Effectiveness of the 2023-to-2024 XBB.1.5 COVID-19 Vaccines Over Long-Term Follow-up : A Target Trial Emulation.

Background: Monovalent 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.

Objective: To determine XBB.1.5 COVID-19 VE and the extent to which it declines over time.

Design: Target trial emulation.

Setting: U.S. Veterans Health Administration.

Participants: Eligible 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.

Intervention: XBB.1.5 COVID-19 vaccination versus no XBB.1.5 vaccination.

Measurements: Outcomes 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).

Results: Participants (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.

Limitation: Potential for residual confounding and incomplete capture of COVID-19 vaccination and SARS-CoV-2-related outcomes.

Conclusion: COVID-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 Source: U.S. Department of Veterans Affairs.