The Effect of Pandemic Prevalence on the Reported Efficacy of SARS-CoV-2 Vaccine Candidates: A Systematic Review and Meta-analysis

Abstract

AbstractImportanceThe efficacy of SARS-CoV-2 vaccine candidates reported in Phase 3 trials varies from ∼45% to ∼95%. It is important to explain the reasons for this heterogeneity.ObjectiveTo test the hypothesis that the efficacy of SARS-CoV-2 vaccine candidates falls with increasing prevalence of the COVID-19 pandemic.Data SourcesClinicalTrials.gov, WHO, McGill and LSHTM trackers of COVID-19 candidate vaccines, peer reviewed publications, and press releases were searched until March 31st, 2021.Study SelectionAll RCTs reporting efficacy outcomes from Phase 3 trials till March 31st, 2021 were included. Of the 11 vaccine candidates that had started their Phase 3 trials by November 1, 2020. Phase 3 efficacy outcomes were available for 8 vaccine candidates. (PROSPERO CRD42021243121).Data Extraction and SynthesisBoth authors independently extracted the data required from identified sources, using PRISMA guidelines. The analysis included all RCTs reported in peer reviewed publications and publicly available sources. A random effects model with restricted maximum likelihood estimator was used to summarize the treatment effects. Cochrane Risk of Bias Assessment Tool was used to assess risk of bias. Certainty of evidence was assessed using the GRADE tool.Main Outcomes and MeasuresSARS-CoV-2 infections per protocol in vaccine and placebo groups, risk ratio, prevalence of the COVID-19 infection rate in the populations where the Phase 3 trials were conducted.Results8 vaccine candidates had reported efficacy data from a total of 20 independent Phase 3 trials, representing a total of 221,968 subjects, 453 infections across the vaccinated groups and 1,554 infections across the placebo groups. The overall estimate of the risk-ratio is 0.24 (95% CI, 0.17-0.34, p < 0.01), with an I2 statistic of 88.73%. The meta-regression analysis with pandemic prevalence as the moderator explains almost half the variance in risk ratios across trials (R2=49.06%, p<0.01).Conclusion and RelevancePandemic prevalence explains almost half of the between-trial variance in reported efficacies. Efficacy of SARS-CoV-2 vaccine candidates declines as the pandemic prevalence increases.Key PointsQuestionDoes the prevalence of the COVID-19 pandemic explain the heterogeneity in efficacies reported across Phase 3 trials of SARS-CoV-2 vaccine candidates?FindingsAlmost 50% of the variance in efficacies reported across Phase 3 trials can be explained by differences in COVID-19 infection rate prevailing across trials. Efficacy of evaluated SARS-CoV-2 vaccine candidates falls significantly with increasing prevalence of the COVID-19 pandemic across trial sites.MeaningEfficacy of SARS-CoV-2 vaccine candidates needs to be interpreted in conjunction with the prevalence of the COVID-19 pandemic. Adjustment for location-level prevalence analysis would provide better insights into the efficacy results of Phase 3 trials.