Two Versus One COVID-19 Vaccine Dose After Prior SARS-CoV-2 Infection: A Nationwide Retrospective Cohort Study

Abstract Background Immune protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies by prior infection and vaccination history. This study evaluated whether two coronavirus disease (COVID-19) vaccine doses after prior infection provide additional protection compared with a single dose. Methods A national matched retrospective cohort study was conducted in Qatar from December 1, 2020–March 3, 2025. Incidence of SARS-CoV-2 reinfection and severe COVID-19 at reinfection was compared between 61,854 previously infected individuals who completed primary-series vaccination (two-dose cohort) and 61,854 matched individuals who received a single dose (single-dose cohort). Results After 360 days of follow-up, cumulative incidence of reinfection was 5.0% (95% CI, 3.8–6.7%) in the two-dose cohort and 7.7% (95% CI, 6.1–9.6%) in the single-dose cohort. No reinfections progressed to severe, critical, or fatal COVID-19 in either cohort. Relative vaccine effectiveness (rVE) of two doses versus one dose was 38.9% (95% CI, 20.4–53.2%). rVE was 26.9% (95% CI, −12.7–53.4%) within <24 days, 51.8% (95% CI, 19.2–71.2%) during days 24–179, and 36.8% (95% CI, 0.9–59.7%) at ≥180 days of follow-up. Subgroup analyses by time between prior infection and vaccination, prior infection variant, and vaccine type yielded broadly similar rVE estimates, while analyses stratified by age and clinical vulnerability suggested higher point estimates among older and clinically vulnerable individuals. Conclusion Among individuals with prior infection, completion of primary-series vaccination provided modest additional protection against reinfection compared with a single dose. These findings support risk-based dose-optimization strategies in settings with constrained vaccine supply.