BNT162b2 LP.8.1 early vaccine effectiveness against COVID-19 emergency department, urgent care, and outpatient visits.

COVID-19 continues to cause substantial illness, particularly among older adults and individuals with underlying conditions. Updated vaccines are designed to better protect against the strains of the virus that are currently circulating. However, real-world evidence on the effectiveness of updated vaccines remains limited. Here we show the early vaccine effectiveness (VE) of the BNT162b2 LP.8.1-adapted COVID-19 vaccine against mild-to-moderate COVID-19 outcomes. We used a test-negative case-control design to estimate early VE of the BNT162b2 LP.8.1-adapted vaccine against COVID-19 emergency department/urgent care (ED/UC) and outpatient visits. Adult patients from the US Veterans Affairs Healthcare System with an acute respiratory infection (ARI) who underwent SARS-CoV-2 testing from September 10 to November 30, 2025, were included. VE was estimated using multivariable logistic regression adjusted for patient demographics and clinical characteristics. Among 34,455 ARI episodes, 10.7% were COVID-19 cases. A total of 1.2% of cases and 2.6% of controls received the BNT162b2 LP.8.1 vaccine, with a median time since vaccination of 29 days (interquartile range 20--41). BNT162b2 LP.8.1 vaccine was effective during the early 2025-2026 respiratory virus season. VE was 57% (95% confidence interval [CI] 39-70%) against ED/UC visits and 54% (95% CI 15-75%) against outpatient visits. These findings inform shared decision-making in clinical practice and support the continued importance of COVID-19 vaccination in populations for whom it is recommended.