Effectiveness of the Third mRNA Vaccine Dose Against COVID-19 During the Omicron Variant Dominant Period: A Systematic Review and Meta-Analysis

Background: Limited and conflicting evidence exists regarding the extra protection conferred by the third dose of mRNA vaccine against COVID-19. We aimed to systematically assess the effectiveness of the third mRNA vaccine dose, compared with the two-dose primary series vaccination. Methods: We search databases for all available data up to July 31, 2023. The primary outcomes were the effectiveness of the third vaccination in preventing SARS-CoV-2 infection, severe disease, and COVID-19-related death by laboratory-confirmed Omicron variant or during the Omicron predominant period. We applied meta-regression to explore sources of heterogeneity between studies. The study was registered on PROSPERO (CRD42022364568). Findings: Out of the 1,703 studies screened from the databases, 185 underwent full-text review, and 35 studies were included in the analysis. Among these, 25 studies were identified to have a moderate risk of bias, while ten studies were found to have a serious risk of bias. The effectiveness against infection was 58% (95% CI: 54% to 62%) during the first month, declining to 9% (95% CI: -7% to 23%) by the sixth month after the third dose. The effectiveness against severe disease also decreased from 80% (95% CI: 68% to 87%) to 55% (95% CI: 49% to 60%) during a fifth-month period. The effectiveness against COVID-19-related death remained stable at 88% (95% CI: 85% to 90%) over a three-month period after the third dose. The heterogeneity between studies can be attributed to time elapsed after vaccination, participant age, and the third vaccine product used (R2 = 70·40%). Overall, moderate-certainty evidence supports the effectiveness against infection, while high-certainty evidence supports the effectiveness against severe COVID-19 disease and death. Interpretation: The third mRNA vaccine dose is highly effective in conferring extra protection against Omicron variant-associated severe COVID-19 disease or death compared with primary series vaccination.Funding: This study was funded by Taiwan Centers for Disease Control (Taipei, Taiwan) (grant # ZH111045) and Taiwan Ministry of Education (grant #NTU-112L9004). Declaration of Interest: The authors declare no competing interests.