Background: In August 2023, the Centers for Disease Control and Prevention recommended nirsevimab, a long-acting monoclonal antibody, for all U.S. infants aged <8 months entering or born during their first respiratory syncytial virus (RSV) season. Our aim was to estimate nirsevimab effectiveness against RSV-associated emergency department (ED) encounters and hospitalisation among U.S. infants during the 2023–2024 RSV season. Methods: We conducted a test-negative analysis using electronic health record (EHR) data from 6 healthcare systems, including ED encounters and hospitalizations with a diagnosis of RSV-like illness (RLI) during October 8, 2023–March 31, 2024, among infants aged <8 months as of October 1, 2023, or born during the study period. Nirsevimab effectiveness was estimated by comparing children who received nirsevimab with those who did not among RSV-positive and RSV-negative encounters, adjusting for age, race and ethnicity, sex, calendar day, and geographic region and excluding infants whose mother received RSV vaccination during pregnancy. Findings: Among 5039 ED encounters with RLI among infants in their first RSV season, 2045 (41%) were RSV-positive and 446 (9%) received nirsevimab, with a median time since dose of 52 days (interquartile range [IQR]: 27–84 days). Among 1025 hospitalizations with RLI among infants in their first RSV season, 605 (59%) were RSV-positive and 95 (9%) received nirsevimab, with a median time since dose of 48 days (IQR: 24–82 days). Nirsevimab effectiveness was 77% (95% CI: 69%–83%) against RSV-associated ED encounters and 98% (95% CI: 95%–99%) against RSV-associated hospitalisation. Interpretation: Nirsevimab was effective in preventing RSV-associated ED encounters and hospitalisation among infants in their first RSV season, with greatest protection against hospitalisation. However, these estimates reflect a short interval from nirsevimab administration to RLI onset. Since nirsevimab is a passive immunization and concentration is expected to wane over time, it is important to continue monitoring effectiveness to assess effectiveness with increased time since dose. Funding: This work was supported by the Centers for Disease Control and Prevention (contracts 75D30121D12779 to Westat and 75D30123C18039 to Kaiser Foundation Hospitals). © 2025 Elsevier B.V., All rights reserved.

IMPORTANCE: SARS-CoV-2 continues to evolve, population immunity changes, and COVID-19 vaccine formulas have been updated, necessitating ongoing COVID-19 vaccine effectiveness (VE) monitoring. OBJECTIVES: To evaluate the VE of 2023-2024 COVID-19 vaccines against COVID-19-associated emergency department (ED) and urgent care (UC) encounters, hospitalizations, and critical illness, including during XBB- and JN.1-predominant periods. DESIGN, SETTING, AND PARTICIPANTS: This test-negative design VE case-control study was conducted using data from September 21, 2023, to August 22, 2024, from EDs, UC centers, and hospitals in 6 US health care systems. Eligible adults 18 years or older with COVID-19-like illness and molecular or antigen testing for SARS-CoV-2 were studied. Case patients were those with a positive molecular or antigen test result; control patients were those with a negative molecular test result. EXPOSURE: Receipt of 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination with products approved or authorized for use in the US. MAIN OUTCOMES AND MEASURES: Main outcomes were COVID-19-associated ED and UC encounters, hospitalizations, and critical illness (admission to the intensive care unit or in-hospital death). VE was estimated comparing the odds of receipt of the 2023-2024 COVID-19 vaccine with no receipt among case and control patients. RESULTS: Among 345 639 eligible ED and UC encounters in immunocompetent adults 18 years or older with COVID-19-like illness and available test results (median [IQR] age, 53 [34-71] years; 209 087 [60%] female), 37 096 (11%) had a positive SARS-CoV-2 test result. VE against COVID-19-associated ED and UC encounters was 24% (95% CI, 21%-26%) during 7 to 299 days after vaccination. Among 111 931 eligible hospitalizations in immunocompetent adults 18 years or older with COVID-19-like illness and available test results (median [IQR] age, 71 [58-81] years), 10 380 (9%) had a positive SARS-CoV-2 test result. During 7 to 299 days after vaccination, VE was 29% (95% CI, 25%-33%) against COVID-19-associated hospitalization and 48% (95% CI, 40%-55%) against COVID-19-associated critical illness. VE was highest 7 to 59 days after vaccination (VE against ED and UC encounters 49%; 95% CI, 46%-52%; hospitalization, 51%; 95% CI, 46%-56%; critical illness, 68%; 95% CI, 56%-76%) and then waned (VE 180-299 days after vaccination against ED and UC encounters, -7% [95% CI, -13% to -2%]; hospitalization, -4% [95% CI, -14% to 5%]; and critical illness, 16% [95% CI, -6 to 34%]). CONCLUSIONS AND RELEVANCE: In this case-control study of VE, 2023-2024 COVID-19 vaccines were estimated to provide additional effectiveness against medically attended COVID-19, with the highest and most sustained estimates against critical illness. These results highlight the importance of receiving recommended COVID-19 vaccination for adults 18 years or older.

COVID-19 vaccination averted approximately 68,000 hospitalizations during the 2023-24 respiratory season. In June 2024, CDC and the Advisory Committee on Immunization Practices (ACIP) recommended that all persons aged ≥6 months receive a 2024-2025 COVID-19 vaccine, which targets Omicron JN.1 and JN.1-derived sublineages. Interim effectiveness of 2024-2025 COVID-19 vaccines was estimated against COVID-19-associated emergency department (ED) or urgent care (UC) visits during September 2024-January 2025 among adults aged ≥18 years in one CDC-funded vaccine effectiveness (VE) network, against COVID-19-associated hospitalization in immunocompetent adults aged ≥65 years in two networks, and against COVID-19-associated hospitalization among adults aged ≥65 years with immunocompromising conditions in one network. Among adults aged ≥18 years, VE against COVID-19-associated ED/UC visits was 33% (95% CI = 28%-38%) during the first 7-119 days after vaccination. Among immunocompetent adults aged ≥65 years from two CDC networks, VE estimates against COVID-19-associated hospitalization were 45% (95% CI = 36%-53%) and 46% (95% CI = 26%-60%) during the first 7-119 days after vaccination. Among adults aged ≥65 years with immunocompromising conditions in one network, VE was 40% (95% CI = 21%-54%) during the first 7-119 days after vaccination. These findings demonstrate that vaccination with a 2024-2025 COVID-19 vaccine dose provides additional protection against COVID-19-associated ED/UC encounters and hospitalizations compared with not receiving a 2024-2025 dose and support current CDC and ACIP recommendations that all persons aged ≥6 months receive a 2024-2025 COVID-19 vaccine dose.