research paper about covid 19 vaccines

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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Qiao Liu and Chenyuan Qin are joint first authors

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

Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu

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

Chenyuan Qin & 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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Correspondence to Min Liu or Jue Liu .

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Supplementary Information

Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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

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

Affiliations.

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

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

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

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

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

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

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Conflict of interest statement

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

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

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Introduction
Conclusions
Article Information

The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among individuals older than 40 years of age, there were no more than 8 reports of myocarditis for any individual age after receiving either vaccine. For the BNT162b2 vaccine, there were 114 246 837 first vaccination doses and 95 532 396 second vaccination doses; and for the mRNA-1273 vaccine, there were 78 158 611 and 66 163 001, respectively. The y-axis range differs between panels A and B.

The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among recipients of either vaccine, there were only 13 reports or less of myocarditis beyond 10 days for any individual time from vaccination to symptom onset. The y-axis range differs between panels A and B.

A, For the BNT162b2 vaccine, there were 138 reported cases of myocarditis with known date for symptom onset and dose after 114 246 837 first vaccination doses and 888 reported cases after 95 532 396 second vaccination doses.

B, For the mRNA-1273 vaccine, there were 116 reported cases of myocarditis with known date for symptom onset and dose after 78 158 611 first vaccination doses and 311 reported cases after 66 163 001 second vaccination doses.

eMethods. Medical Dictionary for Regulatory Activities Preferred Terms, Definitions of Myocarditis and Pericarditis, Myocarditis medical review form

eFigure. Flow diagram of cases of myocarditis and pericarditis reported to Vaccine Adverse Event Reporting System (VAERS) after receiving mRNA-based COVID-19 vaccine, United States, December 14, 2020-August 31, 2021.

eTable 1. Characteristics of all myocarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.

eTable 2. Characteristics of all pericarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.

eTable 3. Characteristics of myocarditis cases reported to Vaccine Adverse Event Reporting System after mRNA-based COVID-19 vaccination by case definition status.

Myocarditis and Pericarditis After Vaccination for COVID-19 JAMA Research Letter September 28, 2021 This study investigates the incidence of myocarditis and pericarditis emergency department or inpatient hospital encounters before COVID-19 vaccine availability (January 2019–January 2021) and during a COVID-19 vaccination period (February-May 2021) in a large US health care system. George A. Diaz, MD; Guilford T. Parsons, MD, MS; Sara K. Gering, BS, BSN; Audrey R. Meier, MPH; Ian V. Hutchinson, PhD, DSc; Ari Robicsek, MD
Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel JAMA Research Letter April 26, 2022 This study assessed whether a third vaccine dose was associated with the risk of myocarditis among military personnel in Israel. Limor Friedensohn, MD; Dan Levin, MD; Maggie Fadlon-Derai, MHA; Liron Gershovitz, MD; Noam Fink, MD; Elon Glassberg, MD; Barak Gordon, MD
Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US—Reply JAMA Comment & Response May 24, 2022 Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA
Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US JAMA Comment & Response May 24, 2022 Sheila R. Weiss, PhD
JAMA Network Articles of the Year 2022 JAMA Medical News & Perspectives December 27, 2022 This Medical News article is our annual roundup of the top-viewed articles from all JAMA Network journals. Melissa Suran, PhD, MSJ
Diagnosis and Treatment of Acute Myocarditis—A Review JAMA Review April 4, 2023 This Review summarizes current evidence regarding the diagnosis and treatment of acute myocarditis. Enrico Ammirati, MD, PhD; Javid J. Moslehi, MD
Patient Information: Acute Myocarditis JAMA JAMA Patient Page August 8, 2023 This JAMA Patient Page describes acute myocarditis and its symptoms, causes, diagnosis, and treatment. Kristin Walter, MD, MS
Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military JAMA Cardiology Brief Report October 1, 2021 This case series describes myocarditis presenting after COVID-19 vaccination within the Military Health System. Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD
Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination JAMA Cardiology Brief Report October 1, 2021 This study describes 4 patients who presented with acute myocarditis after mRNA COVID-19 vaccination. Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD
Association of Myocarditis With BNT162b2 Vaccination in Children JAMA Cardiology Brief Report December 1, 2021 This case series reviews comprehensive cardiac imaging in children with myocarditis after COVID-19 vaccine. Audrey Dionne, MD; Francesca Sperotto, MD; Stephanie Chamberlain; Annette L. Baker, MSN, CPNP; Andrew J. Powell, MD; Ashwin Prakash, MD; Daniel A. Castellanos, MD; Susan F. Saleeb, MD; Sarah D. de Ferranti, MD, MPH; Jane W. Newburger, MD, MPH; Kevin G. Friedman, MD

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CME & MOC

Oster ME , Shay DK , Su JR, et al. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021. JAMA. 2022;327(4):331–340. doi:10.1001/jama.2021.24110

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Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021

1 US Centers for Disease Control and Prevention, Atlanta, Georgia
2 School of Medicine, Emory University, Atlanta, Georgia
3 Children’s Healthcare of Atlanta, Atlanta, Georgia
4 Vanderbilt University Medical Center, Nashville, Tennessee
5 Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
6 Boston Medical Center, Boston, Massachusetts
7 Duke University, Durham, North Carolina
8 US Food and Drug Administration, Silver Spring, Maryland
Research Letter Myocarditis and Pericarditis After Vaccination for COVID-19 George A. Diaz, MD; Guilford T. Parsons, MD, MS; Sara K. Gering, BS, BSN; Audrey R. Meier, MPH; Ian V. Hutchinson, PhD, DSc; Ari Robicsek, MD JAMA
Research Letter Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel Limor Friedensohn, MD; Dan Levin, MD; Maggie Fadlon-Derai, MHA; Liron Gershovitz, MD; Noam Fink, MD; Elon Glassberg, MD; Barak Gordon, MD JAMA
Comment & Response Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US—Reply Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA JAMA
Comment & Response Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US Sheila R. Weiss, PhD JAMA
Medical News & Perspectives JAMA Network Articles of the Year 2022 Melissa Suran, PhD, MSJ JAMA
Review Diagnosis and Treatment of Acute Myocarditis—A Review Enrico Ammirati, MD, PhD; Javid J. Moslehi, MD JAMA
JAMA Patient Page Patient Information: Acute Myocarditis Kristin Walter, MD, MS JAMA
Brief Report Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD JAMA Cardiology
Brief Report Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD JAMA Cardiology
Brief Report Association of Myocarditis With BNT162b2 Vaccination in Children Audrey Dionne, MD; Francesca Sperotto, MD; Stephanie Chamberlain; Annette L. Baker, MSN, CPNP; Andrew J. Powell, MD; Ashwin Prakash, MD; Daniel A. Castellanos, MD; Susan F. Saleeb, MD; Sarah D. de Ferranti, MD, MPH; Jane W. Newburger, MD, MPH; Kevin G. Friedman, MD JAMA Cardiology

Question What is the risk of myocarditis after mRNA-based COVID-19 vaccination in the US?

Findings In this descriptive study of 1626 cases of myocarditis in a national passive reporting system, the crude reporting rates within 7 days after vaccination exceeded the expected rates across multiple age and sex strata. The rates of myocarditis cases were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively).

Meaning Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men.

Importance Vaccination against COVID-19 provides clear public health benefits, but vaccination also carries potential risks. The risks and outcomes of myocarditis after COVID-19 vaccination are unclear.

Objective To describe reports of myocarditis and the reporting rates after mRNA-based COVID-19 vaccination in the US.

Design, Setting, and Participants Descriptive study of reports of myocarditis to the Vaccine Adverse Event Reporting System (VAERS) that occurred after mRNA-based COVID-19 vaccine administration between December 2020 and August 2021 in 192 405 448 individuals older than 12 years of age in the US; data were processed by VAERS as of September 30, 2021.

Exposures Vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna).

Main Outcomes and Measures Reports of myocarditis to VAERS were adjudicated and summarized for all age groups. Crude reporting rates were calculated across age and sex strata. Expected rates of myocarditis by age and sex were calculated using 2017-2019 claims data. For persons younger than 30 years of age, medical record reviews and clinician interviews were conducted to describe clinical presentation, diagnostic test results, treatment, and early outcomes.

Results Among 192 405 448 persons receiving a total of 354 100 845 mRNA-based COVID-19 vaccines during the study period, there were 1991 reports of myocarditis to VAERS and 1626 of these reports met the case definition of myocarditis. Of those with myocarditis, the median age was 21 years (IQR, 16-31 years) and the median time to symptom onset was 2 days (IQR, 1-3 days). Males comprised 82% of the myocarditis cases for whom sex was reported. The crude reporting rates for cases of myocarditis within 7 days after COVID-19 vaccination exceeded the expected rates of myocarditis across multiple age and sex strata. The rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively). There were 826 cases of myocarditis among those younger than 30 years of age who had detailed clinical information available; of these cases, 792 of 809 (98%) had elevated troponin levels, 569 of 794 (72%) had abnormal electrocardiogram results, and 223 of 312 (72%) had abnormal cardiac magnetic resonance imaging results. Approximately 96% of persons (784/813) were hospitalized and 87% (577/661) of these had resolution of presenting symptoms by hospital discharge. The most common treatment was nonsteroidal anti-inflammatory drugs (589/676; 87%).

Conclusions and Relevance Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Myocarditis is an inflammatory condition of the heart muscle that has a bimodal peak incidence during infancy and adolescence or young adulthood. 1 - 4 The clinical presentation and course of myocarditis is variable, with some patients not requiring treatment and others experiencing severe heart failure that requires subsequent heart transplantation or leads to death. 5 Onset of myocarditis typically follows an inciting process, often a viral illness; however, no antecedent cause is identified in many cases. 6 It has been hypothesized that vaccination can serve as a trigger for myocarditis; however, only the smallpox vaccine has previously been causally associated with myocarditis based on reports among US military personnel, with cases typically occurring 7 to 12 days after vaccination. 7

With the implementation of a large-scale, national COVID-19 vaccination program starting in December 2020, the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration began monitoring for a number of adverse events of special interest, including myocarditis and pericarditis, in the Vaccine Adverse Event Reporting System (VAERS), a long-standing national spontaneous reporting (passive surveillance) system. 8 As the reports of myocarditis after COVID-19 vaccination were reported to VAERS, the Clinical Immunization Safety Assessment Project, 9 a collaboration between the CDC and medical research centers, which includes physicians treating infectious diseases and other specialists (eg, cardiologists), consulted on several of the cases. In addition, reports from several countries raised concerns that mRNA-based COVID-19 vaccines may be associated with acute myocarditis. 10 - 15

Given this concern, the aims were to describe reports and confirmed cases of myocarditis initially reported to VAERS after mRNA-based COVID-19 vaccination and to provide estimates of the risk of myocarditis after mRNA-based COVID-19 vaccination based on age, sex, and vaccine type.

VAERS is a US spontaneous reporting (passive surveillance) system that functions as an early warning system for potential vaccine adverse events. 8 Co-administered by the CDC and the US Food and Drug Administration, VAERS accepts reports of all adverse events after vaccination from patients, parents, clinicians, vaccine manufacturers, and others regardless of whether the events could plausibly be associated with receipt of the vaccine. Reports to VAERS include information about the vaccinated person, the vaccine or vaccines administered, and the adverse events experienced by the vaccinated person. The reports to VAERS are then reviewed by third-party professional coders who have been trained in the assignment of Medical Dictionary for Regulatory Activities preferred terms. 16 The coders then assign appropriate terms based on the information available in the reports.

This activity was reviewed by the CDC and was conducted to be consistent with applicable federal law and CDC policy. The activities herein were confirmed to be nonresearch under the Common Rule in accordance with institutional procedures and therefore were not subject to institutional review board requirements. Informed consent was not obtained for this secondary use of existing information; see 45 CFR part 46.102(l)(2), 21 CFR part 56, 42 USC §241(d), 5 USC §552a, and 44 USC §3501 et seq.

The exposure of concern was vaccination with one of the mRNA-based COVID-19 vaccines: the BNT162b2 vaccine (Pfizer-BioNTech) or the mRNA-1273 vaccine (Moderna). During the analytic period, persons aged 12 years or older were eligible for the BNT162b2 vaccine and persons aged 18 years or older were eligible for the mRNA-1273 vaccine. The number of COVID-19 vaccine doses administered during the analytic period was obtained through the CDC’s COVID-19 Data Tracker. 17

The primary outcome was the occurrence of myocarditis and the secondary outcome was pericarditis. Reports to VAERS with these outcomes were initially characterized using the Medical Dictionary for Regulatory Activities preferred terms of myocarditis or pericarditis (specific terms are listed in the eMethods in the Supplement ). After initial review of reports of myocarditis to VAERS and review of the patient’s medical records (when available), the reports were further reviewed by CDC physicians and public health professionals to verify that they met the CDC’s case definition for probable or confirmed myocarditis (descriptions previously published and included in the eMethods in the Supplement ). 18 The CDC’s case definition of probable myocarditis requires the presence of new concerning symptoms, abnormal cardiac test results, and no other identifiable cause of the symptoms and findings. Confirmed cases of myocarditis further require histopathological confirmation of myocarditis or cardiac magnetic resonance imaging (MRI) findings consistent with myocarditis.

Deaths were included only if the individual had met the case definition for confirmed myocarditis and there was no other identifiable cause of death. Individual cases not involving death were included only if the person had met the case definition for probable myocarditis or confirmed myocarditis.

We characterized reports of myocarditis or pericarditis after COVID-19 vaccination that met the CDC’s case definition and were received by VAERS between December 14, 2020 (when COVID-19 vaccines were first publicly available in the US), and August 31, 2021, by age, sex, race, ethnicity, and vaccine type; data were processed by VAERS as of September 30, 2021. Race and ethnicity were optional fixed categories available by self-identification at the time of vaccination or by the individual filing a VAERS report. Race and ethnicity were included to provide the most complete baseline description possible for individual reports; however, further analyses were not stratified by race and ethnicity due to the high percentage of missing data. Reports of pericarditis with evidence of potential myocardial involvement were included in the review of reports of myocarditis. The eFigure in the Supplement outlines the categorization of the reports of myocarditis and pericarditis reviewed.

Further analyses were conducted only for myocarditis because of the preponderance of those reports to VAERS, in Clinical Immunization Safety Assessment Project consultations, and in published articles. 10 - 12 , 19 - 21 Crude reporting rates for myocarditis during a 7-day risk interval were calculated using the number of reports of myocarditis to VAERS per million doses of COVID-19 vaccine administered during the analytic period and stratified by age, sex, vaccination dose (first, second, or unknown), and vaccine type. Expected rates of myocarditis by age and sex were calculated using 2017-2019 data from the IBM MarketScan Commercial Research Database. This database contains individual-level, deidentified, inpatient and outpatient medical and prescription drug claims, and enrollment information submitted to IBM Watson Health by large employers and health plans. The data were accessed using version 4.0 of the IBM MarketScan Treatment Pathways analytic platform. Age- and sex-specific rates were calculated by determining the number of individuals with myocarditis ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes B33.20, B33.22, B33.24, I40.0, I40.1, I40.8, I40.9, or I51.4) 22 identified during an inpatient encounter in 2017-2019 relative to the number of individuals of similar age and sex who were continually enrolled during the year in which the myocarditis-related hospitalization occurred; individuals with any diagnosis of myocarditis prior to that year were excluded. Given the limitations of the IBM MarketScan Commercial Research Database to capture enrollees aged 65 years or older, an expected rate for myocarditis was not calculated for this population. A 95% CI was calculated using Poisson distribution in SAS version 9.4 (SAS Institute Inc) for each expected rate of myocarditis and for each observed rate in a strata with at least 1 case.

In cases of probable or confirmed myocarditis among those younger than 30 years of age, their clinical course was then summarized to the extent possible based on medical review and clinician interviews. This clinical course included presenting symptoms, diagnostic test results, treatment, and early outcomes (abstraction form appears in the eMethods in the Supplement ). 23

When applicable, missing data were delineated in the results or the numbers with complete data were listed. No assumptions or imputations were made regarding missing data. Any percentages that were calculated included only those cases of myocarditis with adequate data to calculate the percentages.

Between December 14, 2020, and August 31, 2021, 192 405 448 individuals older than 12 years of age received a total of 354 100 845 mRNA-based COVID-19 vaccines. VAERS received 1991 reports of myocarditis (391 of which also included pericarditis) after receipt of at least 1 dose of mRNA-based COVID-19 vaccine (eTable 1 in the Supplement ) and 684 reports of pericarditis without the presence of myocarditis (eTable 2 in the Supplement ).

Of the 1991 reports of myocarditis, 1626 met the CDC’s case definition for probable or confirmed myocarditis ( Table 1 ). There were 208 reports that did not meet the CDC’s case definition for myocarditis and 157 reports that required more information to perform adjudication (eTable 3 in the Supplement ). Of the 1626 reports that met the CDC’s case definition for myocarditis, 1195 (73%) were younger than 30 years of age, 543 (33%) were younger than 18 years of age, and the median age was 21 years (IQR, 16-31 years) ( Figure 1 ). Of the reports of myocarditis with dose information, 82% (1265/1538) occurred after the second vaccination dose. Of those with a reported dose and time to symptom onset, the median time from vaccination to symptom onset was 3 days (IQR, 1-8 days) after the first vaccination dose and 74% (187/254) of myocarditis events occurred within 7 days. After the second vaccination dose, the median time to symptom onset was 2 days (IQR, 1-3 days) and 90% (1081/1199) of myocarditis events occurred within 7 days ( Figure 2 ).

Males comprised 82% (1334/1625) of the cases of myocarditis for whom sex was reported. The largest proportions of cases of myocarditis were among White persons (non-Hispanic or ethnicity not reported; 69% [914/1330]) and Hispanic persons (of all races; 17% [228/1330]). Among persons younger than 30 years of age, there were no confirmed cases of myocarditis in those who died after mRNA-based COVID-19 vaccination without another identifiable cause and there was 1 probable case of myocarditis but there was insufficient information available for a thorough investigation. At the time of data review, there were 2 reports of death in persons younger than 30 years of age with potential myocarditis that remain under investigation and are not included in the case counts.

Symptom onset of myocarditis was within 7 days after vaccination for 947 reports of individuals who received the BNT162b2 vaccine and for 382 reports of individuals who received the mRNA-1273 vaccine. The rates of myocarditis varied by vaccine type, sex, age, and first or second vaccination dose ( Table 2 ). The reporting rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.73 [95% CI, 61.68-81.11] per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.86 [95% CI, 91.65-122.27] per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.43 [95% CI, 45.56-60.33] per million doses of the BNT162b2 vaccine and 56.31 [95% CI, 47.08-67.34] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in adolescent males and young men exceeded the upper bound of the expected rates after the first vaccination dose with the BNT162b2 vaccine in those aged 12 to 24 years, after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 49 years, after the first vaccination dose with the mRNA-1273 vaccine in those aged 18 to 39 years, and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 49 years.

The reporting rates of myocarditis in females were lower than those in males across all age strata younger than 50 years of age. The reporting rates of myocarditis were highest after the second vaccination dose in adolescent females aged 12 to 15 years (6.35 [95% CI, 4.05-9.96] per million doses of the BNT162b2 vaccine), in adolescent females aged 16 to 17 years (10.98 [95% CI, 7.16-16.84] per million doses of the BNT162b2 vaccine), in young women aged 18 to 24 years (6.87 [95% CI, 4.27-11.05] per million doses of the mRNA-1273 vaccine), and in women aged 25 to 29 years (8.22 [95% CI, 5.03-13.41] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in females exceeded the upper bound of the expected rates after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 29 years and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 29 years.

Among the 1372 reports of myocarditis in persons younger than 30 years of age, 1305 were able to be adjudicated, with 92% (1195/1305) meeting the CDC’s case definition. Of these, chart abstractions or medical interviews were completed for 69% (826/1195) ( Table 3 ). The symptoms commonly reported in the verified cases of myocarditis in persons younger than 30 years of age included chest pain, pressure, or discomfort (727/817; 89%) and dyspnea or shortness of breath (242/817; 30%). Troponin levels were elevated in 98% (792/809) of the cases of myocarditis. The electrocardiogram result was abnormal in 72% (569/794) of cases of myocarditis. Of the patients who had received a cardiac MRI, 72% (223/312) had abnormal findings consistent with myocarditis. The echocardiogram results were available for 721 cases of myocarditis; of these, 84 (12%) demonstrated a notable decreased left ventricular ejection fraction (<50%). Among the 676 cases for whom treatment data were available, 589 (87%) received nonsteroidal anti-inflammatory drugs. Intravenous immunoglobulin and glucocorticoids were each used in 12% of the cases of myocarditis (78/676 and 81/676, respectively). Intensive therapies such as vasoactive medications (12 cases of myocarditis) and intubation or mechanical ventilation (2 cases) were rare. There were no verified cases of myocarditis requiring a heart transplant, extracorporeal membrane oxygenation, or a ventricular assist device. Of the 96% (784/813) of cases of myocarditis who were hospitalized, 98% (747/762) were discharged from the hospital at time of review. In 87% (577/661) of discharged cases of myocarditis, there was resolution of the presenting symptoms by hospital discharge.

In this review of reports to VAERS between December 2020 and August 2021, myocarditis was identified as a rare but serious adverse event that can occur after mRNA-based COVID-19 vaccination, particularly in adolescent males and young men. However, this increased risk must be weighed against the benefits of COVID-19 vaccination. 18

Compared with cases of non–vaccine-associated myocarditis, the reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination were similar in demographic characteristics but different in their acute clinical course. First, the greater frequency noted among vaccine recipients aged 12 to 29 years vs those aged 30 years or older was similar to the age distribution seen in typical cases of myocarditis. 2 , 4 This pattern may explain why cases of myocarditis were not discovered until months after initial Emergency Use Authorization of the vaccines in the US (ie, until the vaccines were widely available to younger persons). Second, the sex distribution in cases of myocarditis after COVID-19 vaccination was similar to that seen in typical cases of myocarditis; there is a strong male predominance for both conditions. 2 , 4

However, the onset of myocarditis symptoms after exposure to a potential immunological trigger was shorter for COVID-19 vaccine–associated cases of myocarditis than is typical for myocarditis cases diagnosed after a viral illness. 24 - 26 Cases of myocarditis reported after COVID-19 vaccination were typically diagnosed within days of vaccination, whereas cases of typical viral myocarditis can often have indolent courses with symptoms sometimes present for weeks to months after a trigger if the cause is ever identified. 1 The major presenting symptoms appeared to resolve faster in cases of myocarditis after COVID-19 vaccination than in typical viral cases of myocarditis. Even though almost all individuals with cases of myocarditis were hospitalized and clinically monitored, they typically experienced symptomatic recovery after receiving only pain management. In contrast, typical viral cases of myocarditis can have a more variable clinical course. For example, up to 6% of typical viral myocarditis cases in adolescents require a heart transplant or result in mortality. 27

In the current study, the initial evaluation and treatment of COVID-19 vaccine–associated myocarditis cases was similar to that of typical myocarditis cases. 28 - 31 Initial evaluation usually included measurement of troponin level, electrocardiography, and echocardiography. 1 Cardiac MRI was often used for diagnostic purposes and also for possible prognostic purposes. 32 , 33 Supportive care was a mainstay of treatment, with specific cardiac or intensive care therapies as indicated by the patient’s clinical status.

Long-term outcome data are not yet available for COVID-19 vaccine–associated myocarditis cases. The CDC has started active follow-up surveillance in adolescents and young adults to assess the health and functional status and cardiac outcomes at 3 to 6 months in probable and confirmed cases of myocarditis reported to VAERS after COVID-19 vaccination. 34 For patients with myocarditis, the American Heart Association and the American College of Cardiology guidelines advise that patients should be instructed to refrain from competitive sports for 3 to 6 months, and that documentation of a normal electrocardiogram result, ambulatory rhythm monitoring, and an exercise test should be obtained prior to resumption of sports. 35 The use of cardiac MRI is unclear, but it may be useful in evaluating the progression or resolution of myocarditis in those with abnormalities on the baseline cardiac MRI. 36 Further doses of mRNA-based COVID-19 vaccines should be deferred, but may be considered in select circumstances. 37

This study has several limitations. First, although clinicians are required to report serious adverse events after COVID-19 vaccination, including all events leading to hospitalization, VAERS is a passive reporting system. As such, the reports of myocarditis to VAERS may be incomplete, and the quality of the information reported is variable. Missing data for sex, vaccination dose number, and race and ethnicity were not uncommon in the reports received; history of prior SARS-CoV-2 infection also was not known. Furthermore, as a passive system, VAERS data are subject to reporting biases in that both underreporting and overreporting are possible. 38 Given the high verification rate of reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination, underreporting is more likely. Therefore, the actual rates of myocarditis per million doses of vaccine are likely higher than estimated.

Second, efforts by CDC investigators to obtain medical records or interview physicians were not always successful despite the special allowance for sharing information with the CDC under the Health Insurance Portability and Accountability Act of 1996. 39 This challenge limited the ability to perform case adjudication and complete investigations for some reports of myocarditis, although efforts are still ongoing when feasible.

Third, the data from vaccination administration were limited to what is reported to the CDC and thus may be incomplete, particularly with regard to demographics.

Fourth, calculation of expected rates from the IBM MarketScan Commercial Research Database relied on administrative data via the use of ICD-10 codes and there was no opportunity for clinical review. Furthermore, these data had limited information regarding the Medicare population; thus expected rates for those older than 65 years of age were not calculated. However, it is expected that the rates in those older than 65 years of age would not be higher than the rates in those aged 50 to 64 years. 4

Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Corresponding Author: Matthew E. Oster, MD, MPH, US Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333 ( [email protected] ).

Correction: This article was corrected March 21, 2022, to change “pericarditis” to “myocarditis” in the first row, first column of eTable 1 in the Supplement.

Accepted for Publication: December 16, 2021.

Author Contributions: Drs Oster and Su had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Oster, Shay, Su, Creech, Edwards, Dendy, Schlaudecker, Woo, Shimabukuro.

Acquisition, analysis, or interpretation of data: Oster, Shay, Su, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Marquez, Strid, Woo, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.

Drafting of the manuscript: Oster, Shay, Su, Gee, Creech, Marquez, Strid, Woo, Shimabukuro.

Critical revision of the manuscript for important intellectual content: Oster, Shay, Su, Creech, Broder, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.

Statistical analysis: Oster, Su, Marquez, Strid, Woo, Shimabukuro.

Obtained funding: Edwards, DeStefano.

Administrative, technical, or material support: Oster, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Smith, Baumblatt, Thompson, Reagan-Steiner, DeStefano.

Supervision: Su, Edwards, Soslow, Dendy, Schlaudecker, Campbell, Sperling, DeStefano, Shimabukuro.

Conflict of Interest Disclosures: Dr Creech reported receiving grants from the National Institutes of Health for the Moderna and Janssen clinical trials and receiving personal fees from Astellas and Horizon. Dr Edwards reported receiving grants from the National Institutes of Health; receiving personal fees from BioNet, IBM, X-4 Pharma, Seqirus, Roche, Pfizer, Merck, Moderna, and Sanofi; and receiving compensation for being the associate editor of Clinical Infectious Diseases . Dr Soslow reported receiving personal fees from Esperare. Dr Schlaudecker reported receiving grants from Pfizer and receiving personal fees from Sanofi Pasteur. Drs Barnett, Ruberg, and Smith reported receiving grants from Pfizer. Dr Lopes reported receiving personal fees from Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and receiving grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. No other disclosures were reported.

Funding/Support: This work was supported by contracts 200-2012-53709 (Boston Medical Center), 200-2012-53661 (Cincinnati Children’s Hospital Medical Center), 200-2012-53663 (Duke University), and 200-2012-50430 (Vanderbilt University Medical Center) with the US Centers for Disease Control and Prevention (CDC) Clinical Immunization Safety Assessment Project.

Role of the Funder/Sponsor: The CDC provided funding via the Clinical Immunization Safety Assessment Project to Drs Creech, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, and Lopes. The authors affiliated with the CDC along with the other coauthors conducted the investigations; performed collection, management, analysis, and interpretation of the data; were involved in the preparation, review, and approval of the manuscript; and made the decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC or the US Food and Drug Administration. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC or the US Food and Drug Administration.

Additional Contributions: We thank the following CDC staff who contributed to this article without compensation outside their normal salaries (in alphabetical order and contribution specified in parenthesis at end of each list of names): Nickolas Agathis, MD, MPH, Stephen R. Benoit, MD, MPH, Beau B. Bruce, MD, PhD, Abigail L. Carlson, MD, MPH, Meredith G. Dixon, MD, Jonathan Duffy, MD, MPH, Charles Duke, MD, MPH, Charles Edge, MSN, MS, Robyn Neblett Fanfair, MD, MPH, Nathan W. Furukawa, MD, MPH, Gavin Grant, MD, MPH, Grace Marx, MD, MPH, Maureen J. Miller, MD, MPH, Pedro Moro, MD, MPH, Meredith Oakley, DVM, MPH, Kia Padgett, MPH, BSN, RN, Janice Perez-Padilla, MPH, BSN, RN, Robert Perry, MD, MPH, Nimia Reyes, MD, MPH, Ernest E. Smith, MD, MPH&TM, David Sniadack, MD, MPH, Pamela Tucker, MD, Edward C. Weiss, MD, MPH, Erin Whitehouse, PhD, MPH, RN, Pascale M. Wortley, MD, MPH, and Rachael Zacks, MD (for clinical investigations and interviews); Amelia Jazwa, MSPH, Tara Johnson, MPH, MS, and Jamila Shields, MPH (for project coordination); Charles Licata, PhD, and Bicheng Zhang, MS (for data acquisition and organization); Charles E. Rose, PhD (for statistical consultation); and Scott D. Grosse, PhD (for calculation of expected rates of myocarditis). We also thank the clinical staff who cared for these patients and reported the adverse events to the Vaccine Adverse Event Reporting System.

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DOI: 10.2174/1573405620666230620115956
Corpus ID: 259211181

Kikuchi-Fujimoto Disease in the Axilla after COVID-19 Vaccination: A Case Report.

Eun Cho , H. Baek , +5 authors H. An
Published in Current medical imaging 20 June 2023
Current medical imaging

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Kikuchi‐fujimoto disease following sars‐cov‐2 infection: a rare disease with increased incidence during the covid‐19 pandemic, related papers.

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Published: 19 June 2024

Effectiveness of COVID-19 vaccines against severe COVID-19 among patients with cancer in Catalonia, Spain

Felippe Lazar Neto ORCID: orcid.org/0000-0002-0051-9537 1 , 2 ,
Núria Mercadé-Besora 3 ,
Berta Raventós 3 , 4 ,
Laura Pérez-Crespo 3 ,
Gilberto Castro Junior ORCID: orcid.org/0000-0001-8765-3044 2 ,
Otavio T. Ranzani ORCID: orcid.org/0000-0002-4677-6862 1 , 5 na1 &
Talita Duarte-Salles ORCID: orcid.org/0000-0002-8274-0357 3 , 6 na1

Nature Communications volume 15 , Article number: 5088 ( 2024 ) Cite this article

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Epidemiology

Patients with cancer were excluded from pivotal randomized clinical trials of COVID-19 vaccine products, and available observational evidence on vaccine effectiveness (VE) focused mostly on mild, and not severe COVID-19, which is the ultimate goal of vaccination for high-risk groups. Here, using primary care electronic health records from Catalonia, Spain (SIDIAP), we built two large cohorts of vaccinated and matched control cancer patients with a primary vaccination scheme ( n = 184,744) and a booster ( n = 108,534). Most patients received a mRNA-based product in primary (76.2%) and booster vaccination (99.9%). Patients had 51.8% (95% CI 40.3%−61.1%) and 58.4% (95% CI 29.3%−75.5%) protection against COVID-19 hospitalization and COVID-19 death respectively after full vaccination (two-doses) and 77.9% (95% CI 69.2%−84.2%) and 80.2% (95% CI 63.0%−89.4%) after booster. Compared to primary vaccination, the booster dose provided higher peak protection during follow-up. Calibration of VE estimates with negative outcomes, and sensitivity analyses with slight different population and COVID-19 outcomes definitions provided similar results. Our results confirm the role of primary and booster COVID-19 vaccination in preventing COVID-19 severe events in patients with cancer and highlight the need for the additional dose in this population.

Effectiveness of mRNA COVID-19 vaccine booster doses against Omicron severe outcomes

Effectiveness of inactivated COVID-19 vaccines among older adults in Shanghai: retrospective cohort study

COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials

Introduction.

The coronavirus disease 2019 (COVID-19) has caused millions of deaths worldwide since the first reported suspected case in Wuhan, China, in late December 2019 1 . Even though most patients will report mild symptoms, nearly 5% will present the severe form of the disease, requiring intensive support 2 . Vulnerable groups at increased risk of severe illness include patients of older age, nursing home facility residents, and those with severe comorbidities, particularly cancer 3 . Compared to healthier individuals, patients with cancer have an increased risk of death following infection, with an additional incremental risk among those with lung cancer, hematological cancer, or under systemic oncological treatment 4 , 5 , 6 . For instance, in patients with lung cancer, COVID-19-associated mortality was two times higher than in patients without cancer 7 .

Randomized clinical trials of COVID-19 vaccines have shown high efficacy and safety in preventing severe outcomes 8 , 9 , 10 ; however, these trials targeted the general population and included only patients with pre-existing, stable cancers 11 , limiting the generalizability of these results to patients with active cancer. Prospective data on immunogenicity following initial vaccination have shown that patients with cancer develop protective antibodies, but in a lower proportion when compared to the general population. This has been observed particularly after the administration of only one vaccine dose among patients with hematological neoplasms, and those undergoing cytotoxic treatments 12 , 13 , 14 , 15 , 16 , 17 . Booster dose administration can elicit strong and durable immune responses in approximately 50% of the patients who were seronegative after the first dose 18 , 19 , 20 .

Small retrospective, real-world studies focused on patients with cancer have found low rates of COVID-19 infection following vaccination, and decreased risk of severe disease after infection 21 , 22 , 23 , 24 , 25 , 26 . Cohorts including only vaccinated people have shown that patients with cancer are more susceptible to breakthrough infections compared to healthy individuals 5 , 27 , 28 , particularly those with only one dose 27 , 28 . A UK population-level study indicates a reduced temporal cancer COVID-19 fatality rate after vaccination, though still higher than in healthy individuals 29 . Few studies estimated vaccine effectiveness among patients with cancer 30 , 31 , 32 , 33 , 34 and were either focused on COVID-19 infection 31 , 32 , 35 or included cancer as a subgroup of comorbidities 33 , 34 . Only a minority of them estimated booster vaccine effectiveness 32 , 33 . Although there is promising evidence on COVID-19 vaccine effectiveness in the general population, we still lack evidence for cancer patients, particularly for booster doses and severe disease.

The combination of large amounts of population-level data and the causal inference framework of target trials 36 can provide valuable opportunities to assess the real-world effectiveness of medical interventions 37 when randomized data is not available. We aim to investigate COVID-19 vaccine effectiveness against severe COVID-19 outcomes among adults with cancer living in Catalonia, evaluating the vaccine effectiveness (VE) of primary schemes against unvaccinated individuals and the relative VE (rVE) of the booster dose compared with two doses.

Vaccine uptake

Of 171,284 patients with cancer diagnosis excluding non-melanoma skin cancer between 27th December 2015 and 27th December 2020, 111,576 patients remained after excluding those that died (any cause, N = 41461), moved out from SIDIAP area (N = 3575), had previous COVID-19 (N = 11992), or were nursing home residents (N = 2680) before the beginning of the vaccination campaign. The proportion that received one, two, and three (booster) doses of COVID-19 vaccines were 87.2%, 84.9%, and 68.2%, respectively. Among vaccinated patients, nearly 76% received an initial two-dose mRNA-based vaccination scheme compared to 15% that received two doses of ChAdOX1 and 3.2% that received Ad26.COV2.S as the first dose. The booster dose was composed of almost only mRNA vaccines (76% mRNA-1273 and 24% mRNA-BNT-162b). Suppl. Figure 1 shows the number of COVID-19 cases (Suppl. Figure 1A ), the predominant variant of concern (VoC) during each period (Suppl. Figure 1B ), and the cumulative vaccine rollout (Suppl. Figure 1C ). Suppl. Figure 2 shows the product types and doses of vaccines administered by age groups. The ChAdOX1 vaccine scheme was predominantly administered in adult patients aged 69 years or lower.

Baseline cohort characteristics

We built two matched cohorts: 184,744 patients (92,372 matched pairs) were included in the first and second dose (primary) vaccination cohort (Cohort A, Suppl. Figure 3 ) and 108,534 (54,267 matched pairs) in the booster vaccination cohort (Cohort B, Suppl. Figure 4 ). Compared to un-matched but eligible patients, matched patients had lower proportions of very old (>80 years) and younger (<50 years) patients, a higher proportion of recently diagnosed patients, fewer comorbidities as per the Charlson Comorbidity Index, fewer diagnoses of metastatic disease, and a higher number of outpatient visits (Suppl. Table 1 and Supp. Table 2 ).

Matched patients in both cohorts (A and B) had well-balanced characteristics between vaccinated and control groups (Table 1 ). The majority of patients were older (greater than 60 years old), with a similar proportion of males and females. As expected, the majority of vaccinated individuals in Cohort A received a mRNA-based combination scheme. Among those in Cohort B, approximately 24% previously received the ChAdOx1 combination scheme. The most prevalent cancer diagnosis was breast, followed by prostate and colorectal cancers. 14% and 11% of patients had metastatic disease in Cohort A and B, respectively.

Vaccine effectiveness

Figure 1 shows the cumulative incidence for the primary outcome of COVID-19-associated hospitalization, and Fig. 2 and Fig. 3 shows the estimated VE for each time period for the primary vaccination (Cohort A) and booster vaccination (Cohort B) cohorts respectively. For the primary vaccination, the estimated VE against COVID-19 hospitalization for the first (partially vaccinated) and second dose (fully vaccinated) was 42.0% (95%CI 22.3 - 56.7) and 51.8% (95%CI 40.3 - 61.1) respectively. When expanding the time periods, we observed an increase in VEs, particularly after the second dose, which peaked after 60 days (58.4%, 95%CI 34.5 - 73.6) but waned after 120 days (-19.7%, 95%CI -52.7 - 26.6). For the booster vaccine, we found high rVE (> 75%) already in the immediate period post-vaccination, which remained high until 120 days, when a decrease in rVE was observed. Visual inspection of cumulative incidence graphs during the initial period of 0 to 14 days after vaccination (Suppl. Figure 5 ) shows low residual confounding for both cohorts. Results for the secondary outcomes COVID-19 severe hospitalization, and COVID-19 deaths showed similar results (Fig. 2 and Fig. 3 ). Competing hazards model (all-cause death as competing risk) showed comparable results (Suppl. Table 3 ).

Cumulative incidence of COVID-19 hospitalizations (primary outcome) for the primary vaccination (Figure A ) and booster vaccination (Figure B ) cohorts between vaccinated and control groups. The solid lines represent the estimated cumulative hazards, while the shaded areas indicate the 95% confidence intervals.

Forest plot of estimated vaccine effectiveness (point estimate) and its 95% confidence interval (error bars) since the time from vaccination for the initial vaccination scheme (Cohort A). Here we show vaccine effectiveness for the primary (hospitalization) and secondary endpoints (severe hospitalization, and death) separately. VE = Vaccine Effectiveness.

Forest plot of estimated COVID-19 relative vaccine effectiveness (point estimate) and its 95% confidence interval (error bars) since the time from vaccination for the booster vaccination (Cohort B). Here we show vaccine effectiveness for the primary (hospitalization) and secondary endpoints (severe hospitalization, and death) separately. rVE = Relative Vaccine Effectiveness. Counts below five have been masked to protect patients’ privacy.

Subgroup analysis

Figure 4 shows the results for subgroup effect modification analysis for both cohorts. For the primary vaccination scheme (Cohort A), subgroup analysis has found lower VE after full vaccination for the elderly (33.2% vs 74.7%, p < 0.001, Suppl. Figure 6 ) and metastatic patients (24.0% vs 59.6%, p = 0.025), and no effectiveness during the Delta VoC. For the booster (Cohort B), we found higher VE after 14 days for older (82.2% vs 49.3%, p = 0.028, Suppl. Figure 7 ), and male patients (81.4% vs 69.8%, p = 0.006). We found a numerical increase in rVE for those who previously did not receive the mRNA-based vaccination scheme (between 14 and 60 days 80.5% vs 77.4%, after 60 days 73.7% vs 39.4%, p = 0.155). We did not find any effect modification by a diagnosis of hematological malignancy and a lower vaccine effectiveness during the Omicron period for the booster dose compared with the Delta period.

Forest plot of estimated COVID-19 vaccine effectiveness (point estimate) and its 95% confidence interval (error-bars) among subgroups for the primary vaccination (Cohort A) and booster vaccination (Cohort B). The detailed number of events, observations and precise confidence interval estimates for each sub-group are shown in Suppl. Figures 6 and 7 .

Negative Outcomes Calibration

Negative outcomes estimands for each cohort and period are shown in Suppl. Figures 8 and 9. After adjustment for negative outcomes, VE against COVID-19 hospitalization for the primary vaccination scheme was 42.7% (95% CI 11.2 - 63.0) for partially vaccinated and 58.2% (95% CI 43.8 - 68.9) for fully vaccinated individuals. For the booster dose, calibrated VE was 73.5% (95%CI 61.3 - 81.8) during the 14 - 60 days period and 50.8% (95% CI -1.2 - 76.0) after 60 days (Suppl. Table 4 ). Sensitivity analysis with an expanded set of negative outcomes provided similar results (Suppl. Table 4 ).

Non-COVID outcomes

Vaccination was associated with decreased hazards of all-cause hospitalizations and non-COVID deaths in the immediate period post-vaccination for both cohorts (Suppl. Tables 5 and 6 ). For Cohort A, primary vaccination was associated with a non-significant decrease in all-cause hospitalizations during follow-up but a sustained decreased hazard for non-COVID death (Suppl. Table 5 ). For Cohort B, booster vaccination was associated with a lower risk of all-cause hospitalizations and non-COVID death in all time periods (Suppl. Table 6 ). We observed a higher proportion of non-COVID-19 deaths without preceding hospitalization than COVID-19 deaths (Suppl. Table 7 ). Analysis of health services usage (outpatient, telehealth, home, inpatient, and ICU visits) by vaccination status showed lower likelihood in the vaccination group for most outcomes in cohort B, but not for Cohort A; which showed increased hazards for tele-health, home and outpatient visits and lower hazards for inpatient and ICU visits (Suppl. Table 8 ).

Sensitivity analysis

Sensitivity analysis including previous influenza vaccine receipt in matching and excluding those hospitalized a month prior to vaccination in the primary and booster cohorts (restricted matching cohort, Suppl. Tables 9 and 10 ) reduced the vaccine protection for all-cause hospitalizations, but not non-COVID death, which remained lower in the vaccinated group (Suppl.Tables 11 and 12 , Suppl. Figures 10 and 11 ). The COVID-19 primary outcome had comparable results (Suppl. Table 13 ).

Additional sensitivity analyses with different definitions for the cancer cohort and COVID-19 outcomes showed little deviations from the original results (Suppl. Figures 12 and 13 ).

In this matched cohort study, we found that the two-dose primary vaccination scheme effectively reduced COVID-19 hospitalization and mortality outcomes in individuals with cancer, and that administering a booster dose provided substantial and meaningful additional protection for those who had already received the initial two-dose vaccination scheme. We found that the booster dose provided higher peak effectiveness over time.

Two test-negative case-control studies using a network of hospitals across nine states in the United States 34 and linked cancer registry with surveillance data in the United Kingdom (UK) 31 have estimated the initial two-dose VE for hospitalization among patients with cancer as 79% (95% CI, 73-84%) and 84.5% (95% CI, 83.6-85.4) respectively, which is slightly higher than what we found in our study: 52% after the second dose. Regarding the first booster, another study from the same group in the UK 32 showed a VE of 80.5% (95% CI, 77.3-83.2) against hospitalization when comparing booster vs. unvaccinated population, which is not straightforward to compare with our estimate of relative effectiveness (i.e., booster compared with primary vaccination scheme protection). There are several possible explanations for the observed differences, including characteristics both at the individual level, such as different population distribution on age, sex, income, cancer staging, healthy-seeking behavior, vaccine type, and time of follow-up, and at the local level, such as pandemic period and predominant VoC during effectiveness evaluation.

Although previous investigations 30 , 31 , 32 have indicated decreased VE for COVID-19 infection among patients with a hematological neoplasm or within one year of initial diagnosis, we did not find decreased effectiveness for severe COVID-19 for either of these subgroups. This is likely explained by the different outcomes we investigated: severe disease (COVID-19 hospitalization or death), instead of mild COVID-19 infection. For example, patients with lymphoma in the UK cohort had a 10.5% reduction in breakthrough infections following booster dose but a 80% reduction in COVID-19 death 32 . The lack of subgroup analysis for severe outcomes in previous studies limits further comparisons 30 , 31 , 32 .

Older patients (≥ 65 years) had lower VE following the initial scheme, as previously described for the general population 38 , 39 . Interestingly, booster vaccination among this subgroup provided additional significant protection, better explained by the probable different baseline risk following initial vaccination and the higher relative VE estimated. Serological studies have shown that approximately half of seronegative oncological patients can have seroconversion following a booster administration. We found a similar effect for sex: male patients had possibly lower VE following the initial scheme and higher after the booster. Past studies have shown that among vaccinated individuals, male patients may still have a higher risk of severe COVID-19 outcomes 27 , 40 , and serological studies suggest a higher waning effect compared to females 27 , 41 , which can help explain baseline risk differences and different relative effectiveness after booster vaccination.

We found a waning effect for the initial two-dose vaccination scheme but a higher peak effectiveness and more sustained protection against COVID-19 death for the booster dose (> 70% two months after booster). In addition, we have shown that the booster dose was likely effective during the Omicron period (rVE 29.3% 95%CI -1.4 - 50.7), in line with previous serological studies in the general population showing maintained protection against Omicron for mRNA vaccines 42 . This is one of the first studies to assess waning in both schemes (two-dose initial scheme and booster) and evaluate the impact of the VoC period on effectiveness in patients with cancer. Although results are promising, they should be interpreted having in mind the potential bias introduced by susceptibles depletion 43 and undocumented infections. We found an increased numerical benefit for those who received a mRNA booster after a two-dose ChAdOX1 homologous initial scheme. Previous evidence suggests that heterologous schemes may provide additional protection compared to homologous schemes 44 . Because of the restricted range of ages (mostly ≤ 69 years) that received initial ChAdOX1 vaccination, results might be not generalizable to all adults with cancer, particularly the older ones that did not receive ChAdOX1.

Estimation of VE from observational studies 45 is challenging as vaccinated patients are often healthier (healthy bias) and more health conscious (health-seeking bias) than unvaccinated individuals. Although proper matching on relevant covariates may provide well-balanced characteristics between groups, it is often insufficient to adjust for unmeasured confounders. Previous research on COVID-19 vaccine effectiveness has shown that, despite proper matching, vaccinated patients had a lower risk of non-COVID death compared to control 45 , 46 , 47 , partially explained by healthier conditions of vaccinated patients. In our study, we showed a lower risk of non-COVID deaths among vaccinated patients but a much lower magnitude for all-cause hospitalizations. Further adjustment for previous influenza receipt and exclusion of recently hospitalized patients, variables that would capture part of the healthy and health-seeking biases, improved all cause-hospitalization differences between groups, but not non-COVID death. We hypothesize two other reasons for this finding. First, the principal difference between vaccinated and control ones occurred in the immediate period after the vaccine (Suppl. Table 5 and 6 ), a finding observed by other studies and improbable to be related to the biological action of vaccines. This is likely because the most ill or frail individuals ended up dying early on after matching, and in a clinical trial, they would likely not be eligible to be randomized. Second, part of the non-COVID-19 deaths could be actually COVID-19 deaths, leading to misclassification of the outcome. In the analyzed population, there is a high proportion of non-COVID-19 deaths that occurred without hospitalization (60% for Cohort A and 71% for Cohort B), which is associated with a great network of home and palliative care in the region, making us hypothesize that these individuals are unlikely to get tested (and consequently being diagnosed) 48 . Finally, socio-economic variables in large databases can not capture all socio-economic nuances and wealthy bias is a concern. The comparable risk in all-cause hospitalizations and similar effectiveness after negative outcomes calibration and across the sensitivity analyses result in confidence in the vaccine protection observed. However, the magnitude and direction of the potential bias is uncertain.

This study has many strengths. We included a large number of patients in each assessment - 184,744 patients for the two-dose initial vaccination and 108,534 patients for the booster analysis. In addition, cancer diagnosis had been previously validated in the SIDIAP database with good agreement with population-based cancer registries in Catalonia 49 providing a quality assessment of our population of interest. We designed an observational study with robust methodology including a target-trial framework with rolling entry matching on a daily basis with adjustment for all potential observable confounders and similar baseline characteristics between groups. This methodology has already been validated in similar scenarios of vaccine effectiveness 38 , 50 with valid estimates of effectiveness. We calibrated our estimates with negative control outcomes that are highly improbable to be associated with our exposure of interest, addressing unobservable residual confounding which is a major issue in large population studies. Finally, we provided a comprehensive analysis of our findings, presenting sensitivity analyses with different outcomes and cohort definitions, including non-COVID outcomes, and creating additional cohorts matched on previous influenza receipt to investigate for potential healthy-vaccine bias.

The main limitation of this study is its observational design. Although large observational databases with adequate methodology may duplicate the results of randomized clinical trials 37 , residual confounding cannot be excluded. However, we tried to minimize the chances of confounding by including variables associated with health-seeking behaviors (number of outpatient visits) and socioeconomic factors (the MEDEA deprivation index) in addition to calibrating for negative control outcomes. Visual inspection of bias indicators (i.e., during the initial days following vaccination) 51 , 52 showed a low risk of bias, and negative control adjustment showed similar results. Although the selection of negative outcomes might be debatable, we have chosen negative outcomes previously validated in very similar settings 53 . However, the decreased hazards of non-COVID death, particularly in the immediate period post-vaccination, indicates residual healthy bias. We attempt to reduce this bias by matching new cohorts on previous influenza vaccine receipt, excluding frail patients (patients hospitalized a month prior), and adjusting variables that could capture healthy-seeking behavior, but lower hazards for non-COVID death persisted, and our results should be interpreted in light of these findings. It is possible that the VE and rVE estimates are overestimated because of this residual healthy bias, particularly in the immediate period post-vaccination when most non-COVID deaths were observed. We defined COVID-19 outcomes based on the temporal association of a positive diagnosis and the outcome (hospitalization and death) as causes for hospitalization and death were unavailable; however, sensitivity analysis with different definitions provided similar results. Another limitation is the lack of data granularity regarding cancer staging and treatment (including chemotherapy and radiation therapy, among others), which limits our capability of answering questions regarding the timing and type of treatment provided. To overcome this limitation, we used time from cancer diagnosis as a surrogate for cancer treatment receipt, as patients with recent diagnoses may have higher chances of being under treatment. Additionally, during the COVID-19 pandemic, patients at higher risk of severe outcomes might have taken additional measures to prevent infection, such as avoiding gatherings or using face shields which are not captured by data and may influence results 54 . Lastly, during the Omicron wave, we could not differentiate between patients who have been hospitalized with COVID-19 and not because of COVID-19. However, this is even harder to ascertain in patients with cancer. We included a sensitivity analysis with COVID-19 diagnosis up to 3 days after admission with similar results, showing that the time of COVID-19 infection (pre-admission vs during admission) did not change outcomes.

In conclusion, we found a significant protective effect for both the primary and booster vaccination schemes on hospitalization and mortality outcomes among patients with cancer. The booster protective effect was high and more durable, particularly against COVID-19 death. Patients should be encouraged to get vaccinated if not and boosted if they have had only two doses. Because of the higher risk of breakthrough infections, hospitalizations, and death compared to healthy individuals, patients with cancer should be prioritized in future additional dose studies and vaccination campaigns.

Study design, settings, and data source

We conducted a matched population-based cohort study using the Information System for Research in Primary Care (SIDIAP; www.sidiap.org ) database 55 . SIDIAP is a primary care longitudinal database from Catalonia, Spain, which contains pseudo-anonymized individual-level patient data since 2006, with 5.8 million people active in June 2021 (75% of the Catalan population). The present study was conducted using data from December 27th, 2020 to June 30th, 2022. The SIDIAP database includes clinical diagnosis, lifestyle information, and dispensed medications in primary care, including COVID-19 vaccine products, linked to both the SARS-CoV-2 polymerase chain reaction (RT-PCR) and rapid antigen tests results database and hospital records database. The SIDIAP has been mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM), allowing the reproducibility of study definitions across a wide range of mapped databases 56 , 57 . The current work was approved by the Clinical Research Ethics Committee of IDIAPJGol (project code 23/023-EOm).

The Spanish national COVID-19 vaccination campaign was launched on 27th December 2020. Because of the initially limited availability of vaccines, groups considered at higher risk were prioritized, including healthcare workers, nursing home residents, and older subjects 58 . According to national guidelines, patients with cancer under active treatments or other serious immunosuppressive comorbidities were prioritized before the general population but only after older patients. Vaccine products used for the national COVID-19 vaccination campaign were progressively extended as new authorizations were granted and included: BNT162b2 ( Pfizer , mRNA, two-dose, 21-day interval), ChAdOx1 ( AstraZeneca , adenovirus, two-dose, 3-month interval), mRNA-1273 ( Moderna , mRNA, two-dose, 28-days interval), and Ad26.COV2.S ( Janssen , adenovirus, single-dose). People who were vaccinated with Ad26.COV2.S were later recommended for an additional second dose because of lower expected vaccine effectiveness at that time 59 .

Study population, exposure definitions, and outcomes

Eligible individuals were adults aged 18 or older with at least one year of prior observation, with a record of cancer diagnosis (excluding non-melanoma skin cancer) within the last 5 years prior to the index date, which represents the date at which individuals were eligible to enter the matching pool. We excluded patients with any previous diagnosis of COVID-19, defined as a combination of either clinical or laboratory diagnoses of COVID-19 prior to the index date. Patients who were transferred out of SIDIAP before matching and those living in nursing homes were also excluded.

The exposure of interest in this study was COVID-19 vaccination defined as the receipt of any COVID-19 vaccine among all available vaccine products at the time (BNT162b2, mRNA-1273, ChAdOx1, and Ad26.COV2.S). Overall vaccine uptake was described including all eligible patients at the beginning of the vaccination campaign on 27th December 2020.

We built two matched cohorts: Cohort A to evaluate the VE of the first and second doses (primary vaccination) compared with unvaccinated individuals; and Cohort B to evaluate the relative VE of the booster compared with two doses. Cohort A included all adults eligible for primary vaccination with a cancer diagnosis up to five years before the first dose vaccination date. Cohort B, a subset of Cohort A, included only patients that previously received homologous vaccine schemes with BNT162b2, mRNA-1273, and ChAdOx1, with adequate interval between the second and third dose (a minimum of 90 days intervals for ChAdOx1 and 180 days for BNT162b2 and mRNA-1273). For Cohort B, patients had to have a cancer diagnosis before the first dose vaccination date up to five years from the booster vaccination date to ensure the patient had a cancer diagnosis at the time of the primary vaccination.

The index date was set to the first dose date for vaccinated individuals in Cohort A and the booster date for exposed individuals in Cohort B. The Index date for patients in the control groups was set as the index date of their matched counterparts. The study end date for Cohort A was on 20 th November 2021 (one month before the Omicron VoC predominance) and for Cohort B at the last available information date (30 th June 2022)

Predominant variants of concern (VoC) (Delta, Omicron, and others) at each time period were defined as ≥ 50% of weekly tested samples in Catalonia, extracted from the Global Initiative on Sharing All Influenza Data (GISAID) 60 .

The primary outcome of this study was COVID-19 hospitalization, and secondary outcomes included COVID-19 severe hospitalization - defined as a COVID-19 hospitalization with the need for invasive oxygen supplementation, and COVID-19 death. Consistent with prior research on severe COVID-19 61 , 62 , we defined COVID-19 hospitalization as any hospital admission within 21 days from the COVID-19 diagnosis up to the entire duration of hospitalization. Likewise, death was classified as any cause of death occurring within 28 days from the date of COVID-19 diagnosis. In addition to COVID-19-associated outcomes, we report all-cause hospitalizations and non-COVID deaths. A complete list of variables, exposures and outcome definitions can be found in Suppl. Tables 14 , 15 and 16 . The decision to set COVID-19 hospitalization as primary outcome (in contrast with the composite outcome of COVID-19 hospitalization and/or death) and evaluate COVID-19 severe hospitalization, all-cause hospitalizations and non-COVID-19 deaths was made post-hoc during peer review.

Statistical analysis

We emulated a pragmatic target trial of COVID-19 vaccination among patients with cancer within the SIDIAP database using rolling entry matching (REM) 45 , 63 , on a daily basis ( Suppl. Figure 14 ) . For Cohort A, eligible patients upon their first dose date were matched in a 1:1 ratio to eligible un-vaccinated individuals. For Cohort B, individuals with a completed primary scheme upon their booster dose date were matched in a 1:1 ratio to individuals with a completed primary scheme and eligible to receive a booster dose. Matching was performed by combining exact and caliper matching. Age (bins of five years), sex, cancer diagnosis time (categories zero to five years), the municipality of residence, the MEDEA deprivation index 64 (a proxy for deprivation based on place of residence from Q1 [least deprived] to Q5 [most deprived]), the number of outpatient visits in the previous year (as a proxy for healthy seeking behavior), the Charlson Comorbidity Index and metastatic disease were used to build a propensity score with a logistic regression model, which was used for matching in a caliper of 0.01 while ensuring exact matching for age, sex, cancer diagnosis time and the municipality of residence. For Cohort B, the exact matching also included the previous vaccination scheme (i.e., first and second dose product). Matching variables were chosen based on their potential association with receiving the vaccine (exposure of interest) and the risk of severe COVID-19 (outcome of interest).

After matching, patients were followed until an outcome event of interest occurred, death, or were censored at the last follow-up date. In case the control-matched patient was vaccinated, the matched-pair was censored at the date of control vaccination. Patients who had COVID-19 infection but were not hospitalized nor died were censored 28 days after the date of infection to account for a window of susceptibility to events of interest. The censoring of those who had COVID-19 without an event of interest was based on the following rationale: we are evaluating the first COVID-19 infection-associated event, and those with a previous infection would have low susceptibility to subsequent infections and consequently low risk of the outcome (i.e., an individual is still at risk during its first COVID-19 infection and subsequent window of susceptibility to the event, but this risk decreases if no event occurs and immunity is created).

Baseline covariable balance was evaluated by standardized mean differences (SMD) and descriptive characteristics between groups. Continuous variables were described with mean, median, standard deviation (SD), or interquartile range depending on variable distribution, and categorical variables with absolute numbers and relative proportions.

We calculated and plotted the cumulative incidence between groups with the Kaplan-Meyer estimator. VE was estimated using a Cox Proportional hazards model in the matched cohorts as 1 minus the hazard ratio (HR) between groups. HR and 95% confidence intervals (CI) were calculated in different periods of time (time-stratified Cox model) since vaccination (day zero) to investigate the long-term effectiveness and waning effect. Our primary analysis estimated the VE for the period after 14 days of the first dose (partially vaccinated), after 7 days of the second dose (fully vaccinated), and relative VE 14 days and 60 days after the third dose. Potential vaccine waning was evaluated with a larger number of period breaks from vaccination until 120 days or more thereafter (all periods). All Cox models accounted for the competing risk of death under the framework of cause-specific competing risks, more suitable for etiological research questions 65 , 66 , 67 , 68 . In a post-hoc decision during the peer review, we also estimated the VE using the Fine-Gray models considering the competing risk of death, deriving sub-distribution HRs for the main analysis, an approach more suitable for prediction and prognostic, to complement the cause-specific evaluation 65 , 69 . The competing event was all-cause death for the COVID-19 hospitalization outcome.

We investigated residual confounding by visually inspecting the cumulative incidence and estimated VE differences in the immediate (0 - 14 days) post-vaccination period when no protection is expected 52 . In addition, residual confounding could remain after matching due to unobserved confounding variables, particularly ones associated with wealthy-healthy bias that may affect results. Thus, we performed a negative control outcomes (NCO) analysis 70 with a previously published list of 43 validated outcomes that were highly improbable to be associated with our exposure of interest (COVID-19 vaccination) 53 . In addition to these previous validated negative outcomes, we performed an additional analysis including 11 additional outcomes in the negative outcomes set ( Suppl. Table 17 ) . Results from NCO were used to empirically calibrate our estimates with the EmpiricalCalibration package in R 53 , 71 . Additionally, we report estimates of health-services-seeking behavior, including outpatient visits, telehealth visits, home visits, and inpatient and ICU visits after vaccination. The decision to evaluate these other negative control outcomes (expanded set of negative outcomes and health-services-seeking behavior) was made post-hoc during peer review.

Subgroup effect modification of the primary outcome was defined based on previous knowledge of possible effect modifiers in this population and included: age (<65 years old vs ≥ 65 years old), sex (male vs female), cancer diagnosis time (1 year vs 1-5 years), metastatic disease (yes vs no), lung cancer diagnosis (yes vs no), hematological cancer diagnosis (yes vs no), and COVID-19 VoC period (other vs delta vs omicron). For Cohort B (booster vaccine), we also investigate the effect of a previous mRNA vaccine scheme (yes vs no) as a subgroup. Subgroup analyses were evaluated with an interaction term between the vaccine and the subgroup of interest.

Sensitivity analyses were performed and included: stricter cancer definition, only tested patients (any test during the whole period), only RT-PCR COVID-19 diagnosis, and modified COVID-19 hospitalization outcome to any COVID-19 diagnosis from 21 days before admission to 3 days after, and from 14 days before admission to 3 days after, to exclude potential hospital-acquired COVID-19 infections and non-COVID-19 directly related hospitalizations respectively. Finally, to better address health bias, we built two additional matched cohorts for both exposures (primary vaccination and booster vaccination), including previous influenza vaccine receipt as exact matching, excluding patients hospitalized a month prior to the matching date, and propensity matching on a number of outpatient visits as numerical and not categorical variable ( restricted matching cohorts). We compared COVID-19 and non-COVID-19 outcomes between matched cohorts (original versus restricted matching cohorts). The decision to evaluate different matching was made post-hoc during peer review.

We report 95% CI for all estimates. A p-value less than 5% was considered statistically significant. We performed all analyses in R version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria).

Reporting summary

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

Data availability

In accordance with the current European and national law, the data used in this study are only available for the researchers participating in this study. Thus, we are not allowed to distribute or make publicly available the data to other parties. However, researchers from public institutions can request data from SIDIAP if they comply with certain requirements. Further information is available online ( https://www.sidiap.org/index.php/menu-solicitudesen/application-proccedure ) or by contacting SIDIAP ( [email protected] ).

Code availability

R scripts were made available to ensure the reproducibility of results and in accordance with good research practice ( https://github.com/felippelazar/SIDIAP-CovidVaccineCancer/ ) 72 .

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Acknowledgements

We thank all healthcare professionals in Catalonia who daily register information in the populations’ electronic health records; the Institut Català de la Salut and the Programa d’analítica de dades per a la recerca i la innovació en salut for providing access to the different data sources accessible through SIDIAP. OTR acknowledges support from the END-VOC Project (Horizon 2021-2024), funded by the European Union under grant agreement no. 101046314. This manuscript is an honest, accurate, and transparent account of the study being reported. No important aspects of the study have been omitted. The funding source had no role during the design, analysis or writing of the current study.

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These authors jointly supervised this work: Ranzani Otavio T, Duarte-Salles Talita.

Authors and Affiliations

Pulmonary Division, Heart Institute (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

Felippe Lazar Neto & Otavio T. Ranzani

Serviço de Oncologia Clínica, Instituto do Câncer do Estado de São Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

Felippe Lazar Neto & Gilberto Castro Junior

Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain

Núria Mercadé-Besora, Berta Raventós, Laura Pérez-Crespo & Talita Duarte-Salles

Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain

Berta Raventós

ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain

Otavio T. Ranzani

Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands

Talita Duarte-Salles

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F.L.N., O.T.R., and T.D.S. were involved in the conceptualization, methodology, and data curation. F.L.N., O.T.R., G.C.J., N.M.B., B.R., and L.P.C. in formal analysis and investigation. F.L.N and O.T.R were involved in writing—the original draft. All authors were involved in writing—review, and editing.

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Correspondence to Otavio T. Ranzani or Talita Duarte-Salles .

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GCJ reports outside the scope of this paper to have received honorariums from AstraZeneca, Pfizer, Merck, Bristol-Myers, Novartis, Roche, Amgem, Janssen, Lilly, Takeda, Daiichi Sankyo, in addition to playing advisory roles to Boehringer, Pfizer, Bayer, Roche, Merck, Bristol-Meyers, AstraZeneca, Yuhan, Janssen, Libbs, Sanofi, Novartis, Lilly, Takeda, and Daiichi Sankyo. The remaining authors have no conflicts of interest to disclose.

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Lazar Neto, F., Mercadé-Besora, N., Raventós, B. et al. Effectiveness of COVID-19 vaccines against severe COVID-19 among patients with cancer in Catalonia, Spain. Nat Commun 15 , 5088 (2024). https://doi.org/10.1038/s41467-024-49285-y

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DOI : https://doi.org/10.1038/s41467-024-49285-y

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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

S.no.	Vaccine Platform	Advantages	Limitations
1	Live Attenuated Vaccine (LAV) /the whole virus
2	Inactivated Virus Vaccine
3	Sub-unit Vaccine
4	Viral vector-based vaccine
5	DNA Vaccines
6	RNA Vaccines

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

S.no.	Type of Vaccine/ Platform/ Related Use/ Ref	Developer	Clinical Trial Stage	Remarks
Viral vectored vaccines
1	Adenovirus Type 5 Vector/ Non-replicating viral vaccine/ Ebola/ ( )	CanSino Biological Inc./Beijing Institute of Bio-technology	Phase 2 ChiCTR2000031781 Phase 1 ChiCTR2000030906 NCT: NCT04313127	“A randomized, double-blind, placebo parallel-controlled phase I/II clinical trials for inactivated Novel Coronavirus Pneumonia vaccine (Vero cells)” have established a positive antibody response or the seroconversion along with CD4+ and CD8+ T cell response.
2	Inactivated viral vaccine/ Inactivated/ -/ ( )	Wuhan Institute of Biological Products/Sinopharm	Phase 1/2: ChiCTR2000031809	Animal trials suggest that the vaccine protects the model animals without Antibody dependent enhancement (ADE).
3	Lentiviral based Minigene dendritic cell (DC) and T cell vaccine (LV-SMENP-DC)/ - / ( ; )	Shenzhen Geno-Immune Medical Institute	Phase 1: NCT04276896	LV-SMENP-DC vaccine is designed by altering DC with lentivirus vectors to express the “SARS-CoV-2 SMENP minigene and immune modulatory genes”. LV-DC that presents SARS-CoV-2 specific antigens will activate the CTLs
4	The COVID-19/aAPCs : Pathogen-specific artificial antigen presenting cells (aAPC)/-/ ( )	Shenzhen Geno-Immune Medical Institute	Phase 1 NCT04299724	Constructed through modifications of lentivirus by including immune modulatory genes along with viral minigenes, and antigens are presented on artificial antigen presenting cells (aAPCs).
5	ChAdOx1/ Non-replicating viral vector/ MERS, influenza, TB, Chikungunya, Zika, MenB, plague/ ( ; )	University of Oxford/AstraZeneca	Phase 3: ISRCTN89951424 Phase2b/3: NCT04324606	A phase I/II single-blinded, randomized, placebo controlled, multi-center study was conducted to determine efficacy, safety, and immunogenicity of this vaccine in UK with healthy adult volunteers aged 18-55 years. The post-vaccination follow-ups are ongoing for the 1000 volunteers. Meanwhile taking the vaccine to the higher levels of clinical trials.
6	Inactivated (formaldehyde inactivated + alum)/ SARS/ ( ; )	Sinovac	Phase I/II: NCT04352608 NCT04282574	The double-blind, placebo-controlled phase I trials showed the nAb seroconversion rate to be as high as 90% in 143 adults within 14 days of immunization.
7	Adeno-based Gam-COVID-Vac/ Non-replicating viral vector/-/ ( ; )	Gamaleya Research Institute	Phase I: NCT04436471 NCT04437875	Two types of the vaccines— fluid based and powder based for infusions — will be tried on two batches of volunteers, 38 individuals each. The members will be isolated in two Moscow medical clinics.
8	Ad26 (alone or with Modified Vaccinia Virus Ankara {MVA} boost) Non-replicating viral vaccine/ Ebola, HIV, RSV/ ( ; )	Janssen Pharmaceutical Companies/ Beth Israel Deaconess Medical Center	Pre-Clinical (Phase 1 in September 2020)	To accelerate the development of the vaccine the company will use the AdVac® and PER.C6® technologies.
9	Influenza vector expressing RBD: DelNS1-SARS-CoV2-RBD/ Replicating viral vector (LAV)/ MERS/ ( ; )	University of Hong Kong	Pre-Clinical	“It is attenuated by the deletion of a key virulent element and the immune antagonist, NS1, which is potentially more immunogenic than the wild-type influenza virus.”
10	CoroFlu, self-limiting influenza virus (M2SR) Non-replicating Viral Vector/ ( ; )	University of Wisconsin-Madison / FluGen/ Bharat Biotech	Pre-Clinical	The M2SR is self-limiting because it does not undergo viral replication because of the absence of M2 gene. It will be administered via the nasal route.
11	Replicating viral vector/ measles vector/ West Nile, CHIKV, Ebola, Lassa, Zika, MERS/ ( ; )	The Institut Pasteur	Pre-Clinical	The proprietary measles vector (MV) technology is chosen to develop the vaccine against SARS-CoV-2 which was used in the MV-SARS-CoV vaccine candidate.
12	Oral COVID-19 Vaccine/ Recombinant adenovirus type 5 vector/ CHIKV, LASV, NORV, EBOV, RVF, HBV, VEE / ( )	Vaxart	Pre-Clinical	It will be an oral vaccine that aims to induce the mucosal immune response.
DNA vaccines
1	DNA Plasmid Vaccine (INO-4800)/ Lassavirus, Nipah virus, HPV, HIV, Filovirus/ ( ; )	Inovio Pharmaceuticals	Phase 1 NCT04336410	Pre-clinical trials reveal induction of the antigen-specific T cell responses, and functional nAb, thus creating an obstacle for the S protein to bind to the hACE2 receptor. Phase I clinical trials will evaluate the safety, immunogenicity, and tolerability of the vaccine.
2	Electroporated linear DNA vaccine/ ( )	LineaRx \| Takis Biotech	Pre-Clinical	There are 4 candidates of linear DNA vaccine based upon S proteins and some selected epitopes.
3	Electroporated DNA vaccine/ ( ; )	ZydusCadila	Pre-Clinical	-
4	DNA vaccine/ ( )	Karolinska Institute / Cobra Biologics (OPENCORONA Project)	Pre-Clinical	A DNA vaccine, which will be administered via intramuscular injections. It will then form the viral antigens to induce the immune response.
5	DNA Vaccine (GX-19)/ ( )	Genexine Consortium	Pre-Clinical	Expected to soon enter the clinical trials with Kalbe Farma.
RNA Vaccines
1	LNP- Encapsulated mRNA (mRNA-1273)/ Multiple Candidates/ ( ; )	Moderna/NIAID	Phase 2: NCT04405076 Phase 1 NCT04283461	In Phase 1 Trials, the seroconversion resulted in the nAb levels either close to or higher than the convalescent sera. The vaccine was generally safe and well tolerated.
2	CureVac mRNA/ RABV, LASV, YFV, MERS, InfA, ZIKV, DengV, NIPV/ ( ; )	CureVac	Phase 1	mRNA as a data carrier to instruct the human body to produce its own proteins capable of fighting a wide range of diseases is used.
3	LNP-nCoVsaRNA/ RNA/ EBOV, LASV, YFV, MERS, InfA, ZIKV, DENV, NIPV/ ( ; )	Imperial College London	Phase 1: ISRCTN17072692	It is the purified synthetic mRNA which mimics the virus gene for a spike protein on its surface.
4	BNT162/ mRNA/ ( ; ; )	BioNTech\| FosunPharma\| Pfizer	Phase 1 /2: NCT04380701	A robust immunogenic response with the geometric mean of nAb titres to be 1.8 and 2.8 times the nAb titres in the convalescent serum panel after the administration of the second dose.
4	LNP-encapsulated mRNA cocktail encoding VLP/ RNA/ ( ; )	Fudan University/ Shanghai JiaoTong University/RNA Cure Biopharma	Pre-Clinical	-
5	LNP-encapsulated mRNA cocktail encoding RBD/ mRNA/ ( ; )	Fudan University/ Shanghai JiaoTong University/RNA Cure Biopharma	Pre-Clinical	-
6	mRNA onco-vaccine/ ( )	BIOCAD	Pre-Clinical	They work by introducing sequences of molecules designed to make cells produce disease specific antigens and trigger a regular immune response.
Protein Subunit Vaccine
1	VLP Recombinant Sub-unit, Full length S trimer/nanoparticle + Matrix M (NVX-CoV2373)/RSV, CCHF, HPV, VZV, EBOV/ ( ; ; ; )	Novavax \| Emergent BioSolutions	Phase 1: NCT04368988	It demonstrated high immunogenicity in animal model with measuring anti spike antibodies, that prevent the attachment of the spike protein to the receptor, as well as wild-type virus neutralizing antibodies.
2	Molecular Clamp Stabilized Recombinant spike protein/Subunit/ Nipah, influenza, Ebola, Lassa/ ( ; )	University of Queensland \| GSK \| Dynavax	Pre-Clinical	It is a stabilized pre-fusion viral protein sub-unit vaccine which is based upon the Molecular Clamp technology and uses AS03 adjuvant system from GSK.
3	S1 Microneedle array-based (PittCoVacc) Protein Subunit/ MERS/ ( ) ( )	University of Pittsburgh	Pre-Clinical	Micro-needle Array-based delivery of the recombinant SARS-CoV-2 S1 induced a statistically significant antigen-specific antibody response within 2 weeks of administration in the mice models.
4	Recombinant protein Subunit vaccine/Influenza, SARS-CoV/ ( ) ( ) ( )	Sanofi	Pre-Clinical	It is a recombinant vaccine of unrevealed SARS-CoV-2 protein(s) which is expressed in baculovirus vector system.
5	Protein Sub-unit, gp-96 based/ HIV, malaria, Zika/ ( ; )	Heat Biologics	Program announced in March 2020	It is a “Heat-shock protein gp96 complexed with an undisclosed SARS-CoV-2 peptide(s)”. This technology is capable of generating long-term immune responses and may confer immunity to different coronaviruses.
	Virus Like Particle (VLP) vaccine/ ( )	Medigaco	Pre-Clinical	A recombinant SARS-CoV-2 protein (undisclosed) VLP produced in tobacco.
Live Attenuated Vaccine
1	Deoptimized live attenuated virus/ HAV, InfA, ZIKV, FMD, SIV, RSV, DENV / ( ; )	Codagenix/Serum Institute of India	Pre-Clinical	Codagenix's technology allows for the rapid generation of multiple vaccine candidates against emerging viruses, starting with only the digital sequence of the viral genome.
2	TNX-1800, Live Attenuated Horsepox virus/ smallpox, monkeypox/ ( )	Tonix Pharmaceuticals	Pre-IND	It is believed that horsepox has the potential to serve as a vector for vaccines to protect against other infectious agents.
3	Live attenuated recombinant measles virus (rMV)/ ( ; ; )	ZydusCadila	Pre-Clinical	Codon-optimized proteins of the new coronavirus, expressed by rMV, will use reverse genetics to stimulate long-term neutralizing antibodies that protect against the infection
Others
1	Self-assembling vaccine/ ( )	HaloVax (Voltron Therapeutics) \| The Vaccine & Immunotherapy Center at the Massachusetts General Hospital	Pre-Clinical (October 2020)	The biotinylated immunogenic fusion protein is sandwiched between heat shock protein and avidin.

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

Vaccine \| Ref	Developer	Remarks	Clinical Trial Stage
ChAdOx1 \| ( )	University of Oxford/AstraZeneca	The preliminary reports of phase 1/2, single-blind, randomized controlled trials of the ChAdOx1 nCoV-19 vaccine have showcased the spike-specific T-cell responses along with the Anti-spike IgG response in 91% participants as per the micro-neutralization assay (MNA80) while a plaque reduction neutralization assay (PRNT50) depicted a 100% response after a single dose. Nevertheless, after the booster dose neutralizing response was seen in all the participants which had a substantial correlation with the neutralizing antibody titers as measured by ELISA. The volunteers depicted local and systemic reactions which were minimized by the administration of paracetamol. Thus, the vaccine candidate has portrayed adequate safety and immunogenicity profile in the phase 1/2 clinical trials.	Phase 3: ISRCTN89951424
mRNA-1273 \| ( )	Moderna/NIAID	The geometric mean of RBD specific antibody titers showed a rapid increase in all the participants. Seroconversion was observed after 15 days and the median magnitude of antibody responses was similar to the magnitude in convalescent sera. However, the pseudovirus neutralizing activity was not high before the administration of the second dose, which indicates the requirement of a two-dose vaccination schedule. Furthermore, the serum neutralizing activity, a generally accepted functional biomarker of the in vivo humoral response against the respiratory viruses, has not been determined as of now.	Phase 3: NCT04470427
PiCoVacc \| ( )	Sinovac	The phase 1/2 clinical trials of the inactivated viral vaccine candidate PiCoVacc demonstrated that the vaccine induces neutralizing antibodies with a seroconversion rate of 90% in a 0,14 day schedule. The preliminary results confirmed the absence of adverse systemic or local events post-vaccination. The phase 2 clinical trials are expected to be concluded by the end of 2020. The Company has got the permission for conducting the phase 3 clinical trials in Brazil in collaboration with Instituto Butantan. Furthermore, it is expected to get further approvals in Bangladesh for the phase 3 clinical trials.	Phase 3: NCT04456595
BBV152 (A-C) \| ( )	Bharat Biotech/ ICMR/ NIV	It is the whole virion inactivated experimental vaccine under the phase 1/2 clinical trials. These trials are supposed to study the safety and reactogenicity, tolerability, and the immunogenicity in the healthy volunteers. The inactivated vaccine shall be administered intramuscularly in two doses at day 0 and day 14 and the 1125 volunteers shall be observed for the next six months and will be evaluated for post-vaccination immune responses. The viral strain for the vaccine development was isolated by ICMR and transferred to Bharat Biotech where the process of inactivation was executed in a BSL-3 facility.	Phase 1/2: NCT04471519
Adenovirus Type5 Vector/ Non-replicating viral vaccine \| ( )	CanSino Biological Inc./Beijing Institute of Bio-technology	The randomized, double-blind, placebo controlled phase 2 clinical trials of the recombinant Ad5-vectored vaccine represented a positive cellular response at 5 × 10 viral particles along with seroconversion of the humoral immune response. Severe adverse reactions were reported in 9% of the individuals in the 1 × 10 viral particles dose group and 1% volunteers exhibited these adverse reactions in the 5 × 10 viral particles dose group.	Phase 2: ChiCTR2000031781
BNT162 \| ( )	BioNTech\| FosunPharma\| Pfizer	BNT162b1, the mRNA based vaccine induced a high, dose-dependent nAb titers along with the RBD-binding IgG concentrations after the second dose. This was accompanied by the CD4+ and CD8+ T cell responses. The administration of the vaccine was accompanied by certain adverse symptoms like fatigue, fever, chills, muscle pains etc. However, the recipients did not showcase any severe symptoms.	Phase 3: NCT04368728
ZyCoV-D \| ( , ; )	Zydus Cadila	ZyCoV-D is a genetically engineered DNA plasmid based vaccine encoding for the membrane proteins of the virus. The clinical trials to study the immunogenicity, and safety of the vaccine, will administer three doses at an interval of 28 days in 1048 individuals.	Phase 1/2: CTRI/2020/07/026352

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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COMMENTS

Long-term effectiveness of COVID-19 vaccines against infections
Our analyses indicate that vaccine effectiveness generally decreases over time against SARS-CoV-2 infections, hospitalisations, and mortality. The baseline vaccine effectiveness levels for the omicron variant were notably lower than for other variants. Therefore, other preventive measures (eg, face-mask wearing and physical distancing) might be necessary to manage the pandemic in the long term.
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Introduction. The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 192 million cases and 4.1 million deaths as of July 22, 2021. 1 This pandemic has brought along a massive burden in morbidity and mortality in the healthcare systems. Despite the implementation of stringent public health measures, there ...
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Safety and adverse effects of current COVID-19 vaccines. As shown in Table I, current vaccines have demonstrated considerable efficacy in diminishing mild, moderate and severe cases with a low risk of adverse events 21.For some of these vaccines [such as Convidicea (AD5-nCoV), Janssen (Ad26.COV2.S), Sinopharm (BBIBP-CorV), Covaxin (BBV152) and Sinovac (CoronaVac)], there is the information ...
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Although Covid-19 vaccines have been recommended for adults with chronic medical conditions, 22 ... The activity reported in this article was deemed not to be research as defined in 45 Code of ...
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Full article: The evolution, facilitators, barriers, and additional
Paper Context. Main findings: The research found that Bangladesh has achieved a world-standard surveillance system, with facilitating factors including multi-sectoral collaboration, GPEI partners, and political and community support. However, high population growth, hard-to-reach areas and people, and polio transition planning were found to be challenges.
COVID-19 Vaccine: A comprehensive status report
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 ...

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

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Vaccine effectiveness for different clinical outcomes of COVID-19

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

Safety of SARS-CoV-2 vaccines

Sensitivity analysis and publication bias

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COVID-19 Vaccine: A comprehensive status report

1. Introduction

2. Vaccination strategies

2.1. Protein Sub-unit vaccine

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

2.1.2. Molecular Clamp Stabilized spike protein vaccine candidate

2.1.3. PittCoVacc (University of Pittsburgh)

2.1.4. Triple Antigen Vaccine (Premas Biotech, India)

2.2. Viral Vectored vaccines

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