We conducted a test-negative case-control study within the US Veterans Affairs Healthcare System to estimate early vaccine effectiveness (VE) of the BNT162b2 KP.2 vaccine (Pfizer 2024-2025 formulation) against COVID-19 outcomes. Among 44,598 acute respiratory infections between September 5 and November 30, 2024, VE was 68% (42-82%), 57% (46-65%), and 56% (36-69%) against COVID-19-associated hospitalizations, emergency department and urgent care visits, and outpatient visits, respectively. Uptake of updated COVID-19 vaccines remains low.

Haley J. Appaneal has received research funding from Pfizer. Vrishali V. Lopes has no competing interest to declare. Laura Puzniak, Evan J. Zasowski, Luis Jodar, and John M. McLaughlin are employees and shareholders of Pfizer Inc. Aisling R. Caffrey has received research funding from AbbVie, Merck, and Pfizer.

This study was conducted as a collaboration between the University of Rhode Island (URI), VA Providence Healthcare System, and Pfizer. Pfizer is the study sponsor. URI and VA Providence Healthcare System received funding from Pfizer in connection with the development of this manuscript and for data analysis.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Our study complies with all relevant ethical regulations and was determined to be exempt by the VA Providence Healthcare System (VAPHS) Institutional Review Board (IRB) and approved by the VAPHS Research and Development Committee. As this was a retrospective study of existing health records and exempt from IRB review, informed consent requirements are not applicable.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data supporting the findings of this study are not publicly available due to the inclusion of identifiable protected health information from the Veterans Health Administration. Privacy regulations prevent the open sharing of the individual-level data used in this study and any data covered under these regulations cannot be shared. The Veterans Health Administration may approve the sharing of some study data after verifying de-identification, though this may not include all final study data. Each request is subject to approval by the ethics board, privacy office, and information systems and security office. For such requests, please contact the corresponding author.