Effectiveness of the 2024–2025 KP.2 COVID-19 vaccines in the United States during long-term follow-up

Up-to-date estimates of COVID-19 vaccine effectiveness (VE) are needed to inform COVID-19 vaccination strategies and recommendations. This target trial emulation study aimed to estimate the long-term vaccine effectiveness (VE) of the 2024-2025 COVID-19 vaccines targeting the KP.2 Omicron variant within the Veterans Health Administration. The study population (90.9% male, mean age 70.7 years) included 538,631 pairs of vaccinated (i.e., received the KP.2 COVID-19 vaccine) and matched unvaccinated (i.e., did not receive the KP.2 COVID-19 vaccine) persons enrolled from August 2024 to January 2025. Over a mean follow-up of 172 days (range 97-232) extending to April 12, 2025, VE was low against laboratory-diagnosed SARS-CoV-2 infection (16.60%, 95% confidence interval [CI], 11.92-21.44), SARS-CoV-2-associated emergency department/urgent care (ED/UC) visit (21.05%, 95% CI, 14.22-27.21), SARS-CoV-2-associated hospitalization (19.53%, 95% CI 6.56-30.10) and much higher against SARS-CoV-2-associated death (65.53%, 95% CI 27.79-83.37). VE declined from 60 to 90 to 120 days against infection (31.28%, 25.81%, 22.44% respectively), ED/UC visit (34.40%, 29.19%, 25.71% respectively), hospitalization (37.39%, 28.98%, 22.52% respectively) and death (75.02%, 71.02%, 63.08% respectively). In conclusion, COVID-19 vaccines targeting the KP.2 variant used in the 2024-2025 season offered high protection against death and modest protection against infection, ED/UC visits or hospitalization, and VE declined over time.