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A comprehensive analysis of the efficacy and effectiveness of COVID-19 vaccines

It is urgently needed to update the comprehensive analysis about the efficacy or effectiveness of COVID-19 vaccines especially during the COVID-19 pandemic caused by SARS-CoV-2 Delta and Omicron variants. In general, the current COVID-19 vaccines showed a cumulative efficacy of 66.4%, 79.7%, and 93.6% to prevent SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19, respectively, but could not prevent the asymptomatic infection of SARS-CoV-2. Furthermore, the current COVID-19 vaccines could effectively prevent COVID-19 caused by the Delta variant although the incidence of breakthrough infection of the SARS-CoV-2 Delta variant increased when the intervals post full vaccination extended, suggesting the waning effectiveness of COVID-19 vaccines. In addition, one-dose booster immunization showed an effectiveness of 74.5% to prevent COVID-19 caused by the Delta variant. However, current COVID-19 vaccines could not prevent the infection of Omicron sub-lineage BA.1.1.529 and had about 50% effectiveness to prevent COVID-19 caused by Omicron sub-lineage BA.1.1.529. Furthermore, the effectiveness was 87.6% and 90.1% to prevent severe COVID-19 and COVID-19-related death caused by Omicron sub-lineage BA.2, respectively, while one-dose booster immunization could enhance the effectiveness of COVID-19 vaccines to prevent the infection and COVID-19 caused by Omicron sub-lineage BA.1.1.529 and sub-lineage BA.2. Two-dose booster immunization showed an increased effectiveness of 81.8% against severe COVID-19 caused by the Omicron sub-lineage BA.1.1.529 variant compared with one-dose booster immunization. The effectiveness of the booster immunization with RNA-based vaccine BNT162b2 or mRNA-1273 was over 75% against severe COVID-19 more than 17 weeks after booster immunization whereas the heterogenous booster immunization showed better effectiveness than homologous booster immunization. In summary, the current COVID-19 vaccines could effectively protect COVID-19 caused by Delta and Omicron variants but was less effective against Omicron variant infection. One-dose booster immunization could enhance protection capability, and two-dose booster immunization could provide additional protection against severe COVID-19.


Introduction
In December 2019, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified to cause a new severe acute respiratory disease, coronavirus disease 2019 (COVID-19) (1). Development and administration of COVID-19 vaccines are one of the most important strategies to prevent and control the COVID-19 pandemic. At present, different types of COVID-19 vaccine have been developed. Most frequently used vaccines are mRNA vaccine, viral vector-based vaccine, inactivated virus vaccine, and viral protein subunit vaccine. Till now, 194 candidate vaccines have been assessed in the preclinical development stage whereas 132 vaccines are in clinical development stage (2). As of April 23, 2022, the confirmed cumulative COVID-19 cases and deaths reached 505,817,953 and 6,213,876, respectively, while 58.75% of people have been fully vaccinated worldwide and the vaccination coverage rate of over 70% was reported in more than 60 countries according to the data of the World Health Organization (WHO) (3).
SARS-CoV-2 is continuously evolving to produce various variants, which have been classified by WHO into variants of concern (VOCs, including Alpha, Beta, Gamma, Delta, and recently identified Omicron), variants of interest (VOIs, including Lambda and Mu), or variants under monitoring (VUMs, including Kappa, Iota, and Eta) (4). The ongoing pandemic of COVID-19 caused by the Omicron variant of SARS-CoV-2 is a great challenge for the prevention and control of the COVID-19 pandemic. The SARS-CoV-2 variants can compromise the protective efficacy of COVID-19 vaccines due to the mutations in its spike protein especially the newly emerged variant Omicron which has many mutations in the S protein, and has been proved to be associated with increased transmissibility and immune evasion against the acquired immunity (5-7).
Several systematic reviews and meta-analyses have been conducted to evaluate the cumulative efficacy or effectiveness of COVID-19 vaccines (8)(9)(10)(11)(12)(13)(14)(15)(16)(17), but the results need to be updated when more studies about COVID-19 vaccines to prevent the infection of Delta and Omicron variants are available. More and more studies indicated the waning immunity against SARS-CoV-2 infection and the decreased efficacy of COVID-19 vaccines to prevent the infection of Omicron variants (18)(19)(20)(21)(22). Therefore, booster immunization of COVID-19 vaccines has been proposed and evaluated in both clinical trials and observational studies (22)(23)(24)(25)(26)(27). However, the role and effect of booster vaccination, especially two-dose booster immunization, remained to be comprehensively analyzed. Furthermore, SARS-CoV-2 infection among fully vaccinated subjects, so-called breakthrough infection, has been documented (28). It is necessary to evaluate the risk and incidence of the breakthrough infection of SARS-COV-2.
In the current study, we systematically assessed and updated the results about the efficacy and effectiveness of COVID-19 vaccines to prevent the infection of Delta and Omicron variants based on phase III randomized clinical trials (RCTs) and observational studies. We also systematically evaluated the effect of booster vaccination and the risk and incidence of breakthrough infection of the Delta variant among vaccinated people.

Methods
This study was performed according to the statement on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (S1 PRISMA Checklist) (29).

Inclusion and exclusion criteria
Studies were eligible on the COVID-19 vaccine efficacy or effectiveness for inclusion if they (1) were clinical trial studies, case-control, and cohort studies (2); evaluated the efficacy or effectiveness of COVID-19 vaccines (3); reported the efficacy or effectiveness of COVID-19 vaccines and booster immunization to prevent infection of SARS-CoV-2 Delta and Omicron variants (4); compared the efficacy or effectiveness of COVID-19 vaccines between vaccinated and placebo, vaccinated and unvaccinated, or booster and non-booster individuals; and (5) reported adjusted effectiveness in the real-world studies and if (6) all outcomes must be laboratory confirmed. For the studies to utilize the same data sources for their investigations, we only included the studies based on the latest data. Moreover, breakthrough infection was selected among vaccinated subjects at discrete time points after full vaccination during the pandemic of Delta or Omicron variants. COVID-19 vaccines BNT162b2 and NVX-CoV2373; ≥14 days for COVID-19 vaccines BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, CoronaVac, BBV152, CVnCoV, WIV04, Sputnik V, HB02, and SCB-2019; or after the single-dose vaccination for COVID-19 vaccines Ad26.COV2.S; and ≥21 days after the firstdose vaccination for COVID-19 vaccine Sputnik V (Supplementary Tables 2, 3). We defined one-dose booster vaccination as ≥7, 12, or 14 days after the third shot of COVID-19 vaccines BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, and CoronaVac, respectively (Supplementary Table 4). In addition, we included the studies that provided risk ratios, rate ratios, and odds ratios or original data for breakthrough infection of SARS-CoV-2. We specifically selected the studies that included COVID-19 cases caused by the Delta variant (Supplementary Table 5). A total of 47,502 publications were initially screened, of which 47,249 were irrelevant according to the title and abstract. In addition, 155 studies were excluded after reading the full text. Eventually, 98 publications met the inclusion criteria ( Figure 1; Supplementary  Tables 2-718- 27,. Of note, a total of 27 publications including 28 RCTs (32-50, 52, 53, 55-57, 59, 108, 109) reported the symptomatic COVID-19 (Supplementary Table 2). Among them, seven studies (41,44,46,50,59,108,109) were excluded from the overall analysis because their samples overlapped with another four studies (33,34,43,56). Moreover, one RNA-based vaccine candidate CVnCoV (48) was not analyzed in the present study due to their lower efficacy than the goal of 50% efficacy set by WHO. One protein subunit candidate SCB-2019 vaccine (56) was not further analyzed in the present study because it was not listed as a vaccine of emergency use by WHO. The Flow chart of literature search in the present study.

Risk of bias within individual studies
Two authors independently evaluated the risk of bias for eligible studies and checked the results. A ROBINS-I risk-of-bias tool was used to assess the case-control and cohort studies (119) (Supplementary Table 9). Moreover, a revised tool for assessing the risk of bias in randomized trials (ROBINS-2) was used (120) (Supplementary Table 8). The overall risk of bias was categorized as low, moderate, high, or serious in the current study.

Statistical analysis
According to the WHO recommendation, the lowest vaccine efficacy or effectiveness and lower 95% confidence interval (CI) were set at 50% and 30%, respectively (121). The probability of type 1 error and statistical power were set at onesided 0.025 and 0.90, respectively. The minimum sample size should be 44,488 when the incidence rate was 850 per 100,000 person-years (122). A random-effect model was applied to calculate the pooled ratio risk (RR) or odd ratio (OR) for the occurrence of COVID-19 and its 95% CI when three or more studies reported the same type of effect measure. The heterogeneity was evaluated by the Cochran Q test and the I 2 value (123). For RCTs, subgroup analysis was conducted according to the vaccine type as well as age and gender of vaccinees. The 95% CIs were not included if the lower bound was up to 0% and the upper bound was 100%. For the analysis of breakthrough infection, we calculated incidence rate or risk by dividing the numerator (number of cases) over the denominator (total number of persons or number of personyears). Rate ratio or RR was calculated by dividing the risk of a vaccinated group over a reference group while its 95% CI was calculated using the Byar and Taylor series methods (124,125). Publication bias was analyzed by using Begg's funnel plot (126) and Egger's test (127) when the number of studies was >10. The vaccine efficacy or effectiveness was calculated as (1-RR) × 100% or (1-OR) × 100%. When a meta-analysis was not feasible, we directly described the results reported in the studies. For all the analyses, P < 0.05 was considered statistically significant. All statistical analyses were performed using STATA version 12.0 (STATA Corporation, College Station, TX).
Incidence and risk of breakthrough infection of the SARS-CoV-2 Delta variant stratified by the intervals postvaccination and age of vaccinees  (Table 4). Similar results were also observed for the two mRNA-based vaccines BNT162b2 and mRNA-1273 (Table 4). Furthermore, the incidence of breakthrough infection of the SARS-CoV-2 Delta variant decreased from 6.0% (1.4%, 10.5%) for those 18-49 years old, 4.3% (1.2%, 7.5%) for those 50-64 years old, to 1.0% (0.1, 2.0) for those over 65 years old within 2-26 weeks post-vaccination (Table 4). The decreased incidence of breakthrough infection of SARS-CoV-2 Delta variant risk among old people was also found when the interval post-vaccination was more than 26 weeks (Table 4).
RCTs showed that the incidence of COVID-19 caused by the breakthrough infection of the SARS-CoV-2 Delta variant increased from 5.0% within 26-34 weeks post-vaccination to 7.4% within 34-56 weeks post-vaccination with an RR of 0.71 (95% CI: 0.58, 0.87, p < 0.001, Table 4). Furthermore, the incidence of COVID-19 was significantly higher in those 18-64 years old than those over 65 years old with an RR of 0.57, 95% CI: 0.38, 0.86, p < 0.001) within 34-56 weeks post-vaccination (Table 8). Similar results were observed in the cohort studies and confirmed the relatively higher incidence of COVID-19 in the young people and those with extended intervals postvaccination (Table 4).
The effectiveness of any RNA-based vaccine BNT162b2 or mRNA-1273 homologous or heterogenous booster immunization    Table 13).

Discussion
In the present study, we updated the results about the efficacy or effectiveness of COVID-19 vaccines before the pandemic of the Omicron variant and comprehensively analyzed the effectiveness of COVID-19 vaccines in preventing infection of Delta and Omicron variants, which are the two most important and dominant strains of SARS-CoV-2. Our results further confirm the important role of COVID-19 vaccines in preventing the occurrence of COVID-19.
Our results indicated that the current COVID-19 vaccines could effectively prevent COVID-19 illness, especially severe COVID-19 and COVID-19-related death based on phase III RCTs before the pandemic of the Omicron variant. However, a major challenge for COVID-19 vaccines is its effectiveness in preventing infection and COVID-19 caused by SARS-CoV-2 variants. In the past 2 years, the pandemic of COVID-19 was dominated by Delta and Omicron variants. The mutations in the spike protein of SARS-CoV-2 have dramatically changed its biological features including its interaction with host receptor ACE2, weakened the host immune system, and compromised vaccine efficacy (30, 31). In the present study, we confirmed the effectiveness of COVID-19 vaccines to prevent Delta variant infection, in particular the symptomatic COVID-19, severe COVID-19, and COVID-19-related death caused by the Delta variant after full vaccination. However, we found the incidence of breakthrough infection of the SARS-CoV-2 Delta variant increased when the intervals after full vaccination extended due to the waning immunity for the current vaccines. These findings are consistent with neutralization data. Several studies showed that neutralizing antibody titers induced by the first two doses of vaccines declined 6 months later to near or below the seropositive cutoff (100, 128,129). A booster vaccination of CoronaVac then dramatically increased neutralizing antibody titers to 137·9 and 143·1 GMTs 14-28 days later (128). Moreover, one phase II RCT (129) demonstrated the potential of all vaccines tested (AZD1222 (ChAdOx1 nCoV-19), mRNA-1273, NVX-CoV2373, Ad26.COV2.S, CVnCoV, Valneva, and BNT162b2) to boost immunity following an initial course of ChAd/ChAd and of six vaccines (AZD1222 (ChAdOx1 nCoV-19), BNT162b2, mRNA-1273, NVX-CoV2373, Ad26.COV2.S, and CVnCoV) following an initial course of BNT/BNT. These results indicated that a booster dose might provide longer-lasting immunity and higher levels of protection than a two-dose schedule. Therefore, an ongoing strategy is to adapt booster immunization to enhance the protection efficacy of COVID-19 vaccines. In the present study, we observed that the effectiveness of one-dose booster immunization was over 74.5% to prevent COVID-19 caused by the Delta variant, which confirmed the role of booster immunization.
However, the SARS-CoV-2 virus is continuously mutating from the original strain to the current epidemic strains of Omicron variants. Therefore, it is urgently needed to comprehensively analyze the effectiveness of COVID-19 vaccines and booster vaccination during the pandemic of the SARS-CoV-2 Omicron variant. In the present study, our results showed that two RNA vaccines BNT162b2 and mRNA-1273 could prevent 64.8% and~70% of symptomatic and severe COVID-19 cases caused by Omicron sub-lineage BA.1.1.529, respectively. Moreover, both RNA vaccine BNT162b2 and inactivated virus CoronaVac could effectively prevent severe COVID-19 cases and COVID-19-related death caused by Omicron sub-lineage BA.2 after full vaccination. These results indicate that the current COVID-19 vaccines are still able to prevent COVID-19 caused by the SARS-CoV-2 Omicron variant. However, the current COVID-19 vaccines could not effectively prevent the infection of the Omicron variant, suggesting that SARS-CoV-2 variants especially the Omicron variant significantly decreased the effectiveness of COVID-19 vaccines. One possibility is its decreased virulence to result in the large amount of asymptomatic infection of Omicron variants (130), which affect the overall efficacy of COVID-19 vaccines. Another possibility for the decreased efficiency of COVID-19 vaccines for the Omicron variant is likely due to a combination of extended time interval post-vaccination and the immune escape caused by the mutations in the viral spike proteins (30, 31,131). In this study, we found that booster immunization could enhance the effectiveness of COVID-19 vaccines to prevent the infection, symptomatic COVID-19, severe COVID-19, and COVID-19-related death which were about 62%, 65%, 88%, and 94% for Omicron sub-lineage BA.1.1.529, respectively. Moreover, the overall effectiveness was about 61%, 98%, and 98% in preventing symptomatic, severe COVID-19, and COVID-19-related death caused by Omicron sub-lineage BA.2, respectively. Two doses of booster immunization could provide additional protection for severe COVID-19 and COVID-19-related death with an effectiveness of 81.8% and 93% compared with dose 3 over 3 months, respectively, but not for the infection and symptomatic COVID-19 caused by the Omicron variant. These results indicated that booster immunization could effectively protect COVID-19 illness caused by the Omicron variant. Although booster immunization is less effective for the Omicron variant against infection, it could effectively protect COVID-19 and COVID-19related death.
Another important issue is about the duration of COVID-19 vaccination since the waning immunity post-vaccination has been repeatedly reported. In our study, we systematically evaluated the duration of the effectiveness of COVID-19 vaccines to prevent SARS-CoV-2 infection and COVID-19 during the pandemic of SARS-CoV-2 Omicron variant infection. Our results confirmed that the effectiveness of COVID-19 vaccines was rapidly waning. Fortunately, homologous or heterogenous booster immunization with RNA-based vaccine BNT162b2 or mRNA-1273 could effectively prevent severe COVID-19 with over 75% efficacy. Moreover, we found that heterogenous booster immunization showed better effectiveness than homologous booster immunization. These findings are consistent with neutralization data for the Omicron variant. Several studies indicated a reduction in neutralizing antibody activity in serum specimens by a factor of 20-to 40-fold for the neutralizing antibodies acquired after two doses of BNT162b2 vaccination against SARS-CoV-2 strains from the early pandemic and by a factor of at least 10 against the Delta variant (132-134). In serum specimens obtained from the recipients of two doses of ChAdOx1 nCoV-19, a greater reduction in neutralizing activity was also observed among the serum samples of vaccines and a large proportion of them showed neutralizing activity below the limit of quantification (134). Low neutralizing antibody responses against the Omicron variant have been observed in individuals receiving two doses and three doses of CoronaVac (135-138). However, a heterogenous booster immunization could increase neutralizing activity (132)(133)(134). In addition, one booster dose of mRNA vaccine BNT162b2 has been shown to increase the neutralizing antibodies against the Omicron variant when compared to the original inactivated CoronaVac vaccine or mRNA vaccine BNT162b2 (135-138). Several possibilities may explain a decline in the effectiveness of COVID-19 vaccines when the time interval extended after vaccination. The decreased efficacy may reflect lower vaccine effectiveness against SARS-CoV-2 variants, or the true waning immunity caused by loss of vaccine-induced immunological protection, or sampling biases that may cause large heterogeneity of the studies or inconsistent results among the studies.
Our results indicate that the overall efficacy of COVID-19 vaccines is <50% in preventing asymptomatic infection of SARS-CoV-2 (Table 1), indicating that the current COVID-19 vaccines are inefficient in preventing infection of SARS-CoV-2, especially against asymptomatic SARS-CoV-2 infection. Unlike traditional vaccines, WHO also defines COVID-19 rather than SARS-CoV-2 infection as the primary endpoint of the efficacy of COVID-19 vaccines (121). SARS-CoV-2 infection exhibits symptomatic COVID-19 (including severe COVID-19) and asymptomatic infection (139). Sah et al. found that 35.1% (95% CI: 30.7, 39.9) of SARS-CoV-2-infected persons never developed clinical symptoms and thus were truly asymptomatic infection (140). Hence, it is necessary to evaluate the vaccine efficacy to prevent asymptomatic SARS-CoV-2 infection. People with asymptomatic infection of SARS-CoV-2 may be an important source of COVID-19 epidemic and may inevitably distort the dynamics of the COVID-19 pandemic especially for the pandemic of the Omicron variant since they may have high viral loads even a few days prior to symptom onset and cannot be timely diagnosed (141). In the present study, the current COVID-19 vaccines were not effective in preventing asymptomatic SARS-CoV-2 infection based on the RCTs. The efficacy was only 53.6% for RNA-based vaccine mRNA-1273, 48.4% for inactivated vaccines, and 45.1% for the viral vector (non-replicating) vaccines (Table 1). Moreover, the case-control studies showed that the overall effectiveness was only 47.3% to prevent asymptomatic COVID-19 illness caused by Delta variant for the two RNA-based vaccines BNT162b2 and mRNA-1273. Of note, the data about asymptomatic infection of SARS-CoV-2 and the efficacy evaluation of COVID-19 vaccines are prone to some biases. Some studies did not record negative PCR results of patients, which may lead to some presymptomatic cases to be mistakenly classified as asymptomatic patients. Moreover, the recorded symptoms of patients mainly based on self-reporting data in some studies, which may not be accurate and reliable. Furthermore, the proportion of asymptomatic infections was different and is associated with SARS-CoV-2 variants (130). Therefore, the efficacy or effectiveness of COVID-19 vaccines against asymptomatic COVID-19 infection should be further evaluated and explained with caution. In addition, the reasons and factors that affect the efficacy of COVID-19 vaccines to prevent SARS-CoV-2 infection, especially asymptomatic infection, remain to be elucidated.
Furthermore, breakthrough infection is urgently needed to be investigated since the studies may provide important information for the development of refined COVID-19 vaccines and for the identification of the subjects who are susceptible to breakthrough infection of SARS-CoV-2. In the present study, we found that the risk and incidence of breakthrough infections with the delta variant were increased when the time extended after vaccination. These results confirmed the feature of waning vaccine efficacy or effectiveness over time. Moreover, young people had a higher risk of breakthrough infection, which may indicate the presence of potential confounding behavioral factors in these people to cause a higher exposure to the virus. In addition, older people had a higher risk of severe COVID-19 of the SARS-CoV-2 Delta variant due to breakthrough infection probably because they had coexisting medical conditions, which are the major risk factors associated with the occurrence of severe COVID-19. Therefore, COVID-19 vaccination should give priority to the elderly people to prevent severe COVID-19 illness. This study has several limitations and some biases. First, it is possible that additional studies on the COVID-19 vaccines' effectiveness were not captured by our search strategy, and new studies will become available considering the rapid pace and multiple preprint publishing options for COVID-19-related papers. Second, preprint studies involved might change their results in the final publication. Third, a small number of vaccines were evaluated in observational studies that may affect the quality and reliability of the study results. Fourth, all the included studies did not evaluate the effectiveness to prevent asymptomatic Omicron infection. Fifth, we did not evaluate the effectiveness of COVID-19 vaccines among the subjects with chronic diseases and those with previous SARS-CoV-2 infections; Sixth, the major bias was incomplete adjustment for the confounders for the observational studies. Moreover, some potential biases in assessing the vaccine effectiveness over time can occur. For example, people who are vaccinated change behavior over time. Seventh, publication bias was observed on the efficacy of COVID-19 vaccines to prevent symptomatic COVID-19 illness based on RCT studies. However, when we applied a non-parametric "trim and fill" method ( Figure 6), the analysis showed that no more study should be added. Ninth, heterogeneity between studies was much large in overall and among several subgroups. Our analysis indicated that the heterogeneity may come from the data itself since adequate statistical correction and analysis did not significantly improve the heterogeneity. The source of heterogeneity may be due to the factors such as the areas in which the studies were conducted, the risk of exposure to SARS-CoV-2, and other factors that were beyond our control, such as type of vaccines and different vaccine manufacturers. Moreover, non-reporting of negative data and heterogeneity of samples may also be a source of heterogeneity and may affect the accuracy of results. Further analysis is needed to use real-world data about the efficacy or effectiveness of COVID-19 vaccines.
In summary, the current COVID-19 vaccines could effectively protect COVID-19 caused by the Delta variant and relatively less effective for the Omicron variant. The waning immunity was observed especially in old people after full vaccination. Breakthrough infection seems rare within 6 months and is less likely to cause severe COVID-19 in young people after full vaccination against the Delta variant. Booster immunization could enhance protection capability. Moreover, two doses' immunization could provide additional protection for severe COVID-19 against the Omicron variant.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.