Assessing the relative vaccine effectiveness of a fourth COVID-19 dose on hospitalization in Malaysia amidst evolving omicron variants: An emulated target trial

The emergence of new COVID-19 variants necessitates continuous evaluation of vaccine effectiveness to guide evolving vaccine strategies. This study assessed the relative effectiveness of a fourth COVID-19 vaccine dose compared to a third dose in Malaysia during the Omicron BA.4/BA.5/XBB wave. A target trial emulation design was employed using data from the vaccinated population. Malaysian adults aged 18 and above who had received at least three vaccine doses and had no prior documented SARS-CoV-2 infection were included. The primary outcome was COVID-19 hospitalization, with death as a secondary outcome. Propensity score matching and Cox proportional hazard models with time-varying intervention were utilized for analysis. Among 241,434 participants, no significant reduction in COVID-19 hospitalizations or deaths was observed with the fourth dose compared to the third dose over a 360-day period. However, a significant protective effect against hospitalization was seen within 90 days post-fourth dose (HR = 0·77; 95 % CI: 0·35, 0·92; p = 0·01). Subgroup analysis revealed a non-significant trend towards reduced hospitalizations among individuals 60 and above. This study demonstrates the time-limited effectiveness of a fourth dose COVID-19 vaccine (second booster), predominantly the monovalent mRNA (original-strain BNT162b2) vaccine, against COVID-19 hospitalization. While short-term benefits were observed, protection diminished by 360 days. These findings are relevant for countries with diverse primary vaccination schemes and highlight the need for ongoing monitoring of vaccine effectiveness and adaptive approaches to optimise vaccination strategies. None.