Early effectiveness of the BNT162b2 KP.2 vaccine against COVID-19 in the US Veterans Affairs Healthcare System

Categories: Disease & Virus

April 29, 2025

Ethics approval

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 was exempt from IRB review, informed consent requirements are not applicable.

Setting and participants

We conducted a nationwide test-negative case-control study using clinical data from patients of the US Veterans Affairs (VA) Healthcare System, the largest integrated healthcare system in the US. We assessed VE of BNT162b2 KP.2 vaccine among adult patients (age ≥18 years of age) diagnosed with an acute respiratory infection (ARI, Supplemental Table 1) in the hospital, ED/UC, or outpatient setting (in-person or virtual) between September 5, 2024 and November 30, 2024. As in our prior work⁶, to be included patients had to be tested for SARS-CoV-2 via nucleic acid amplification test (NAAT) or rapid antigen test (RAT) within 14 days prior through 3 days after the ARI encounter and patients were excluded if they (1) did not have at least one visit to the VA Healthcare System in the previous 12 months, (2) had another prior positive SARS-CoV-2 test in the 90 days prior to their ARI episode, (3) received a KP.2 vaccine other than BNT162b2, (4) received BNT162b2 KP.2 vaccine within 8 weeks of a prior COVID-19 vaccine dose, (5) received BNT162b2 KP.2 vaccine within 14 days prior to their ARI episode, (6) received BNT162b2 KP.2 vaccine but the date of administration was unknown, or (7) received a COVID-19 antiviral (nirmatrelvir/ritonavir, remdesivir, or molnupiravir) within 30 days prior to their ARI episode. Patients could contribute more than one ARI episode to the study if the episodes were more than 30 days apart (Supplemental Fig. 1).

Outcomes

Within each ARI outcome category (hospitalizations, ED/UC visits, outpatient visits), cases were those with a positive SARS-CoV-2 test result, and controls were those who tested negative.

Exposure

Exposed patients received the BNT162b2 KP.2 vaccine at least 14 days before the ARI encounter. Unexposed patients did not receive a KP.2 strain-adapted COVID-19 vaccine of any kind, regardless of prior COVID-19 vaccination history. Vaccine exposure status was determined from the VA’s integrated electronic health record, which captures vaccines administered both within and outside of the VA Healthcare System¹⁵. COVID-19 vaccines were offered free of charge to all Veterans enrolled in the VA Healthcare System based on CDC recommendations at the time of study conduct¹⁶.

Statistical analyzes

Separate multivariable logistic regression models were used to compare the odds of receiving BNT162b2 KP.2 vaccine among SARS-CoV-2 positive cases and test-negative controls within each ARI outcome category, while adjusting for potentially confounding variables. We selected the following variables to control for a priori based on previous literature and previous work: age (18–64, 65–74, or ≥75 years), sex (male or female), race (Black, White, or other race), ethnicity (Hispanic or non-Hispanic), body mass index (underweight, healthy weight, overweight, obese, or missing), Charlson Comorbidity Index (0, 1, 2, 3, or ≥4), smoking status (current/former smoker or never smoker/unknown), immunocompromised status (yes or no), receipt of pneumococcal vaccine in the past 5 years (yes or no), number of interactions with the VA healthcare system in the year prior (hospital admission, nursing home admission, ED/UC visit, primary care visit; 0 or ≥1 for each), evidence of documented prior SARS-CoV-2 infection (yes or no), and US Census region (Northeast, Midwest, South, or West). We checked for assumptions and model fit in all logistic regression models. To calculate VE, we subtracted the corresponding adjusted odds ratios (OR) and 95% confidence intervals (CI) from 1 and multiplied by 100%. Subgroup analyzes were conducted in those ≥ 65 years of age and by prior COVID-19 vaccination history. Due to small and zero cells preventing the inclusion of influenza vaccination as a covariate in the adjusted model, given that very few patients received the COVID-19 vaccine without also receiving the influenza vaccine, we conducted a sensitivity analysis comparing individuals who received both the COVID-19 and influenza vaccines versus those who received neither. This analysis excluded individuals who received only one of the two vaccines. We also conducted sensitivity analyzes using shorter post-vaccination follow-up windows starting at 5 and 7 days, as vaccine protection may occur sooner than 14 days, particularly in previously vaccinated patients. All analyzes were conducted using SAS (Version 9.4 and Enterprise Guide 8.3, SAS Institute Inc., Cary, NC, USA).