Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review (original) (raw)

Abstract

Background

Vaccines are critical cost-effective tools to control the coronavirus disease 2019 (COVID-19) pandemic. However, the emergence of variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may threaten the global impact of mass vaccination campaigns.

Aims

The objective of this study was to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness and impact of the variants of concern for 19 COVID-19 vaccines.

Sources

References for this review were identified through searches of PubMed, Google Scholar, BioRxiv, MedRxiv, regulatory drug agencies and pharmaceutical companies' websites up to 22nd September 2021.

Content

Overall, all COVID-19 vaccines had a high efficacy against the original strain and the variants of concern, and were well tolerated. BNT162b2, mRNA-1273 and Sputnik V after two doses had the highest efficacy (>90%) in preventing symptomatic cases in phase III trials. mRNA vaccines, AZD1222, and CoronaVac were effective in preventing symptomatic COVID-19 and severe infections against Alpha, Beta, Gamma or Delta variants. Regarding observational real-life data, full immunization with mRNA vaccines and AZD1222 seems to effectively prevent SARS-CoV-2 infection against the original strain and Alpha and Beta variants but with reduced effectiveness against the Delta strain. A decline in infection protection was observed at 6 months for BNT162b2 and AZD1222. Serious adverse event rates were rare for mRNA vaccines—anaphylaxis 2.5–4.7 cases per million doses, myocarditis 3.5 cases per million doses—and were similarly rare for all other vaccines. Prices for the different vaccines varied from 2.15to2.15 to 2.15to29.75 per dose.

Implications

All vaccines appear to be safe and effective tools to prevent severe COVID-19, hospitalization, and death against all variants of concern, but the quality of evidence greatly varies depending on the vaccines considered. Questions remain regarding a booster dose and waning immunity, the duration of immunity, and heterologous vaccination. The benefits of COVID-19 vaccination outweigh the risks, despite rare serious adverse effects.

Keywords: Coronavirus, COVID-19, Delta, Efficacy, Review, SARS-CoV-2, Seroneutralization, Vaccines, Variants

Background

The implementation of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major asset in slowing down the coronavirus disease 2019 (COVID-19) pandemic. At the time of writing, more than 100 vaccines have been developed, and 26 vaccines have been evaluated in phase III clinical trials, according to the World Health Organization (WHO) [1].

Recently, several variants of concern (VOCs) have emerged, including Alpha (known as 501Y.V1 with GISAID nomenclature or B.1.1.7 variant with PANGO nomenclature), Beta (501Y.V2 or B.1.351), Gamma (501Y.V3 or P1) and Delta (G/478K.V1 or B.1.617.2). These variants have been associated with an increase in the transmission or mortality of COVID-19 [[2], [3], [4], [5], [6]] or may escape immunity when compared to the original strain or D614G variant [[7], [8], [9], [10], [11]].

While phase III trials assess the efficacy under controlled conditions, phase IV studies evaluate the real-world effectiveness of the vaccines in an observational design among a larger general population. These studies bring crucial information about rare or long-term effects, the prevention of asymptomatic infection, and the severity of COVID-19.

The administration of COVID-19 vaccines is a major priority for many countries around the world. Due to the speed of production of scientific data in the context of this pandemic, it can be difficult for healthcare professionals to update themselves on the latest data concerning COVID-19 vaccines.

The objective of this review is to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness, and impact of the variants of concern on the following 19 COVID-19 vaccines: mRNA vaccines (BNT16b2, mRNA-1273, CVnCoV), viral vector vaccines (AZD1222, Sputnik V, Sputnik V Light, Ad5-nCoV (Convidecia), Ad26.COV2.S), inactivated vaccines (NVX-COV2373, CoronaVac, BBIBP-CorV, Wuhan Sinopharm inactivated vaccine, Covaxin, QazVac, KoviVac, COVIran Barekat), and protein-based vaccines (EpiVacCorona, ZF2001, Abdala).

Methods

Electronic searches for studies were conducted using Pubmed and Google scholar until 22nd September 2021 using the search terms “SARS-CoV-2”, “COVID-19”, “efficacy”, “effectiveness”, “neutralization assays”, and “neutralization antibodies” in addition to the scientific or commercial names of the vaccines reported by WHO in phase III/IV. The ClinicalTrials.gov database was consulted using the terms “COVID-19” and “vaccine”. BioRxiv and MedRxiv, regulatory drug agencies and pharmaceutical companies' websites were also consulted for unpublished results and additional information. Vaccines included in this review were approved in at least one country. CVnCoV and NVX-CoV2373 were in rolling review by the European Medicine Agency (EMA) and were included in this review.

Efficacy refers to the degree to which a vaccine prevents symptomatic or asymptomatic infection under controlled circumstances such as clinical trials. Effectiveness refers to how well the vaccine performs in the real world. In clinical trials, the main endpoint was the prevention of symptomatic COVID-19, whereas in observational studies endpoints were various and included asymptomatic SARS-CoV-2 infection, COVID-19, hospitalization or mortality.

Regarding seroneutralization assays, we extracted the age of the study population, dosage, and fold decrease in geometric mean titre for 50% neutralization compared to the SARS-CoV-2 reference strain for each vaccine and each SARS-CoV-2 variant when it was available.

Evidence on vaccine efficacy and effectiveness

At the time of this review, 17 vaccines have been authorized in at least one country (Supplementary Material Table S1) and two vaccines (CVnCoV and NVX-CoV2373) are under evaluation.

We briefly compared the COVID-19 vaccines schedule, type of vaccine, manufacturer, dosage, conditions of use/storage/transport, composition and price (Table 1). The main results of phase III clinical trials for each vaccine are described in Table 2and in Fig. 1). Characteristics of SARS-CoV-2 variants (Alpha, Beta, Gamma, Epsilon, Eta, Zeta, Iota, Kappa and Delta) are described in Table 3. The results of observational real-world studies are specified in Fig. 2, Fig. 3, Fig. 4and in the Supplementary Material Table S2. Seroneutralization assay results are summarized in Fig. 5using boxplots per vaccine and per variant, and Supplementary Material Table S3 describes the 54 studies in detail.

Table 1.

Characteristics of coronavirus disease 2019 (COVID-19) vaccines

Table 2.

Phase III trials for coronavirus disease 2019 (COVID-19) vaccines

Fig. 1.

Vaccine efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from clinical trials (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area.

Table 3.

Coronavirus disease 2019 (COVID-19) vaccines and variants

Fig. 2.

Vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) asymptomatic or symptomatic infection from real-world studies (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area.

Fig. 3.

Vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospitalization or death from real-world studies (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area.

Fig. 4.

Vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from real-world studies (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area. Blue, orange, red, pale blue, green refer to Alpha, Beta, Delta, Gamma and unsequenced strains, respectively.

Fig. 5.

Average fold reduction in neutralizing response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant versus wild type/D614G SARS-CoV-2 for each coronavirus disease 2019 (COVID-19) vaccine in 54 seroneutralization assays. The line in the middle of the box is the median. The box edges are the 25th and 75th percentiles. These boxplots included different methods assessing neutralizing antibody titres. Methods are detailed in the Supplementary Material Table S2.

Randomized clinical trials on vaccine efficacy

In phase III trials (Table 2 and Fig. 1), all the main outcomes were efficacy against symptomatic infection after the second dose. In most trials, the strain was not sequenced.

Messenger RNA (mRNA) vaccines

mRNA-based drugs are new but not unknown. In 1990, the direct injection of mRNA in mouse muscle cells proved the feasibility of mRNA vaccines [12]. mRNA instability, high innate immunogenicity and delivery issues were the main obstacles. BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 were the first authorized mRNA-based vaccines. They contain the mRNA of the antigen of interest which enters cells and is translated into the spike protein to induce an immune response. Against the historical strain, BNT162b2 and mRNA-1273 vaccines had an efficacy of >90% at 5–6 months' follow-up post second dose, whereas CVnCoV had a lower efficacy of 48%.

Viral vector vaccines

Viral vectors are delivery systems containing nucleic acid encoding an antigen. AZD1222, Ad5-nCoV and Sputnik V had an efficacy of 65–91.6% against the historical strain. AZD1222 had an efficacy of 70.4 against Alpha. Ad26.COV2.S had an efficacy of 69.4% in Brazil (mainly P2). AZD1222 and Ad26.COV2.S had efficacies of 10.4% and 64.7%, respectively, against Beta in South Africa.

Inactivated and protein subunit vaccines

Inactivated vaccines are whole viruses that cannot infect cells and replicate [13]. Subunit vaccines are made of fragments of proteins or polysaccharides. NVX-COV2373 had an efficacy of 89–91.6% against the historical strain, 86.3–93.2% against Alpha and 60% against Beta. CoronaVac, BBIBP-CorV, Wuhan inactivated vaccine, Covaxin and Abdala had an efficacy of 50.6–92.3% but the SARS-CoV-2 strains were not specified. KoviVac, Barekatn QazVac, RBD-Dimer, EpiVacCorona had no phase III trial data published at the time of this review.Real world studies.

Post-marketing surveillance studies results are summarized in Table 3 and detailed in Supplementary Material Table S2. Most studies have a follow-up of 90 days post-vaccination.

Effectiveness against COVID-19 (symptomatic infection)

After full immunization, mRNA vaccine effectiveness against disease was 88–100% against Alpha [[36], [37], [38], [39], [40], [41], [42], [43]], 76–100% against Beta/Gamma [37,38,40], 47.3–88% against Delta [38,[44], [45], [46], [47]], and 89–100% when SRAS-CoV-2 strain was not sequenced [40,41,[48], [49], [50], [51], [52], [53]] (Fig. 2). AZD1222 effectiveness against disease was 74.5% against Alpha [45] and 67% against Delta [44,54] in the UK. CoronaVac effectiveness was 36.8–73.8% against Alpha/Gamma/D614G strain in Chile and Brazil [[55], [56], [205]]. CoronaVac or BBIBP-COrV administration was associated with an effectiveness of 59% in China [57].

Effectiveness against COVID-19-related hospitalization and death

After full immunization (Fig. 3), mRNA vaccine or AZD1222 effectiveness against hospitalization or death was over 87–94% [48,58] when the strain was not sequenced, 89–95% against Alpha [36,38,39], 95% against Beta/Gamma [38], 96% against Alpha/Delta [39], and 80–95% against Delta [59,60]. CoronaVac was very effective against hospitalization (87.5%) and mortality (86.3%) after full immunization [56]. Ad26.COV1.S had an effectiveness of 60–85% against Delta [60,61].

Overall, the effectiveness of mRNA-vaccine and CoronaVac was reduced for Delta infection, but they still offered a high level of protection against severe COVID-19 and hospitalization for all variants after full immunization [36,38,39,43,48,56,59,62,63].

Effectiveness against asymptomatic SARS-CoV-2 infection

After full immunization, effectiveness was 90–92% for AZD1222 and BNT162b2 against unspecified strains [64,65] (Fig. 4). For mRNA vaccines, effectiveness against infection was 89.5–99.2% against Alpha [36,37,48,49,49,66], 75–96.4% against Beta [37,49], 42–84.4% against Delta [44,[66], [67], [68], [69]] and 80–98.2% against unspecified strains [48,50,51,62,[70], [71], [72], [73], [74], [75], [76], [77], [78]]. AZD1222 had an effectiveness of 49–67% in the UK [44,66,79]. mRNA vaccines and Ad26.COV2.S vaccines in the USA had an effectiveness of 47–80% against Delta [59,80,81]. Among pregnant women, a single dose or two doses led to an effectiveness of 78% against the original strain and 96% against Alpha, respectively. These previous studies focused on ≤6 years in people, but a retrospective cohort of teenagers aged 12–15 years in Israel also reported a high effectiveness of 91.5% against Delta infections [82].

Impact on viral load, infectivity, transmission and long COVID

Before Delta propagation, mRNA vaccines were associated with a lower viral load and a reduced duration of illness [83,84]. Against Delta, surveillance studies in the US found both vaccinated and unvaccinated people had similarly low cycle threshold (Ct) values, indicating high viral load [85,86]. However, the large UK REACT-1 study—using random sampling and including participants who tested positive without showing symptoms—showed that vaccinated people had a lower viral load on average [79]. A preprint in Singapore found that BNT162b2 vaccination was associated with a faster decline in viral loads among vaccinated people [87]. Ad26.COV2.S and BNT162b2 vaccines were associated with a lower probability of viral culture positivity, suggesting less shedding of infectious Delta virus in vaccinated people [88]. Before the spread of Delta, a study in England reported a reduced transmission associated with BNT162b2 or AZD1222 vaccines in a household setting [89], and two other preliminary analyses confirmed these results [90,91]. A Chinese preprint analysed infections among 5153 participants with 73 close-contact COVID-19 cases and observed a higher infection risk among unvaccinated or partially vaccinated participants (versus two doses of inactivated vaccines) [92]. In a large nested case–control study from the UK, participants with one or two vaccine doses reported having fewer symptoms and lower odds of having long COVID (symptoms over 28 days, OR =0.51 (95%CI: 0.32 to 0.82, after two doses) [93].

Waning immunity

Several studies have suggested that the levels of antibodies after BNT162b2, mRNA-1273 and Ad26.COV2.S vaccines could last for at least 6 months but decrease over time thereafter [[94], [95], [96], [97]]. For mRNA-1273, at 6 months neutralizing activity was maintained against Alpha, Gamma, Delta, Epsilon, whereas neutralizing activity was considerably decreased against Beta for half the participants [97].

Observational studies stratified by time since vaccination identified a decreasing effectiveness at 4–6 months (42–57%) for mRNA vaccines and 47.3% for AZD1222 against Delta infection [54,68,69,81]. In the USA, effectiveness of mRNA vaccines against symptomatic infection fell from 94.3% in June to 65.5% in July 2021. The effectiveness against hospitalization remained high (>85%) for mRNA-1273 (92%), BNT162b2 (77–93%) and AZD-1222 (70.3%) at 4–6 months after full vaccination [54,69,81,98] and 68% at >28 days after full immunization for Ad26.COV2.S [98]. It is difficult to know whether the reduction in effectiveness against Delta infection is due to waning immunity over time or/and variants escaping immunity and/or increasing in collective immunity.

Neutralization assays with variants of concern and variants of interest

Mutations and variations occur in the SARS-CoV-2 virus due to evolution and adaptation processes [99]. Some SARS-CoV-2 variants of concern with mutations in the spike protein have an increased transmissibility [[100], [101], [102], [103], [104], [105]], which may be explained by an enhanced spike-protein-binding affinity for the ACE2 receptor. For example, Alpha and Beta have been shown to have a 1.98x and 4.62x greater binding affinity than original strain [106]. These variants may cause more severe disease [4] and/or have a potential ability to escape the host or vaccine-induced immune response [7,10]. Results from several seroneutralization assays assessing the neutralizing response of vaccine-induced antibodies are described in Fig. 5 and in Supplementary Material Table S3. In general, Alpha had a minimal impact on neutralization activity of antibodies by post-vaccination sera (Table 3). Neutralization was further reduced for variants with mutation E484K and Gamma. Beta had the highest reduction in neutralizing titres. Data were lacking for C.1.2 identified in South Africa in May 2021, but C.1.2 had a 1.7-fold higher substitution rate than the current global substitution rate [107].

Limitations of neutralizing assays

Limitations concerning neutralizing assays should be emphasised. First, most studies were preprints. Second, results are not necessarily linked to clinical consequences. However, one study based on seven vaccines reported a high correlation between neutralization titres and protection estimated in phase III trials [155]. A 50% protection against SARS-CoV-2 infection corresponded to a neutralization level of 20.2% of the mean convalescent level. Third, the methods of the studies varied (pseudovirus assay, plaque reduction neutralization testing, microneutralization assay, focus reduction neutralization test). We included 28 pseudovirus assays and 26 live virus assays. Pseudovirus assays approximate authentic SARS-CoV-2 neutralization and only evaluate neutralizing antibodies on pseudoviruses with mutations in the spike protein. Additionally, the choice of cell lines and virus models (vesicular stomatitis virus or human immunodeficiency virus-1 for example) can impact the neutralizing activity. Pseudoviruses are surrogates and cannot complete the same life cycle as the live virus, thus it is not possible to assess the inhibitory effect on viral replication, but they are used to study virus entry into cells. Live virus neutralization assay remains the reference standard, but it needs a higher safety level (a biosafety level 3 laboratory). Fourth, the time post-vaccination and study populations were not always comparable regarding age or COVID-19 history. Fifth, T-cell responses were not assessed. Most studies on in vitro vaccine efficacy focused on the ability of the vaccine antibodies to bind to the virus, which partially reflect vaccine effectiveness, but cell-mediated immunity should also be considered. Studies have shown that BNT162b2 and Ad26.COV2.S induce CD4+ and CD8+ T-cell responses [94,156]. Preliminary reports have identified vaccine-induced CD4+ T cells 6 months after the second dose of RNA-1273 [157] and memory B cells at 6 months after two doses of BNT162b2 [158]. SARS-CoV-2-specific memory T cells and B cells are important for long-term protection. A main limitation of these studies on cell-mediated immunity is small sample size.

Vaccine regimens

Heterologous prime-boost vaccination

Changing recommendations for young people regarding use of AZD1222 and the need to accelerate the vaccination campaign has led some countries to advise heterologous prime-boost vaccination with a second dose of mRNA vaccines. An RCT conducted in the UK indicated an increase in systemic reactogenicity in a heterologous vaccination context versus homologous vaccination [159], but efficacy data have not yet been published. A press communication from El Instituto de Salud Carlos III from a phase II trial in Spain showed that the combination of AZD1222 and BNT162b2 induced a strong humoral response when compared to no second dose [160]. The Com-Cov randomized trial also supported flexibility in the use of AZD1222 and BNT162b2 with a 28-day interval inducing similar levels of SARS-CoV-2 anti-spike IgG [161]. A preliminary study in Thailand observed an increase in neutralizing antibodies against Delta after a third dose of BNT162b2 or AZD1222 among participants who received two doses of CoronaVac [162].

Extension of the dose interval

More generally, evidence on the extension of the interval between doses is scarce. Trials for AZD1222 showed that a longer delay was better, but for mRNA and other vaccines trials did not test different dose gaps [163]. A preprint reported that extending the interval to 6 weeks for BNT162b2 vaccine led to higher titres in neutralizing antibodies and a sustained T-cell response against the variants of concern [164]. Another analysis found that a second dose at 12 weeks induced a stronger humoral response than at a 3-week interval among older people [165].

A booster dose for specific populations

Immunogenicity studies amongst transplant patients and patients with cancer showed a poor antibody response after a single dose or two doses of Pfizer vaccine [[166], [167], [168]]. Facing this issue, French, German, British and US health authorities have recommended a third dose for immunocompromised people and transplant recipients. A randomized trial in transplant recipients showed that a third dose of mRNA-1273 was safe, and 26 out of 59 participants who had negative antibody responses prior to the booster developed antibody responses after the third dose [169]. However, this study did not look at the cellular immune response. Another study found that an additional dose of mRNA-1273 induced a serological response among 50% of kidney transplant recipients who hadn't responded after two doses [170]. A case–control study in preprint found an effectiveness against SARS-CoV-2 infection 14–20 days after the third dose increased by 79% (versus the second dose) [171]. Another observational study in Israel found that a booster dose reduced the rate of confirmed infections and severe disease by a factor of 11.3 and 19.5, respectively, among elderly participants [172]. Two studies also showed that Moderna boosters (at least 6 months after the second dose) and Pfizer booster (8–11 months after the second dose) induced a strong humoral response against Beta [173] and other variants of concern [174]. The expected local and systemic adverse events were mild and moderate and similar to those after the second dose.

Vaccination of previously infected individuals

Several neutralization assays have suggested that a single dose of BNT16b or mRNA-1273 among previously infected subjects could boost the cross-neutralization response against emerging variants such as Alpha, Beta or Gamma [121,175]. These studies have demonstrated the potential benefits of vaccinating both non-infected and previously infected people. Finally, several studies have suggested that a single dose of mRNA vaccine may be sufficient to boost the antibody response in previously infected subjects and that the benefit of the second dose may be small [[176], [177], [178], [179], [180]].

Severe adverse events

The main severe adverse events reported in pharmacovigilance systems and post-authorization studies are summarized in Table 4. Among adults, the main severe adverse events reported were very rare: anaphylaxis (2.5–4.8 cases per million doses among adults) and myocarditis (6–27 cases per million) for mRNA vaccines; thrombosis with thrombocytopenia syndrome for the Janssen vaccine (three cases per million) and AstraZeneca vaccine (two cases per million), and Guillain–Barré syndrome (GBS) (7.8 cases per million) for the Janssen vaccine. For AZD1222, capillary leak syndrome was also identified as a possible adverse effect, and multisystem inflammatory syndrome is under investigation. The EMA excluded an association between AZD1222 and menstrual disorders [181].

Table 4.

Main severe adverse events following coronavirus disease 2019 (COVID-19) vaccination in observational studies and pharmacovigilance systems

Occurrence of adverse events changes with age. Myocarditis associated with mRNA vaccination was identified mainly among males aged <30 years with 39–47 cases per million vaccine doses in the USA (versus three to four myocarditis cases expected among male aged ≥30 years) [182]. On 23rd April, the EMA estimated two cases of thrombosis with thrombocytopenia (TTS) associated with AZD1222 per 100 000 doses for people aged 20–49 years, one case/100 000 doses for those aged 50–69 years, and even lower case rates (<1/100 000 doses) for older people. Similarly, the case rate of TTS was higher for the Janssen vaccine among young women. Surveillance studies found rare cases of Bell's palsy (3.8 cases per 100 000), anaphylaxis (two cases per million), thromboembolic event (1.2 cases per million), GBS (0.29 cases per million) associated with CoronaVac. Several observational and survey studies with low sample sizes did not find specific severe adverse events for Sputnik V, BBIBP-COrV, or Covaxin. Studies on adverse events were lacking for CIGB-66, QazVac, COVIran, Barkat, ZF2001, and EpiVacCorona. Pregnant women were excluded from clinical trials, but surveillance systems did not report an excess of adverse pregnancy and neonatal events after mRNA vaccination [183,184], while an increased risk of severe COVID-19 in pregnancy and babies' admission in the neonatal unit was consistently observed [185].

Limitations of this review

This review has several limitations. Several analyses were not peer-reviewed, and only press communications or regulatory market authorization files were available for CoronaVac, BBIBP-CorV, Wuhan inactivated vaccine, Covaxin and NVX-CoV2373. Clinical trials used different definitions for COVID-19 and different primary endpoints, which make direct comparisons difficult. Janssen's primary endpoint is moderate/severe/critical COVID-19 whereas Pfizer and Moderna included mild COVID-19. The endpoint time was also heterogeneous across trials, but most trials used 14 days after the full immunization.

Observational studies, unlike randomized studies, cannot guarantee comparability in the exposition of different populations to SARS-CoV-2 and to the variants of concern. Indeed, real-world studies present large variations in time post-vaccination, exposition to SARS-CoV-2 strain, susceptibility to infection (previously infected or not), study population (healthcare workers, older adults, immunocompromised patients, those with chronical medical conditions, etc.). Moreover, due to a lack of randomization, observational studies are subject to bias when assessing effectiveness, such as misclassification from diagnostic errors, imbalances in socioeconomic status, exposure risk, healthcare-seeking behaviours, or immunity status between vaccinated and unvaccinated groups. Not all the observational studies used adjustments to take into account confounding biases. For example, healthcare workers treating COVID-19 patients may be more frequently exposed to SARS-CoV-2, leading to decreased estimates of effectiveness. Various designs—cohort, case–control study, test-negative design (TND)—were used in observational studies, each of them having limitations. Cohorts require large sample sizes for uncommon outcomes (i.e. severe COVID-19), but vaccination status may be more difficult to determine in retrospective cohorts. In case–control studies, vaccinated people may be more likely to seek health care and SARS-CoV-2 testing, biasing toward a reduction in the estimation of effectiveness.

Conclusion

To date, the availability of data varies greatly depending on the vaccine considered. mRNA vaccines, AZD1222, Ad26.COV2.S, Sputnik V, NVX-CoV2373, Ad5-nCoV, BBIBP-COrV, CoronaVac, COVAXIN and Wuhan inactivated vaccine showed an efficacy against COVID-19 in >50% in phase III studies. Most observational studies assessed the mRNA vaccines, CoronaVac and AZD1222 which appear to be safe and highly effective tools to prevent severe disease, hospitalization and death against all variants of concern (Alpha, Beta, Gamma and Delta). Large observational studies were lacking for several authorized vaccines: Sputnik V, Sputnik V Light, BBIBP-CorV, COVAXIN, EpiVacCorona, ZF2001, Abdala, QazCovid-In, Wuhan Sinopharm inactivated vaccine, KoviVac and COVIran Barekat. The protection against symptomatic and asymptomatic infection was high for Alpha, Beta and Gamma for mRNA vaccines and AZD1222. mRNA vaccines and Ad26.COV2.S were associated with a faster decline in viral load against several variants, including Delta, and a lower probability of viral culture positivity. Effectiveness against infection and COVID-19 declined following infection with the Delta variant and over time, possibly due to a waning of immunity.

Heterologous prime-boost vaccination and a third dose of vaccine both induced a strong humoral response. Vaccinating previously infected people with a single dose provided an equivalent neutralizing response compared to people vaccinated with two doses against all the variants.

According to safety monitoring, reported serious adverse events were very rare and the benefits of COVID-19 vaccination far outweighed the potential risks.

More research is needed to consider booster doses, heterologous vaccination, dosing intervals, vaccine breakthrough infections, and duration of vaccine immunity against variants of concern.

Author contributions

TF and NPS designed and conducted the research. TF wrote the first draft of the paper. All authors (TF, YK, CJM, JG, NPS) contributed to the data interpretation, revised each draft for important intellectual content, and read and approved the final manuscript.

Transparency declaration

All authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. Thibault Fiolet received a PhD grant from the Fondation Pour la Recherche Médicale (FRM) n°ECO201906009060. This funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Editor: L. Kaiser

Footnotes

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Multimedia component 1

Multimedia component 2

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