Abstract
Concerns about waning immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the emergence of new variants underscore the need for booster doses. Using a matched cohort design, this study evaluated the relative effectiveness and durability of a fourth dose of ancestral-strain mRNA vaccines (BNT162b2 or mRNA-1273) in preventing SARS-CoV-2 infection, compared to three doses, between February 10, 2021 and May 13, 2024 in Qatar. The fourth dose conferred modest additional protection against infection, with an adjusted hazard ratio for infection of 0.91 (95% CI: 0.81-1.02), corresponding to a relative vaccine effectiveness of 9.2% (95% CI: - 1.7 to 18.9%). Protection peaked within the first three months of vaccination at 35.0% (95% CI: 20.6-46.8%) but waned rapidly thereafter, becoming negligible beyond that period. These findings highlight the modest and short-term protection of ancestral-strain vaccines against omicron subvariants and support the need for next-generation vaccines offering more durable immunity.