.C. reports grants from National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford, John Fell Oxford University Press Research Fund, Cancer Research UK and Oxford Wellcome Institutional Strategic Support Fund and other research councils, during the conduct of the study outside the scope of this work. J.H.C. is founder and was shareholder until 9 Aug 2023 of ClinRisk Ltd, which produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems. J.H.C. is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health who supply the QResearch database used for this work and is a consultant for Endeavour Predict Ltd outside this work. A.S. serves on a number of UK and Scottish Government COVID-19 advisory groups and was a member of AstraZeneca’s Thrombotic Thrombocytopenic Taskforce; all roles are unremunerated. A.H. is Deputy Chair of the Joint Committee on Vaccination and Immunisation. D.H. serves on the UK Government Commission on Human Medicines P.M. has received speaker and advisory board fees from Moderna and Astra Zeneca. All other authors declare no competing interests related to this paper.

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Copland, E., Patone, M., Saatci, D. et al. Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England. Nat Commun 15 , 3822 (2024). https://doi.org/10.1038/s41467-024-47745-z

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COVID-19 Vaccine: A comprehensive status report

Affiliations.

• 1 Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi 110021, India.
• 2 Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi 110021, India. Electronic address: [email protected].
• PMID: 32800805
• PMCID: PMC7423510
• DOI: 10.1016/j.virusres.2020.198114

The current COVID-19 pandemic has urged the scientific community internationally to find answers in terms of therapeutics and vaccines to control SARS-CoV-2. Published investigations mostly on SARS-CoV and to some extent on MERS has taught lessons on vaccination strategies to this novel coronavirus. This is attributed to the fact that SARS-CoV-2 uses the same receptor as SARS-CoV on the host cell i.e. human Angiotensin Converting Enzyme 2 (hACE2) and is approximately 79% similar genetically to SARS-CoV. Though the efforts on COVID-19 vaccines started very early, initially in China, as soon as the outbreak of novel coronavirus erupted and then world-over as the disease was declared a pandemic by WHO. But we will not be having an effective COVID-19 vaccine before September, 2020 as per very optimistic estimates. This is because a successful COVID-19 vaccine will require a cautious validation of efficacy and adverse reactivity as the target vaccinee population include high-risk individuals over the age of 60, particularly those with chronic co-morbid conditions, frontline healthcare workers and those involved in essentials industries. Various platforms for vaccine development are available namely: virus vectored vaccines, protein subunit vaccines, genetic vaccines, and monoclonal antibodies for passive immunization which are under evaluations for SARS-CoV-2, with each having discrete benefits and hindrances. The COVID-19 pandemic which probably is the most devastating one in the last 100 years after Spanish flu mandates the speedy evaluation of the multiple approaches for competence to elicit protective immunity and safety to curtail unwanted immune-potentiation which plays an important role in the pathogenesis of this virus. This review is aimed at providing an overview of the efforts dedicated to an effective vaccine for this novel coronavirus which has crippled the world in terms of economy, human health and life.

Keywords: COVID-19; Clinical Trials; Convalescent Plasma Therapy; Monoclonal Antibodies; SARS-CoV-2; Vaccine.

Copyright © 2020 Elsevier B.V. All rights reserved.

Publication types

• Angiotensin-Converting Enzyme 2
• Antibodies, Viral / biosynthesis*
• Betacoronavirus / drug effects
• Betacoronavirus / immunology*
• Betacoronavirus / pathogenicity
• COVID-19 Serotherapy
• COVID-19 Vaccines
• Clinical Trials as Topic
• Coronavirus Infections / epidemiology
• Coronavirus Infections / immunology
• Coronavirus Infections / prevention & control*
• Coronavirus Infections / therapy
• Coronavirus Infections / virology
• Genetic Vectors / chemistry
• Genetic Vectors / immunology
• Immunity, Innate / drug effects
• Immunization, Passive / methods
• Immunogenicity, Vaccine
• Pandemics / prevention & control*
• Patient Safety
• Peptidyl-Dipeptidase A / genetics
• Peptidyl-Dipeptidase A / immunology
• Peptidyl-Dipeptidase A / metabolism
• Pneumonia, Viral / epidemiology
• Pneumonia, Viral / immunology
• Pneumonia, Viral / prevention & control*
• Pneumonia, Viral / virology
• Receptors, Virus / genetics
• Receptors, Virus / immunology
• Receptors, Virus / metabolism
• Vaccines, Attenuated
• Vaccines, DNA
• Vaccines, Subunit
• Vaccines, Virus-Like Particle / administration & dosage
• Vaccines, Virus-Like Particle / biosynthesis
• Vaccines, Virus-Like Particle / immunology
• Viral Vaccines / administration & dosage
• Viral Vaccines / biosynthesis
• Viral Vaccines / immunology*
• Antibodies, Viral
• Receptors, Virus
• Vaccines, Virus-Like Particle
• Viral Vaccines
• Peptidyl-Dipeptidase A
• ACE2 protein, human

Repeat COVID-19 vaccinations elicit antibodies that neutralize variants, other viruses

Response to updated vaccine is shaped by earlier vaccines yet generates broadly neutralizing antibodies.

The COVID-19 pandemic is over, but the virus that caused it is still here, sending thousands of people to the hospital each week and spinning off new variants with depressing regularity. The virus's exceptional ability to change and evade immune defenses has led the World Health Organization (WHO) to recommend annual updates to COVID-19 vaccines.

But some scientists worry that the remarkable success of the first COVID-19 vaccines may work against updated versions, undermining the utility of an annual vaccination program. A similar problem plagues the annual flu vaccine campaign; immunity elicited by one year's flu shots can interfere with immune responses in subsequent years, reducing the vaccines' effectiveness.

A new study by researchers at Washington University School of Medicine in St. Louis helps to address this question. Unlike immunity to influenza virus, prior immunity to SARS-CoV-2, the virus that causes COVID-19, doesn't inhibit later vaccine responses. Rather, it promotes the development of broadly inhibitory antibodies, the researchers report.

The study, available online in Nature, shows that people who were repeatedly vaccinated for COVID-19 -- initially receiving shots aimed at the original variant, followed by boosters and updated vaccines targeting variants -- generated antibodies capable of neutralizing a wide range of SARS-CoV-2 variants and even some distantly related coronaviruses. The findings suggest that periodic re-vaccination for COVID-19, far from hindering the body's ability to recognize and respond to new variants, may instead cause people to gradually build up a stock of broadly neutralizing antibodies that protect them from emerging SARS-CoV-2 variants and some other coronavirus species as well, even ones that have not yet emerged to infect humans.

"The first vaccine an individual receives induces a strong primary immune response that shapes responses to subsequent infection and vaccination, an effect known as imprinting," said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. "In principle, imprinting can be positive, negative or neutral. In this case, we see strong imprinting that is positive, because it's coupled to the development of cross-reactive neutralizing antibodies with remarkable breadth of activity."

Imprinting is the natural result of how immunological memory works. A first vaccination triggers the development of memory immune cells. When people receive a second vaccination quite similar to the first, it reactivates memory cells elicited by the first vaccine. These memory cells dominate and shape the immune response to the subsequent vaccine.

In the case of the flu vaccine, imprinting has negative effects. Antibody-producing memory cells crowd out new antibody-producing cells, and people develop relatively few neutralizing antibodies against the strains in the newer vaccine. But in other cases, imprinting can be positive, by promoting the development of cross-reactive antibodies that neutralize strains in both the initial and subsequent vaccines.

To understand how imprinting influences the immune response to repeat COVID-19 vaccination, Diamond and colleagues including first author Chieh-Yu Liang, a graduate student, studied the antibodies from mice or people who had received a sequence of COVID-19 vaccines and boosters targeting first the original and then omicron variants. Some of the human participants also had been naturally infected with the virus that causes COVID-19.

The first question was the strength of the imprinting effect. The researchers measured how many of the participants' neutralizing antibodies were specific for the original variant, the omicron variant or both. They found that very few people had developed any antibodies unique to omicron, a pattern indicative of strong imprinting by the initial vaccination. But they also found few antibodies unique to the original variant. The vast majority of neutralizing antibodies cross-reacted with both.

The next question was how far the cross-reactive effect extended. Cross-reactive antibodies, by definition, recognize a feature shared by two or more variants. Some features are shared only by similar variants, others by all SARS-CoV-2 variants or even all coronaviruses. To assess the breadth of the neutralizing antibodies, the researchers tested them against a panel of coronaviruses, including SARS-CoV-2 viruses from two omicron lineages; a coronavirus from pangolins; the SARS-1 virus that caused the 2002-03 SARS epidemic; and the Middle Eastern Respiratory Syndrome (MERS) virus. The antibodies neutralized all the viruses except MERS virus, which comes from a different branch of the coronavirus family tree than the others.

Further experiments revealed that this remarkable breadth was due to the combination of original and variant vaccines. People who received only the vaccines targeting the original SARS-CoV-2 variant developed some cross-reactive antibodies that neutralized the pangolin coronavirus and SARS-1 virus, but the levels were low. After boosting with an omicron vaccine, though, the cross-reactive neutralizing antibodies against the two coronavirus species increased.

Taken together, the findings suggest that regular re-vaccination with updated COVID-19 vaccines against variants might give people the tools to fight off not only the SARS-CoV-2 variants represented in the vaccines, but also other SARS-CoV-2 variants and related coronaviruses, possibly including ones that have not yet emerged.

"At the start of the COVID-19 pandemic, the world population was immunologically naïve, which is part of the reason the virus was able to spread so fast and do so much damage," said Diamond, also a professor of molecular microbiology and of pathology & immunology. "We do not know for certain whether getting an updated COVID-19 vaccine every year would protect people against emerging coronaviruses, but it's plausible. These data suggest that if these cross-reactive antibodies do not rapidly wane -- we would need to follow their levels over time to know for certain -- they may confer some or even substantial protection against a pandemic caused by a related coronavirus."

• COVID and SARS
• Infectious Diseases
• Cold and Flu
• Flu vaccine
• MMR vaccine
• Vaccination

Story Source:

Materials provided by Washington University School of Medicine . Original written by Tamara Schneider. Note: Content may be edited for style and length.

Journal Reference :

• Chieh-Yu Liang, Saravanan Raju, Zhuoming Liu, Yuhao Li, Guha Asthagiri Arunkumar, James Brett Case, Suzanne M. Scheaffer, Seth J. Zost, Cory M. Acreman, Matthew Gagne, Shayne F. Andrew, Deborah Carolina Carvalho dos Anjos, Kathryn E. Foulds, Jason S. McLellan, James E. Crowe, Daniel C. Douek, Sean P. J. Whelan, Sayda M. Elbashir, Darin K. Edwards, Michael S. Diamond. Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines . Nature , 2024; DOI: 10.1038/s41586-024-07539-1

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COVID-19 Vaccine: A comprehensive status report

The current COVID-19 pandemic has urged the scientific community internationally to find answers in terms of therapeutics and vaccines to control SARS-CoV-2. Published investigations mostly on SARS-CoV and to some extent on MERS has taught lessons on vaccination strategies to this novel coronavirus. This is attributed to the fact that SARS-CoV-2 uses the same receptor as SARS-CoV on the host cell i.e. human Angiotensin Converting Enzyme 2 (hACE2) and is approximately 79% similar genetically to SARS-CoV. Though the efforts on COVID-19 vaccines started very early, initially in China, as soon as the outbreak of novel coronavirus erupted and then world-over as the disease was declared a pandemic by WHO. But we will not be having an effective COVID-19 vaccine before September, 2020 as per very optimistic estimates. This is because a successful COVID-19 vaccine will require a cautious validation of efficacy and adverse reactivity as the target vaccinee population include high-risk individuals over the age of 60, particularly those with chronic co-morbid conditions, frontline healthcare workers and those involved in essentials industries. Various platforms for vaccine development are available namely: virus vectored vaccines, protein subunit vaccines, genetic vaccines, and monoclonal antibodies for passive immunization which are under evaluations for SARS-CoV-2, with each having discrete benefits and hindrances. The COVID-19 pandemic which probably is the most devastating one in the last 100 years after Spanish flu mandates the speedy evaluation of the multiple approaches for competence to elicit protective immunity and safety to curtail unwanted immune-potentiation which plays an important role in the pathogenesis of this virus. This review is aimed at providing an overview of the efforts dedicated to an effective vaccine for this novel coronavirus which has crippled the world in terms of economy, human health and life.

1. Introduction

The novel beta-coronavirus SARS-CoV-2 is believed to have emerged last year in 2019 in Wuhan from Bats. Crossing the species barrier it entered human beings with furtherance of infection through human to human transmission. The beta-coronaviruses have jumped between the species and have caused three zoonotic outbreaks namely, SARS CoV (2002-03), MERS-CoV (2012), and SARS-CoV-2 (2019- till date) in the last 2 decades. The existence of a myriad of coronaviruses in bats, including many SARS-related CoV (Severe Acute Respiratory Syndrome related Coronaviruses) and the sporadic crossing over of the species barriers of the coronaviruses to humans, suggest that the future occurrences of zoonotic transmission events may sustain ( Ou et al., 2020 ).

Since its emergence in Nov 2019, it has spread to 188 countries and 25 territories around the globe, despite elaborate efforts by WHO and Governments to contain the infection, primarily owing to the highly infectious nature of this virus ( Anon, 2020a ; Anon, 2020b ). As of 2 July 2020, 10,533,779 cases have been reported globally with 512,842 deaths ( (WHO) World Health Organisation, 2020 ). There has been a monumental increase in the number of infected patients, with a 7-day moving average of 210,209 cases per day, as of 2 July 2020 ( Anon, 2020a ). SARS-CoV-2, a highly contagious virus, tends to spread by the inhalation of the respiratory aerosols, direct human contact, and via fomites. Social distancing, personal hygiene, frequent hand washing or sanitizing using the alcohol (61-70%) based hand-sanitizers, and disinfection of the surfaces are some steps which can protect the individuals from getting infected ( (CDC), Centers for Disease Control and Prevention, 2020 ). R 0 is an epidemiological scale; used to measure the contagiousness of an infectious agent. Its magnitude depends upon various biological, environmental, and socio-behavioral factors. It can be defined as “the average number of secondary cases one would produce in a completely susceptible population in the absence of any deliberate intervention in disease transmission ( Delamater et al., 2019 ).” SARS-CoV-2 has an R 0 value range of 2-3 ( Park, 2020 ) which is significantly higher in comparison to Spanish flu for which the R 0 was recorded at 0.9-2.1 ( Pyrek, 2018 ). According to WHO, people living with non-communicable diseases (co-morbid conditions) are prone to severe illness due to COVID-19 infection. The incubation period of the virus ranges from 2-14 days with a median of 5.1 days ( Lauer et al., 2020 ). The symptoms include fever, dry cough, fatigue, shortness of breath, chills, muscles pain, headache, gastric disturbances and weight loss ( CDC, 2020 ). Some patients may have lymphopenia and bilateral ground-glass opacity changes in the chest CT scans. The histological examinations of the lungs’ biopsy samples have shown a bilaterally diffused alveolar damage with cellular fibromyxoid exudates. A few interstitial mononuclear inflammatory infiltrates were observed both in the liver and the heart specimens ( Xu et al., 2020 ). However, a large population of the infected patients have no or mild symptoms and remain asymptomatic ( Shang et al., 2020 ).

Structurally coronaviruses are pleomorphic, enveloped viruses with a characteristic fringe of projections composed of S protein on their surface. These viruses are equipped with a positive sense ssRNA genome, which is complexed with the nucleocapsid (N) protein forming helical nucleocapsids. The genome is both capped and polyadenylated ( Carter and Saunders, 2007 ). The genetic analysis of SARS-CoV-2 and SARS-CoV has revealed 79% similarity with a total of 380 amino acid substitutions condensed mainly within the NSP genes. Out of these substitutions, there are 27 amino acid replacements in the immune-dominant S protein while 102 and 61 amino acid substitutions are found in the NSP3 and NSP2. Whereas, NSP7, NSP13, E protein, and some accessory proteins are devoid of any amino acid substitutions ( Wu et al., 2020 ). SARS-CoV and SARS-CoV-2 bind a common host receptor, hACE2, to gain entry into the cell but SARS-CoV-2 binds the receptor with a higher affinity than the SARS-CoV. MERS-CoV uses an entirely different receptor that is, Dipeptidyl Peptidase 4 (DPP4) ( Wan et al., 2020 ) and the virus is distantly related to SARS-CoV-2 with around 50% similarity as per the sequence analysis of the two viruses ( Prof Roujian et al., 2020 ).

The genome of SARS-CoV-2 is transcribed in at least 10 Open Reading Frames (ORFs). ORF1ab translates into a polyprotein which is processed into 16 non-structural proteins (NSPs) ( Yoshimoto, 2020 ). The NSPs perform various functions like genome replication, inducing the cleavage of host mRNA, membrane rearrangement, generation of the autophagosome, cleavage of the NSP polyprotein, capping, tailing, methylation, unwinding of the RNA duplex, etc. which are essential for the viral life cycle ( da Silva et al., 2020 ). Besides, the SARS-CoV-2 virus contains four structural proteins namely, spike (S), nucleocapsid (N), envelope (E), and membrane (M) proteins which are encoded by the 3’-end of the viral genome ( Wrapp et al., 2020 ). Amongst the 4 structural proteins the S glycoprotein, being a large multi-functional trans-membrane protein, plays the vital role of viral attachment, fusion, and entry into the host cell ( Wrapp et al., 2020 ). The S protein consists of S1 and S2 subunits, which are further split into different functional domains. The S1 subunit has two functional domains viz. N-terminal Domain (NTD) and Receptor Binding Domain (RBD) and the latter contains conserved receptor binding motif (RBM) ( Jiang et al., 2020 ). The alignment studies have revealed that the region of RBD sequence lies between the residues 331 and 524 of the S protein ( Tai et al., 2020 ). Whereas, the S2 subunit has three operational domains namely, fusion peptide (FP), heptad repeat (HR) 1, and 2. The S1 protein trimer aligns itself at the top of the trimeric S2 stalk to form the immune-dominant S protein ( Jiang et al., 2020 ). Interestingly, a furin cleavage site is observed within the spike protein of SARS-CoV-2 while it is absent in the SARS-CoV which may be a possible explanation of the variation in the pathogenicity of the virus ( Walls et al., 2020 ). A host trans-membrane protease serine 2, (TMPRSS2) is responsible for the initial priming of the spike protein. The virus can utilize both TMPRSS2 and endosomal cysteine proteases cathepsin B and L (CatB/L) to initiate entry into the cell. The TMPRSS2 is responsible for the cleavage of the S protein to expose the FP region of the S2 subunit which is responsible for the initiation of the endosome mediated entry into the host cell. This indicates that TMPRSS2 is a host factor that is essential for viral entry; therefore, the drugs approved for the inhibition of this protease (like camostatmesylate) could be used for therapeutic purposes ( Hoffmann and Kleine-Weber, 2020 ). SARS-CoV-2 uses the human angiotensin-converting enzyme 2 (hACE2) receptor to seize the target cell through the spike glycoprotein (S-Protein), . It has been suggested that the coronaviruses exercise the use of conformational masking and glycan shielding of the spike protein to circumvent the host immune cells. The Cryo-EM structures have revealed the presence of two distinct: closed and open conformations of the S-Protein ectodomain trimer, as a consequence of the opening of the structure at the trimer apex. This conformational diversification is necessary for the receptor binding as the trimer opening exposes the RBM which is present at the interface between the protomers in the closed trimers ( Walls, 2020 ).

The E protein that forms E channels (called the viroporins), and is involved in a myriad of functions in the viral replication cycle involving assembly, release, pathogenesis, etc. ( Gralinski and Menachery, 2020 ). These reprobate ion channels exist in the form of homo-pentamers with each subunit containing 50-120 amino acids. E channels contain at least one trans-membrane domain (TMD) which facilitates the linkage in host cell membranes. SARS CoVs generally contain three categories of ion channels namely: E, 8a, and 3a. The E and 8a ion channels contain the PDZ (Post Synaptic Density Protein; Disc Large Tumor Suppressor; Zonula Occludens-1 Protein) Domain Binding Motif (PBM) which is responsible for the over-expression of the inflammatory cytokines which may result in the cytokine storm ( Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: the Screening for Inhibitors in Approved Drugs, 2020 ). From the sequence alignment study of the E protein, it was observed that a negatively charged glutamate residue (E69) in SARS-CoV corresponds to a positively charged arginine residue (R69) in SARS-CoV-2 ( Yoshimoto, 2020 ). However, this mutation is remote from the inhibitor binding site; therefore, E protein can be used as a pharmaceutical target ( Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: the Screening for Inhibitors in Approved Drugs, 2020 ).

M protein, the central organizer of CoV assembly, is most abundantly expressed in the virus particle. It functions crucially in the morphogenesis and assembly of the SARS-CoV-2 by interacting with the essential structural proteins ( Conserved Protein Domain Family: SARS-like-CoV_M, 2020 ). The binding of the M and N protein stabilizes the N protein and RNA complex, and the internal core of the virus. In case of SARS-CoV, the M protein has also been shown to induce the process of apoptosis in the host cell ( Yoshimoto, 2020 ).

In addition to stabilizing the ssRNA genome of the virus particle, the N protein is an antagonist of the antiviral RNAi. It is responsible for the inhibition of the cell cycle of the host cell as it can inhibit the entry of the cell into the S-phase ( Yoshimoto, 2020 ).

Immunotherapy is considered as an effective method for the prophylaxis and treatment of various infectious diseases and cancers, which involves the artificial triggering of the immune system to elicit the immune response ( Masihi, 2001 ). A vaccine that elicits the production of S protein neutralizing antibodies in the vaccinated subjects is the primary aim of all the programs for COVID-19 vaccines. Studies have revealed that there is a limited to no cross-neutralization between the sera of SARS-CoV and SARS-CoV-2, indicating that recovery from one infection may not shield against the other ( Ou et al., 2020 ). Furthermore, a database of approximately 5500 full-length genomes of SARS-CoV-2 isolated from various countries is now available at NCBI which facilitates delineating the polymorphisms in S protein and other important proteins of the virus concerning vaccine development. The rationale for writing this review is to gather all the information about the COVID-19 vaccine development programs and give the readers and researchers insight into types of vaccines being worked upon and the current status of the clinical trials of these vaccines for ready reference.

2. Vaccination strategies

Many efforts have been directed towards the development of the vaccines against COVID-19, to avert the pandemic and most of the developing vaccine candidates have been using the S-protein of SARS-CoV-2 ( Dhama et al., 2020 ). As of July 2, 2020, the worldwide SARS-CoV-2 vaccine landscape includes 158 vaccine candidates, out of which 135 are in the preclinical or the exploratory stage of their development. Currently, mRNA-1273 (Moderna), Ad5-nCoV (CanSino Biologicals), INO-4800 (Inovio, Inc.), LV-SMENP-DC, Pathogen-specific aAPC (ShinzenGeno-Immune Medical Institute), and ChAdOx1 (University of Oxford) have entered the phase I/II clinical trials ( WHO, 2020 ). The vaccines which are in the conduit are based upon inactivated or live attenuated viruses, protein sub-unit, virus-like particles (VLP), viral vector (replicating and non- replicating), DNA, RNA, nanoparticles, etc. with each exhibiting unique advantages and hindarances ( Table 1 ) ( Ning et al., 2020 ). COVID-19 vaccine landscape with percentage share of different types of vaccine is represented in Fig. 1 . To enhance the immunogenicity, various adjuvant technologies like AS03 (GSK), MF-59 (Novartis), CpG 1018 (Dynavax), etc. are now accessible to the researchers for the vaccine development ( Le et al., 2020 ). The immuno-informatics approach is also used for the epitope identification for the SARS-CoV-2 vaccine candidates. It can be used to identify the significant cytotoxic T cell and B-cell epitopes in the viral proteins ( Gupta et al., 2006 ; Baruah and Bose, 2020 ).

Outline of the vaccine production platforms for SARS-CoV-2 and their advantages and limitations

Pie Chart showing the different categories of SARS-CoV-2 vaccines under research ( Anon, 2020c ).

2.1. Protein Sub-unit vaccine

A subunit vaccine is the one which is based on the synthetic peptides or recombinant antigenic proteins, which are necessary for invigorating long-lasting protective and/or therapeutic immune response ( Ning et al., 2020 ). The subunit vaccine, however, exhibits low immunogenicity and requires auxiliary support of an adjuvant to potentiate the vaccine-induced immune responses. An adjuvant may enhance the biological half-life of the antigenic material, or it may ameliorate the immunomodulatory cytokine response. The addition of an adjuvant, therefore, helps in overcoming the shortcomings of the protein subunit vaccines ( Cao et al., 2018 ). The S protein of the SARS-CoV-2 is the most suitable antigen to induce the neutralizing antibodies against the pathogen. The S Protein consists of two subunits. The S1 subunit has the NTD, RBD, and RBM domains while the S2 subunit comprises of FP, HR 1, &2 ( Ou et al., 2020 ). The virus enters into the cell via endocytosis by utilizing the S-Protein mediated binding to the hACE2 receptor. Therefore, the S-Protein and its antigenic fragments are the prime targets for the institution of the subunit vaccine ( Ning et al., 2020 ). The S glycoprotein is a dynamic protein, possessing two conformational states i.e. pre-fusion and post-fusion state. Therefore, the antigen must maintain its surface chemistry and profile of the original pre-fusion spike protein to preserve the epitopes for igniting good quality antibody responses ( Graham, 2020 ). Moreover, means to target the masked RBM as an antigen will enhance the neutralizing antibody response and improve the overall efficacy of the vaccine.

2.1.1. NVX-CoV2373 (Novavax, Inc.| Emergent BioSolutions)

NVX-CoV2373 is a nano-particle based immunogenic vaccine which is based upon the recombinant expression of the stable pre-fusion, coronavirus S-Protein ( Coleman et al., 2020 ). The protein was stably expressed in the Baculovirus system ( Tu et al., 2020 ). The company plans to use the Matrix-M adjuvant to enhance the immune response against SARS-CoV-2 spike protein by the induction of high levels of neutralizing antibodies. In the animal models, a single immunization resulted in the high level of anti-spike protein antibodies which blocked the hACE2 receptor binding domain and could elicit SARS-CoV-2 wild type virus-neutralizing antibodies ( Novavax covid 19 vaccine trial, 2020 ).

2.1.2. Molecular Clamp Stabilized spike protein vaccine candidate

It is being developed by the University of Queensland in collaboration with GSK and Dynavax. The University will have access to vaccine adjuvant platform technology (AS03 Adjuvant system), which is believed to strengthen the vaccine response and minimize the amount of vaccine required per dose ( Lee, 2020 ). The University is developing a stabilized pre-fusion, recombinant viral protein sub-unit vaccine which is based upon the Molecular Clamp technology. This technology has been proved to induce the production of the neutralizing antibodies ( Tu et al., 2020 )

2.1.3. PittCoVacc (University of Pittsburgh)

It is a Micro-Needle Array (MNA) based recombinant SARS-CoV-2 vaccine which involves the administration of rSARS-CoV-2 S1 and rSARS-CoV-2-S1fRS09 (recombinant immunogens). A substantial increase in the antigen specific antibodies with a statistical significance was observed in the pre-clinical trials at the end of two weeks in the mice models. Furthermore, the immunogenicity of the vaccine was maintained even after the sterilization using gamma radiation. The statistically significant titers of antibodies at the early stages and also before boosting, support the feasibility of the MNA-SARS-CoV-2 vaccine ( Kim et al., 2020 ).

2.1.4. Triple Antigen Vaccine (Premas Biotech, India)

It is a multi-antigenic VLP vaccine prototype wherein the recombinant spike, membrane, and envelope protein of SARS-CoV-2 have been co-expressed in an engineered Saccharomyces cerevisiae expression platform (D-Crypt™). The proteins then undergo self-assembly as the VLP. The TEM and allied analytical data simultaneously furnished the biophysical characterization of the VLP. This prototype has the potential to enter the pre-clinical trials as a vaccine candidate after further research and development. Furthermore, it is thought to be safe and easy to manufacture on a mass scale, in a cost-effective manner ( Arora and Rastogi, 2020 ).

2.2. Viral Vectored vaccines

A vaccine based on viral vectors is a promising prophylactic solution against a pathogen. These vaccines are highly specific in delivering the genes to the target cells, highly efficient in the gene transduction, and efficiently induce the immune response, ( Ura et al., 2014 ). They offer a long term and high level of antigenic protein expression and therefore, have a great potential for prophylactic use as these vaccines trigger and prime the cytotoxic T cells (CTL) which ultimately leads to the elimination of the virus infected cells ( Le et al., 2020 ).

2.2.1. Ad5-nCoV (CanSino Biologics Inc | Beijing Institute of Biotechnology)

It is a recombinant, replication defective adenovirus type-5 vector (Ad5) expressing the recombinant spike protein of SARS-CoV-2. It was prepared by cloning an optimized full-length gene of the S Protein along with the plasminogen activator signal peptide gene in the Ad5 vector devoid of E1 and E3 genes. The vaccine was constructed using the Admax system from the Microbix Biosystem ( Zhu et al., 2020 ). The phase I clinical trials have established a positive antibody response or seroconversion. A four-fold increase in the RBD and S protein-specific neutralizing antibodies was noted within 14 days of immunization and peaked at day 28, post-vaccination. Furthermore, the CD4 + T cells and CD8 + T cells response peaked at day 14 post-vaccination. However, the pre-existing anti-Ad5 immunity partly limited both the antibody and the T cell responses ( Zhu et al., 2020 ). The study will further evaluate antibody response in the recipients who are between the age of 18 and 60, and received one of three study doses, with follow-up taking place at 3- and 6-months post-vaccination ( Anon, 2020d ).

2.2.2. Coroflu (University of Wisconsin-Madison | FluGen | Bharat Biotech)

M2SR, a self-limiting version of the influenza virus, which is modified by insertion of the SARS-CoV-2 gene sequence of the spike protein. Furthermore, the vaccine expresses the hemagglutinin protein of the influenza virus, thereby inducing immune response against both the viruses. The M2SR is self-limiting and does not undergo replication as it lacks the M2 gene. It is able to enter into the cell, thereby inducing the immunity against the virus. It shall be administered intra-nasally, mimicking the natural route of viral infection. This route activates several modes of the immune system and has higher immunogenicity as compared to the intramuscular injections ( Anon, 2020e ).

2.2.3. LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute)

The LV-SMENP-DC vaccine is prepared by engineering the dendritic cells (DC) with the lentiviral vector expressing the conserved domains of the SARS-CoV-2 structural proteins and the protease using the SMENP minigenes. The subcutaneous inoculation of the vaccine presents the antigens on antigen presenting cells (APCs), that ultimately activate the Cytotoxic T cells and generate the immune response ( Le et al., 2020 ).

2.2.4. ChAdOx1 (University of Oxford)

ChAdOx1 recombinant adenovirus vaccine was developed using codon optimized S glycoprotein and synthesized with the tissue plasminogen activator (tPA) leader sequence at 5’ end. The sequence of SARS-CoV-2 coding for amino acids (2 to 1273) and the tPA leader and was propagated in the shuttle plasmid. This shuttle plasmid is responsible for encoding the major immediate early genes of the human cytomegalovirus (IE CMV) along with tetracycline operator (TetO) sites and polyadenylation signal from bovine growth hormone (BGH) between the Gateway® recombination cloning site. The Adenovirus vector genome is constructed in the Bacterial Artificial Chromosome by inserting the SARS-CoV-2 S gene into the E1 locus of ChAdOx1 adenovirus genome. The virus was then allowed to reproduce in the T-Rex 293 HEK (Human Embryonic Kidney 293) cell lines and purified by the CsCl gradient ultracentrifugation. The absence of any sub-genomic RNA (sgRNA) in the intra-muscularly vaccinated animals from the pre-clinical trials is indicative of the escalated immunity against the virus ( Doremalen et al., 2020 ). The previous studies have suggested that a single shot should marshal the immune response ( Ou et al., 2020 ). The vaccine has entered phase II clinical trials, where it shall be evaluated in a large sample of the population ( Anon, 2020f ).

2.3. mRNA Vaccine

mRNA is an emerging, non-infectious, and a non-integrating platform with almost no potential risk of insertional mutagenesis. Currently, the non-replicating RNA and the virus derived self-replicating RNAs are being studied. The immunogenicity of the mRNA can be minimized, and alterations can be made to increase the stability of these vaccines. Furthermore, the anti-vector immunity is also avoided as the mRNA is the minimally immunogenic genetic vector, allowing repeated administration of the vaccine ( Cuiling et al., 2020 ). This platform has empowered the rapid vaccine development program due to its flexibility and ability to mimic the antigen structure and expression as seen in the course of a natural infection ( Mulligan and Lyke, 2020 ).

2.3.1. mRNA-1273 (Moderna TX, Inc)

It is a vaccine composed of synthetic mRNA encapsulated in Lipid nanoparticle (LNP) which codes for the full-length, pre-fusion stabilized spike protein (S) of SARS-CoV-2. It has the potential to elicit a highly S-protein specific antiviral response. Furthermore, it is considered to be relatively safe as it is neither made up of the inactivated pathogen nor the sub-units of the live pathogen ( Tu et al., 2020 ). The vaccine has got a fast-track approval from FDA, to conduct the Phase II trials ( Anon, 2020g ).The company has released the interim phase I antibody data of eight participants who received various dose levels. The participants of the 25 μg dose group gave results comparable to the convalescent sera. Whereas, in participants who received the 100 μg dose, the levels of nAb essentially surpassed the levels found in convalescent sera. The vaccine was found to be predominantly safe and well tolerated in the 25 μg and 100 μg dose cohorts, while three participants experienced grade 3 systemic symptoms after the administration of the second dose of 250 μg dose levels ( Anon, 2020h ).

2.3.2. BNT162b1 (BioNTech| FosunPharma| Pfizer)

BNT162b1 is a codon-optimized mRNA vaccine that encodes for the trimerized SARS-CoV-2 RBD, a critical target of the virus nAb. The vaccine portrays an increased immunogenicity due to the addition of T4 fibritin-derived foldon trimerization domain to the RBD antigen. The mRNA is encapsulated in 80 nm ionizable cationic lipid nanoparticles, which ensures its efficient delivery. The Phase 1/2 clinical trials have revealed elevated RBD-specific IgG antibodies levels with a geometric mean concentration to be as high as 8 to 46.3 times titer of convalescent serum. Whereas, the geometric mean titers of the SARS-CoV-2 neutralizing antibodies were found to be 1.8 to 2.8 times the convalescent serum panel. Moderate and transient local reactions and systemic events were observed with no adverse effect. However, the data analysis did not evaluate the safety and immune responses beyond 2 weeks following the administration of the second dose ( Mulligan and Lyke, 2020 ).

2.4. DNA Vaccines

The most revolutionary approach to vaccination is the introduction of the DNA vaccine which encodes for the antigen and an adjuvant which induces the adaptive immune response. The transfected cells express the transgene which provides a steady supply of the transgene specific proteins which is quite similar to the live virus. Furthermore, the antigenic material is endocytosed by the immature Dendritic Cells which ultimately present the antigen to the CD4+ and CD8+ T cells in association with MHC 2 and MHC 1 antigens on the cell surface hence stimulating effective humoral as well as cell-mediated immune responses ( Hobernik and Bros, 2018 ).

2.4.1. INO-4800 (Inovio Pharmaceuticals)

It is a prophylactic DNA vaccine against SARS-CoV-2 ( Anon, 2020i ). It uses codon optimized S protein sequence of SARS-CoV-2 to which an IgE leader sequence is affixed. The SARS-CoV-2 IgE-spike sequence was synthesized and digested using BamHI and XhoI . The digested DNA was incorporated into the expression plasmid pGX0001 under the governance of IE CMV, and BGH polyadenylation signal. The presence of functional antibodies and T cell response in the preclinical trials suggest that the vaccine can produce an effective immune response within 7 days post-vaccination ( Smith et al., 2020 ). The vaccine has entered the Phase I clinical trials (Phase I: {"type":"clinical-trial","attrs":{"text":"NCT04336410","term_id":"NCT04336410"}} NCT04336410 ) and it is estimated to complete this phase of clinical trials by July, wherein the participants received 1.0 mg of INO-4800 by electroporation using CELLECTRA® 2000 device per dosing visit. The trial will evaluate the immunological profile, safety, and tolerability of the vaccine candidate upon intradermal injection and the electroporation in healthy human adults ( Anon, 2020i ).

2.5. Live Attenuated Vaccines

2.5.1. delns1-sars-cov2-rbd (university of hong kong).

This LAV is influenza-based vaccine strain with a deletion in the NS1 gene. It is re-organized to express the RBD domain of SARS-CoV-2 spike protein on its surface and, is cultivated in the chick embryo and/or Madin Darby Canine Kidney Cells (MDCK) cells. It is potentially more immunogenic than the wild type influenza virus and can be administered as a nasal spray ( Anon, 2020j ).

2.6. Others

The revelation of the structure and genome of the SARS-CoV-2 has led to the rapid development of various vaccine candidates with potential immunogenicity but also adverse reactogenicities. The task of vaccine development is long and cumbersome which requires evaluation in some long-lasting clinical trials. Various Biotech ventures are using different technologies for the development of their vaccine candidates; British and American Tobacco Company (BAT) recently unfolded the COVID-19 vaccine using their new, and fast-growing tobacco plant technology ( Anon, 2020k ), while Tianjin University has developed an oral vaccine which has successfully employed Saccharomyces cerevisiae to carry the S protein. The GRAS (Generally Regarded As Safe) status of the yeast provides high scalability, robustness, and cost-effective production of cosmic dosages required to fight off this pandemic ( Zhai et al., 2020 ). Furthermore, in silico studies, using various databases like VaxiJen, have revealed that the epitope sequences WTAGAAAYY and YDPLQPEL can be employed for the formulation of epitope-based peptide vaccines ( Garg et al., 2020 ).

2.6.1. Self Assembling Vaccine (HaloVax)

The vaccine uses a heat shock protein (hsp) to activate the immune system. It is composed of a fusion protein sandwiched between an hsp and Avidin. Biotinylated immunogenic peptides are also incorporated to customize the vaccine ( Voltron Therapeutics, Inc., 2020 ) Table 2 , Table 3 .

Rapidly progressing Anti COVID-19 vaccines. This table contains the information of rapidly developing vaccine candidates only, the list of all vaccine candidates in the pipeline can be accessed from: https://airtable.com/shrSAi6t5WFwqo3GM/tblEzPQS5fnc0FHYR/viweyymxOAtNvo7yH?blocks=bip

Legend: CCHF: Crimean-Congo Hemorrhagic Fever; CHIKV: Chikungunya Virus; DengV: Dengue Virus; FMD: Foot and Mouth Disease; EBOV: Ebola Virus; HAV: Hepatitis A Virus; HBV: Hepatitis B Virus; HIV: Human Immunodeficiency Virus; HPV: Human Papilloma Virus; Inf: Influenza; LASV: Lassa Fever Virus; MenB: Meningitis B; NIPV: Nipah Virus; NORV: Norovirus; RABV: Rabies Virus; RVF: Rift Valley Fever; SARS: Severe Acute Respiratory Syndrome; SIV: Simian Immunodeficiency Virus; TB: Tuberculosis; VEE: Venezuelan Equine; Encephalitis Virus; VZV: Varicella Vaccine (Chickenpox); YFV: Yellow Fever Virus; ZIKV: Zika Virus.

Latest developments in the status of the promising SARS-CoV-2 vaccines

3. Passive Immunization/adoptive immunity

It is the use of preformed antibodies in therapeutics of various diseases. It can be achieved by use of sera from convalescent patients, polyclonal serum raised in other animals such as horse, neutralizing monoclonal antibodies produced by hybridoma technology or humanized antibodies.

3.1. Convalescent Plasma therapy

To date, no distinct treatment has been proven to be efficacious against the COVID-19. Convalescent plasma (CP) therapy has been approved as an empirical treatment during the outbreaks ( (WHO), World Health Organisation, 2014 ). It is considered as the archetypal immunotherapy which has been used for the treatment and prevention of various viral diseases in the past such as SARS, MERS, H1N1 pandemic, measles, mumps, etc. ( Kai et al., 2020 ). A possible explanation for the efficacy of this classic adoptive immunotherapy is that the neutralizing immune-globulins from CP may conquer viremia, block new infection, and accelerate clearance of the infected cells.

Various studies conducted to evaluate therapeutic potential of CP have convincingly shown that administration of the neutralizing antibodies in the critically ill patients led to the amelioration of the clinical status in all patients without any deaths ( Kai et al., 2020 ; Shen et al., 2020a ; Ahn et al., 2020a ; Anon, 2020C ). The dosage prescribed for the CP therapy has not been standardized yet and needs Randomised Clinical Trials not only to eliminate the effect of other medicines but also to evaluate the efficacy and safety of CP therapy. ( Zhang et al., 2020 ). The patients who were considered critically ill with some of them having co-morbid conditions like hypertension, cardiovascular diseases, cerebrovascular diseases, chronic renal failure, etc. were included in the study. They were all admitted to the ICUs and were receiving either mechanical ventilation, high-flow nasal cannula oxygenation, or the low-flow nasal cannula oxygenation. All the patients in these studies were receiving antiviral or antibacterial or antifungal drugs for the treatment of co-infections ( Kai et al., 2020 ). Compared to the control group, the CP treatment group showed no notable differences in the baseline characteristics but exhibited a sizable difference in the clinical outcomes (i.e. normalization of the body temperature, absorption of pulmonary lesions, resolution of ARDS, weaning off the mechanical ventilators, etc.), and the death rates. The patients were tested negative for the viral loads after 7-37 days of CP infusion ( Shen et al., 2020b ). A reduction in the net quantity of inflammatory biomarkers CRP, procalcitonin, and Interleukin 6 (IL-6) in the trial group was observed along with a significant increase in the antibody titers (RBD specific IgM and IgG) post-convalescent plasma therapy ( Ahn et al., 2020b ). However, these uncontrolled and non-randomized trials for the CP therapy impede the researchers to come to a conclusive statement about the prospective potency of this treatment, and these observations require further evaluation which is ongoing in the clinical trials ( Yan, 2020 ).

3.2. Monoclonal Antibody

The monoclonal antibodies (mAb) or therapeutic antibodies, created in the laboratory are the clones of a unique parent which can bind to a single epitope, that is, they have a monovalent affinity ( Gelboin et al., 1999 ). The use of mAb in the prevention and treatment of infectious diseases can overcome various drawbacks which are cognate with the convalescent plasma therapy in terms of specificity, safety, low risk of blood-borne infection, purity, and other factors. A wide array of monoclonal antibodies have already been developed which are implemented in the anti-tumor, anti-platelet, or antiviral therapy ( Breedveld, 2000 ).

A SARS-CoV specific human mAb CR3022 has been found to bind with the RBD of the S protein of SARS-CoV-2, stipulating it as a prospective therapeutic agent, which can either be used alone or in combination therapy for the management of COVID-19 ( Tian et al., 2020 ). To achieve higher efficiency of disease prevention and treatment, a combinatorial effect of monoclonal antibodies recognizing different epitopes of the viral surface can be considered for the neutralization of the virus as it may prove to be more effective and prevent the viral escape ( Tian et al., 2020 ).

There are over 61 patents which claim to have prepared the SARS-specific, MERS-specific, and the diagnostic antibodies. Another group of 38 patents claims to have developed the antibodies that target the host proteins like IL-6/IL-6R, TLR3, CD16, ITAM (immune-receptor tyrosine-based activation motif), DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin), ICAM-3 (intercellular adhesion molecule 3), or IP-10/CXCL10 (interferon γ-inducible protein 10). These antibodies can be used to counteract against the cytokine storm that has been reported to harmonize with the SARS-CoV-2 infection ( Liu et al., 2020 ). Tocilizumab, an anti-IL 6 receptor antibody is likely to control the hyper-inflammatory pulmonary symptoms which are coupled with the cytokine storm involving the chemokine dysregulation and various interleukins. Tocilizumab has been reported to block the cytokine axis IL6 hence inhibiting the inflammatory cascade. However, further clinical trials are essential to establish the effectiveness of the mAb ( Michot et al., 2020 ). Israel Institute for Biological Research (IIBR) claims to have successfully developed the mAb against SARS-CoV-2. The institute is in the process of patenting it which may soon be commercialized ( Upadhyay, 2020 ). A group led by Professor Vijay Chaudhary at the University of Delhi, Centre for Innovation in Infectious Disease Research, Education and Training (UDSC-CIIDRET), is isolating the genes encoding the antibodies responsible for the neutralization of the SARS-CoV-2. These genes will be employed to foster the recombinant Ab by exploiting the pre-existing in-house antibody library and a library fabricated from the cells of convalescent COVID-19 patients ( PIB, Delhi, 2020 ).

4. Limitations

The duration of clinical trials poses a sizable amount of hindrance to swift vaccine development. According to the norms laid down by the US Food and Drug Administration (FDA), and WHO, a vaccine candidate has to pass through at least three phases of placebo-controlled clinical trials for the validation of its safety and efficacy, which can take years to complete. Considering the severity of the pandemic, which has forced a complete shut-down of the global economy, speedy vaccine development is necessary. Some authors suggest that the controlled human challenge studies may be conducted to suitably divert the Phase 3 testing, and allow the rapid licensure of the immunogenic vaccines. However, in the expanded field study participants will be monitored constantly to look for any long-term implications posed by the vaccine. Furthermore, the safety trials for the special groups including, children and pregnant women, and immuno-compromised patients can be conducted before the extension of the vaccination to these groups ( Eyal et al., 2020 ).

The testing and development of safe and effective vaccines rely upon laboratory animal models. These animal models must show a similar course of the disease as in human beings. However, the standard inbred strains of mice are not susceptible to the COVID-19 infection, due to the difference between the humans and mice ACE2 receptors ( Anon, 2020D ). This calls for the development of transgenic mice, expressing the hACE2 receptor. Two animal models (hACE2 transgenic mice model and another, primate Macaques model) were previously developed for the SARS-CoV but the current situation requires steady breeding and distribution of these animal models to meet demands of the researchers around the globe ( Mice and Bao, 2020 ). The SARS-CoV-2 virus isolates can efficiently replicate in the lungs of the Syrian hamsters. The lungs of infected hamsters exhibit the pathological lesions analogous to the COVID-19 patients with pneumonia. Moreover, the nAb response exhibited by the infected hamster demonstrated immunity against the succeeding re-challenge studies. Furthermore, the transfusion of convalescent sera into the naïve hamsters mounted the antibody response and hence hindered the viral replication in the lungs. The assemblage of these experiments have illustrated the Syrian hamster may be a perfect model for comprehending SARS-CoV-2 pathogenesis, and evaluating antiviral drugs, and the immunotherapies ( Imai and Iwatsuki-Horimoto, 2020 ). Nevertheless, the assessment of the vaccine dependent immune enhancement cannot be extrapolated from the animal models and requires a legitimate survey from stage III human trials or the human challenge studies.

The Antibody dependent enhancement (ADE) is exploited by various viruses like Dengue, HIV, animal coronaviruses, etc. as an alternative method of infecting a variety of host cells. The virus-antibody complex can bind to the Fc receptors, activate the complement system, or induce a conformational change in the glycoprotein of the viral envelope ( Yip et al., 2016 ). This mechanism is observed when the vaccine-induced antibodies are either non-neutralizing or they are present in inadequate concentrations. This process triggers the viral entry into the cell due to the intensified binding efficiency of the virus-antibody complexes to FcR bearing cells. The clinical and preclinical trials of SARS-CoV vaccine candidates have demonstrated the aggravation of the disease due to ADE. Vaccine Associated Enhanced Respiratory Disease (VAERD) can also be induced by virus-antibody immune complex and T H 2-biased responses ( Graham, 2020 ).

The viral genome is vulnerable to mutations and can undergo the antigenic shift and the antigenic drift, as it continues to spread from one population to the next. The mutations may vary according to the environmental conditions of a geographical area, and the population density. By screening the 7500 samples of the infected patients, the scientists were able to figure out 198 mutations that may have materialized independently which may indicate the evolution of the virus inside the human host. These mutations may lead to different subtypes which may allow the virus to escape the immune system even after the administration of the vaccine ( Dorp et al., 2020 ).

5. Conclusion

SARS-CoV-2 has been the matter of the moment from the date it was declared as a pandemic, it has led to the termination of economic activities universally. Scientists across the continents are joining hands for the innovative tie-ups with both the pharmaceutical giants and the medical start-ups to repurpose drugs, develop vaccines, and devices to impede the progress of this overwhelming pandemic. A large number of COVID-19 vaccine candidates based upon various platforms have already been identified. Despite the undergoing efforts, a definitive answer does not exist. The process of vaccine development is quite laborious with various stages, including the pre-clinical stage, and clinical development which is a three-phase process. However, if sufficient data is already available, it has been recommended to skip a few stages, to accelerate the attainment of a vaccine faster with a quick regulatory review, approval, manufacturing, and quality control. This novel Coronavirus has therefore forced the scientific community to use unconventional approaches to accelerate the process of vaccine development. According to WHO: “vaccine must provide a highly favorable benefit-risk contour; with high efficacy, only mild or transient adverse effects and no serious ailments.” The vaccine must be suitable for all ages, pregnant, and lactating women and should provide a rapid onset of protection with a single dose and confer safety for at least up to one year of administration.

The use of novel technologies for vaccine development requires extensive testing for the safety and efficacy of a vaccine. The scientific community needs to construct various processes and capacities for the largescale manufacturing and administration of the coronavirus vaccines. The Coalition for Epidemic Preparedness Innovation (CEPI), an international non-governmental organization, which is funded by the Wellcome Trust, the European Commission, the Bill and Melinda Gates Foundation, and eight countries, is subsidizing the development of a large number of pandemic vaccine candidates around the globe. Moderna and the Vaccine Research Centre are co-developing an mRNA based vaccine candidate, wherein the mRNA is encapsulated in the lipid nanoparticles while Codagenix in collaboration with the Serum Institute of India is currently focused on developing the live attenuated viral vaccine. The pharmaceutical giants like Novavax, Sichuan Clover Biopharmaceuticals, iBio, and the University of Queensland are in the preclinical stage of the recombinant S glycoprotein vaccines. Additional strategies like the viral vector-based vaccines, targeting the S glycoprotein are being developed by the University of Oxford and CanSino Biologics, and other companies, Inovio and the Applied DNA Sciences are currently developing the DNA based vaccine candidates against the SARS-CoV-2 S Protein. Some of these vaccine candidates are at least months, away from being ready for human use, while others may take longer if at all approved for final use.

In India alone, six biotech ventures i.e. Serum Institute of India, ZydusCadila, Biological E, Indian Immunologicals, Bharat Biotech, and Mynvax are working in collaboration with various international vaccine developers. They are working on DNA vaccines, live attenuated recombinant measles vaccines, inactivated viral vaccines, subunit vaccines, and the vaccines developed by codon-optimization ( Coronavirus, 2020 ). Furthermore, the academic institutes like National Institute of Immunology (NII), Indian Institute of Science (IISc), International Center for Genetic Engineering and Biotechnology (ICGEB) New Delhi, Translational Health Science and Technology Institute (THSTI), etc. are attempting to develop the vaccines, and therapies, and the SARS-CoV-2 animal models to restrain the pandemic shortly ( Nandi, 2020 ).

The need of the hour is to develop a safe and effective COVID-19 vaccine which can induce an appropriate immune response to terminate this pandemic. It is the universal priority to spot the international funding mechanisms to support the development, manufacturing, and stockpiling of the coronavirus vaccines. This pandemic should serve as the guidepost to the international research community to not only acknowledge the outbreak but also indurate the following coronavirus crossing into mammals. A pan-coronavirus vaccine is urgently needed as the delay of vaccine rollout even by one week will accompany millions of deaths. Furthermore, it appears to be a scientifically feasible task if sufficient resources are made available in due time.

Funding Information

This work received no specific grant from any funding agency.

Declaration of Competing Interest

The author(s) declare that there are no conflicts of interest.

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