• George N Ioannou, Kristin Berry, Nallakkandi Rajeevan, Yuli Li, Lei Yan, Yuan Huang, Hung-Mo Lin, David Bui, Denise M Hynes, Mazhgan Rowneki, Amy Bohnert, Edward J Boyko, Theodore J Iwashyna, Matthew L Maciejewski, Valerie A Smith, Theodore S Z Berkowitz, Ann M O'Hare, Elizabeth M Viglianti, Mihaela Aslan, and Kristina L Bajema.
• Research and Development and Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System, and Division of Gastroenterology, University of Washington, Seattle, Washington (G.N.I.).
• Ann. Intern. Med. 2025 Feb 4.

BackgroundMonovalent COVID-19 vaccines targeting the XBB.1.5 Omicron variant were introduced in September 2023. In the absence of randomized controlled trials demonstrating their efficacy, information on real-world vaccine effectiveness (VE) is needed.ObjectiveTo determine XBB.1.5 COVID-19 VE and the extent to which it declines over time.DesignTarget trial emulation.SettingU.S. Veterans Health Administration.ParticipantsEligible XBB.1.5 vaccine recipients were matched 1:1 to unvaccinated persons in 7 sequential biweekly trials with enrollment from 2 October 2023 through 3 January 2024.InterventionXBB.1.5 COVID-19 vaccination versus no XBB.1.5 vaccination.MeasurementsOutcomes were ascertained through 10 May 2024 and included any positive result on a SARS-CoV-2 test from day 10 after the matched index date, subsequent hospitalization within 1 day before or 10 days after the positive result, or death within 30 days after the positive result. Vaccine effectiveness was estimated as 100 × (1 - risk ratio).ResultsParticipants (91.3% male; mean age, 69.9 years) included 587 137 pairs of vaccinated and matched unvaccinated persons. Over a mean follow-up of 176 days (range, 118 to 211 days), VE was -3.26% (95% CI, -6.78% to -0.22%) against documented SARS-CoV-2 infection, 16.64% (CI, 6.47% to 25.77%) against SARS-CoV-2-associated hospitalization, and 26.61% (CI, 5.53% to 42.32%) against SARS-CoV-2-associated death. When estimated at 60, 90, and 120 days, respectively, VE against documented infection (14.21%, 7.29%, and 3.15%), hospitalization (37.57%, 30.84%, and 25.25%), or death (54.24%, 44.33%, and 30.25%) showed substantial waning.LimitationPotential for residual confounding and incomplete capture of COVID-19 vaccination and SARS-CoV-2-related outcomes.ConclusionCOVID-19 vaccines targeting the XBB.1.5 variant of Omicron were not effective in preventing infection and had relatively low VE against hospitalization and death, which declined rapidly over time.Primary Funding SourceU.S. Department of Veterans Affairs.

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