Learning from the omicron BA.4/5 dominance: Strategies for future vaccination preparedness

Objectives: To investigate the protective effectiveness of various COVID-19 booster strategies against the Omicron BA.4/5 variant and examine the impact of vaccination-infection sequence on subsequent immunity, focusing on individuals with waned immunity (>6 months since last vaccination/infection). Methods: We conducted a territory-wide observational study of 1,737,475 adults in Hong Kong during the BA.4/5-dominant period (November 2022–January 2023). The Andersen-Gill model was employed to assess infection risks across different vaccination and infection history cohorts, comparing homologous versus heterologous boosting strategies, bivalent versus standard vaccines, and vaccination-first versus infection-first approaches. Results: Platform-switching heterologous boosting (inactivated to mRNA vaccines) reduced infection risk by 9–21 % compared to homologous strategies. Bivalent Omicron BA.4/BA.5 BNT162b2 vaccines provided 30–58 % lower hazard versus standard BNT162b2 vaccine options. Vaccination before infection consistently yielded superior protection compared to infection-first scenarios, with infection-first CoronaVac recipients facing 97–141 % higher subsequent infection risk. The temporal sequence of immune exposures proved critical in determining ultimate protective benefits. Conclusions: This study provides evidence-based principles for future pandemic vaccination strategies. Platform-switching heterologous boosting (from inactivated vaccines to mRNA vaccines) offers meaningful advantages for inactivated vaccine recipients, bivalent vaccines provide substantial additional protection, and vaccination-first approaches consistently outperform infection-first scenarios. These findings support proactive vaccination policies over reliance on infection-acquired immunity and inform rapid response strategies for future pandemic threats.