Background:The 2024-25 influenza season was the most severe in the United States (US) since 2017- 18, with co-circulation of both influenza A virus subtypes (H1N1 and H3N2). Influenza vaccine effectiveness (VE) has varied by season, setting, and patient characteristics. Methods:Using electronic healthcare encounter data from eight US states, we evaluated influenza vaccine effectiveness (VE) against influenza-associated hospitalizations and emergency department or urgent care (ED/UC) encounters from October 2024-April 2025 among children aged 6 months-17 years and adults aged ≥18 years. Using a test-negative, case-control design, we compared the odds of influenza vaccination between acute respiratory illness (ARI) encounters with a positive (cases) versus negative (controls) test for influenza by molecular assay, adjusting for confounders. Results:Analyses included 108,618 encounters (5,764 hospitalizations and 102,854 ED/UC encounters) among children and 309,483 encounters (76,072 hospitalizations and 233,411 ED/UC encounters) among adults. Among children across care settings, 17.0% (6,097/35,765) of cases versus 29.4% (21,449/72,853) of controls were vaccinated. Among adults, 28.2% (21,832/77,477) of cases versus 44.2% (102,560/232,006) of controls were vaccinated. VE was 51% (95% confidence interval [95% CI]: 41-60%) against influenza-associated hospitalizations and 54% (95% CI: 52-55%) against influenza- associated ED/UC encounters among children. VE was 43% (95% CI: 41-46%) against influenza- associated hospitalizations and 49% (95% CI: 47-50%) against influenza-associated ED/UC encounters among adults. Conclusions:Influenza vaccination provided protection against influenza-associated hospitalizations and ED/UC encounters among children and adults in the US during the severe 2024-25 influenza season. These findings support influenza vaccination as an important tool to reduce influenza-associated disease.

Test negative design studies allow for COVID-19 vaccine effectiveness (VE) estimation while minimizing selection bias from healthcare seeking and testing practices. However, failure to consider correlation between vaccination behaviors may result in biased COVID-19 VE estimates. Using different methods to account for potential correlation between COVID-19, influenza, and respiratory syncytial virus (RSV) vaccination status, we investigated variability in VE estimates of the 2023-2024 COVID-19 vaccine against COVID-19-associated emergency department and urgent care (ED/UC) encounters and hospitalizations during the 2023-2024 respiratory virus season. Data were leveraged from VISION, an electronic health record-based platform. VE estimates ≥7 days post vaccination did not increase by more than 5 percentage points against ED/UC encounters and 3 percentage points against hospitalizations when accounting for influenza and RSV vaccination status or excluding influenza and RSV positive controls. As the magnitude of this influence depends on season-specific factors, ongoing monitoring is warranted.

Respiratory syncytial virus (RSV) caused approximately 100,000-160,000 hospitalizations annually in adults aged ≥60 years in the United States (US) before RSV vaccine introduction. In 2023, two vaccines were recommended for prevention of severe RSV disease in adults aged ≥60 years using shared clinical decision making. In 2024, a third product was licensed, and all three available vaccines were recommended for all adults aged ≥75 years and for adults aged 60-74 years at increased risk of severe RSV disease. We assessed post-licensure vaccine effectiveness (VE) to inform future recommendations and public communications. VISION is a multi-site electronic health record-based study including >200 hospitals in the US. Adults aged ≥60 years hospitalized with RSV-like illness and tested for RSV were included. Cases had a positive molecular or antigen RSV test; controls had a negative molecular RSV test. Critical illness included admission to the intensive care unit or in-hospital death. VE against hospitalization and critical illness was calculated using a test negative design as (1-adjusted odds ratio) x 100% where the odds ratio compares odds of vaccination in cases and controls after adjusting for confounders. Results were stratified by time since RSV vaccination, age group, and immunocompromised status. Among 83,652 hospitalizations during October 2023-March 2024 and October 2024-March 2025, VE was 62% (95% CI: 56-67%, Table) against RSV-associated hospitalization, median 279 days after RSV vaccination. VE was 83% (95% CI: 73-89%) at 14-59 days after vaccination and 42% (95% CI: 30-53%) at least 1 year after vaccination (median 429 days). VE against RSV-associated critical illness was 69% (95% CI: 55-78%), median 277 days after vaccination. VE was similar by age group and among those with and without immunocompromising conditions. RSV vaccines are effective at preventing severe RSV and have the potential to reduce the burden of RSV-associated hospitalizations among older adults, although waning protection was apparent during the second season after vaccination. Ongoing monitoring of RSV VE is warranted to ensure vaccines are working as expected, to understand duration of protection, and to inform policy decisions. All Authors: No reported disclosures

Importance:The 2025-2026 COVID-19 vaccine, targeting JN.1 and JN.1-derived sublineages, became available in the US in September 2025. Objective:To assess the estimated interim effectiveness of 2025-2026 COVID-19 vaccines against medically attended COVID-19 among immunocompetent adults aged 18 years or older in the US. Design, Setting, and Participants:This case-control study used a test-negative design to investigate patient encounters captured in the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network, an electronic medical record-based network of health care systems (253 emergency departments/urgent cares [ED/UCs] and 179 hospitals in 7 states) from September 3, 2025, to December 31, 2025. Patient encounters with COVID-19-like illness and a molecular or antigen SARS-CoV-2 test 10 days before to 3 days after the encounter date were included. Exposure:2025-2026 COVID-19 vaccination regardless of prior COVID-19 vaccination. Main Outcomes and Measures:The main outcomes were COVID-19-associated ED/UC encounters and COVID-19-associated hospitalizations. Cases were defined as encounters with a positive molecular or antigen SARS-CoV-2 test and controls as encounters with a negative molecular SARS-CoV-2 test. The odds of 2025-2026 COVID-19 vaccination among cases and controls, adjusting for confounders, were compared and used to estimate vaccine effectiveness (VE) as (1 - adjusted odds ratio) × 100%. Results:In 85 725 ED/UC encounters among adults aged 18 years and older (51 841 [60%] aged 18-64 years; 51 775 female [60%]), 206 of 3941 cases (5%) and 9453 of 81 784 controls (12%) received a 2025-2026 COVID-19 vaccination. Estimated VE against COVID-19-associated ED/UC encounters was 50% (95% CI, 42%-57%; median [IQR] time since 2025-2026 COVID-19 vaccine dose receipt, 47 [27-69] days). In 26 073 hospitalizations with a COVID-19-like illness (17 530 [67%] aged ≥65 years; 13 985 female [54%]), 60 of 1022 cases (6%) received a 2025-2026 COVID-19 vaccination compared with 3080 of 25 051 controls (12%). Estimated VE against COVID-19-associated hospitalization was 55% (95% CI, 41%-66%; median [IQR] time since 2025-2026 COVID-19 vaccine dose receipt, 46 [26-68] days). Among patients aged 65 years or older, estimated VE against ED/UC encounters was 48% (95% CI, 37%-56%; median [IQR] time since dose receipt, 48 [27-69] days; 33 884 encounters) and against hospitalization was 53% (95% CI, 37%-65%; median [IQR] time since dose receipt, 46 [26-69] days; 17 530 hospitalizations). Conclusions and Relevance:In this study, receipt of 2025-2026 COVID-19 vaccination was associated with additional protection beyond existing immunity in adults against medically attended COVID-19, including ED/UC encounters and hospitalizations, compared with no receipt of a 2025-2026 vaccine dose. These findings suggest that adults can reduce their likelihood of severe COVID-19-associated outcomes by obtaining a 2025-2026 COVID-19 vaccination.

Vaccine effectiveness (VE) studies are necessary to understand how well vaccines work in the real world. Many VE studies rely on health records to capture underlying medical conditions (UMCs) from a single acute respiratory illness- (ARI) associated encounter, which may bias VE if UMCs are not fully captured. We assessed capture of UMCs from a single acute encounter and a lookback period. Data were used from MarketScan® Treatment Pathways, a healthcare claims dataset, between September 1, 2023 – August 31, 2024. We included beneficiaries aged ≥18+ years with ≥1 inpatient or emergency department (ED) claim containing an ICD-10 code for ARI who had 3 years of continuous enrollment in a participating insurance plan prior to the date of their first ARI claim (i.e., index encounter). The prevalence of UMCs was calculated using ICD-10 codes from 1) the index encounter, and 2) the 1-year lookback period; and the difference was reported. Negative predictive value (NPV) with 95% exact binomial confidence intervals was calculated for identification of UMCs on the index encounter date, using the 1-year lookback period to define true negatives. Results were stratified by age group and encounter setting. Among 65,056 beneficiaries with ≥1 inpatient ARI event and 162,943 with ≥1 ED ARI event, the most prevalent UMC categories were cardiovascular, endocrine/metabolic, and respiratory (Tables 1-4). Among beneficiaries aged 18–64 years, NPV was < 80% for cardiovascular, endocrine/metabolic, and obesity categories; median difference in prevalence was 9.5 percentage points (pp) (min=0, max=30) (Tables 1 and 3). Among beneficiaries aged ≥65+ years, NPV was ≤80% for respiratory, cardiovascular, neurological and musculoskeletal, endocrine/metabolic, renal, and obesity categories; median difference in prevalence was 13.5 pp (min=0, max=52) (Tables 2 and 4). NPV, regardless of age, was > 90% for UMC categories with the lowest overall prevalence (i.e., cerebrovascular, hematologic, and underweight categories) (Tables 1-4). NPV was < 80% for common UMCs when identified using a single ARI encounter compared to a 1-year lookback period. Misclassification may influence VE estimates if UMCs are confounders in VE studies. Sara Y. Tartof, PhD, MPH, Centers for Disease Control and Prevention: Grant/Research Support Karthik Natarajan, PhD, Centers for Disease Control and Prevention: Grant/Research Support Stephanie Irving, MHS, Westat: Grant/Research Support Nicola P. Klein, MD, PhD, AstraZeneca: Grant/Research Support|Centers for Disease Control and Prevention: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Janssen: Grant/Research Support|Merck: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Grant/Research Support|Seqirus: Grant/Research Support Shaun J. Grannis, MD, MS, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health NCATS: Grant/Research Support|National Institutes of Health NIMH: Grant/Research Support Toan Ong, PhD, Centers for Disease Control and Prevention via Westat: Grant/Research Support|Patent Title: Systems and Methods For Record Linkage: Patent Number: PCT/US2018/047961|PCORI: Travel Support|Regenstrief Institute: Advisor/Consultant|Regenstrief Institute: Travel Support Sarah W. Ball, MPH, ScD, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support|Centers for Disease Control and Prevention, Contract #75D30121D12779: Grant/Research Support|Novavax: Grant/Research Support Malini B. DeSilva, MD, MPH, Centers for Disease Control and Prevention Vaccine Safety Datalink: Grant/Research Support|Westat: Grant/Research Support Ryan E. Wiegand, PhD, Merck & Co., Inc.: Stocks/Bonds (Public Company)|Sanofi S.A.: Stocks/Bonds (Public Company)

CDC recommends annual influenza vaccination for all persons aged ≥ 6 months. We estimated 2024–2025 seasonal influenza vaccine effectiveness (VE) against influenza–associated hospitalizations among adults.Figure 1.2024–2025 seasonal influenza vaccine effectiveness against influenza–associated hospitalizations among adults aged ≥ 18 years — VISION Network, October 2024–March 2025Abbreviations: CI = Confidence interval; ICU = Intensive care unit; IQR = Interquartile range; VE = vaccine effectiveness.a) Patients were considered vaccinated if they received ≥1 2024–2025 influenza vaccine dose ≥14 days before the index date, defined as the earlier date of the most recent influenza test and the hospital admission date.b) VE was estimated using multivariable logistic regression models comparing the odds of receipt of ≥1 2024–2025 influenza vaccine dose versus no dose among cases and controls. Models were adjusted for age, sex, race and ethnicity, calendar day, and healthcare system. Age and calendar day were treated as natural cubic splines with 4 degrees of freedom.c) Influenza A and B coinfections were excluded from influenza A and B case counts and from VE estimates against influenza A and B.d) Patients were considered immunocompromised if they had ≥1 ICD-10 discharge diagnosis code for any of the following conditions: hematologic malignancy, solid malignancy, bone marrow transplant, solid organ transplant, rheumatologic/inflammatory disorder, other intrinsic immunodeficiency condition, or HIV/AIDS.e) To estimate VE against ICU admission, cases were restricted to encounters with ICU admission and no in-hospital death. Data from the VISION Network were used to estimate influenza VE using a test-negative, case-control design. The analysis included hospitalizations among adults aged ≥ 18 years with ≥ 1 acute respiratory illness (ARI)–associated ICD-10 discharge diagnosis code from October 1, 2024–March 7, 2025 in six US healthcare systems. Cases were ARI hospitalizations with a positive molecular influenza test within 10 days before to 72 hours after the admission date. Controls were ARI hospitalizations with a negative molecular influenza test during the same interval. VE was estimated using multivariable logistic regression comparing the odds of receipt of ≥ 1 2024–2025 influenza vaccine dose versus no dose among cases and controls. VE models were adjusted for age, sex, race and ethnicity, calendar day, and healthcare system. A total of 31,338 ARI hospitalizations met inclusion criteria, including 4,969 cases and 26,369 controls (Figure). Overall VE against influenza–associated hospitalizations was 46% (95% CI=43–50%) with a median time since vaccination of 79 days (IQR=50–107). When stratified by time since vaccination, VE was 46% (95% CI=38–53%) at 14–59 days, 41% (95% CI=36–45%) at 60–119 days, and 9% (95% CI=-1 to 19%) at ≥ 120 days. VE was 46% (95% CI=42–50%) against influenza A and 65% (95% CI=41–80%) against influenza B. Among immunocompetent and immunocompromised adults, VE was 49% (95% CI=45–53%) and 33% (95% CI=23–42%), respectively. VE against influenza–associated intensive care unit (ICU) admission was 49% (95% CI=38–58%) and against in-hospital death was 48% (95% CI=31–62%). 2024–2025 seasonal influenza vaccines provided protection against influenza–associated hospitalizations among adults with evidence of decreased VE ≥ 120 days after vaccination. VE point estimates were higher against influenza B than against influenza A and among immunocompetent versus immunocompromised adults. VE against influenza–associated ICU admission and in-hospital death were similar to that against hospitalization. Zachary Weber, PhD, MS, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support Duck-Hye Yang, PhD, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support Stephanie Irving, MHS, Westat: Grant/Research Support Sara Y. Tartof, PhD, MPH, Centers for Disease Control and Prevention: Grant/Research Support Nicola P. Klein, MD, PhD, AstraZeneca: Grant/Research Support|Centers for Disease Control and Prevention: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Janssen: Grant/Research Support|Merck: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Grant/Research Support|Seqirus: Grant/Research Support Shaun J. Grannis, MD, MS, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health NCATS: Grant/Research Support|National Institutes of Health NIMH: Grant/Research Support Toan Ong, PhD, Centers for Disease Control and Prevention via Westat: Grant/Research Support|Patent Title: Systems and Methods For Record Linkage: Patent Number: PCT/US2018/047961|PCORI: Travel Support|Regenstrief Institute: Advisor/Consultant|Regenstrief Institute: Travel Support Sarah W. Ball, MPH, ScD, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support|Centers for Disease Control and Prevention, Contract #75D30121D12779: Grant/Research Support|Novavax: Grant/Research Support Malini B. DeSilva, MD, MPH, Centers for Disease Control and Prevention Vaccine Safety Datalink: Grant/Research Support|Westat: Grant/Research Support Padma Kppolu, MPH, Westat: Grant/Research Support S. Bianca Salas, MPH, Centers for Disease Control and Prevention: Grant/Research Support|Pfizer: Grant/Research Support Lina S. Sy, MPH, AstraZeneca: Grant/Research Support|Dynavax: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support Bruno Lewin, MD, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health: Grant/Research Support Richard Contreras, MS, Centers for Disease Control and Prevention: Grant/Research Support Ousseny Zerbo, PhD, Centers for Disease Control and Prevention: Grant/Research Support|Moderna: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer: Grant/Research Support John R. Hansen, MPH, Centers for Disease Control and Prevention: Grant/Research Support Lawrence Block, MPH, MPA, Centers for Disease Control and Prevention: Grant/Research Support Karen B. Jacobson, MD, MPH, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer: Grant/Research Support William F. Fadel, PhD, Centers for Disease Control and Prevention: Grant/Research Support Catia Chavez, MPH, Westat: Grant/Research Support Adam Yates, PhD, Beehive Study: Grant/Research Support|Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support Lindsey Kirshner, MPH, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support Charlene E. McEvoy, MD, MPH, Astra Zeneca: Grant/Research Support|Centers for Disease Control and Prevention: Grant/Research Support|Department of Defense: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|National Institutes of Health: Grant/Research Support|PCORI: Grant/Research Support Karthik Natarajan, PhD, Centers for Disease Control and Prevention: Grant/Research Support

Background Accurate patient record linkage is essential for clinical care, health information exchange, research, and public health surveillance. However, linkage accuracy may vary across demographic groups due to differences in data completeness, quality, and the structural factors underlying how demographic information is captured. Objective This study aimed to explore whether probabilistic patient matching accuracy varies by age, sex, race, and ethnicity and to identify potential sources of bias that may influence matching performance. Methods We used 4 Indiana data sources—the Indiana Network for Patient Care, Newborn Screening, Social Security Administration Death Master File, and Marion County Public Health Department—and applied a modified Fellegi-Sunter probabilistic linkage algorithm accommodating missing data under a missing at random assumption. Gold standard match status was established through dual manual review with adjudication. For each dataset, matching sensitivity, positive predictive value, and F1-scores were estimated and stratified by age, sex, race, and ethnicity. Data completeness, distinct value ratio, and Shannon entropy were assessed to characterize data quality. Ninety-five percent bootstrap CIs were used to assess significance. Results The algorithm-matching F1-score was greater than 0.82 for all age strata, ranging from 0.88 to 0.97 for sex, 0.85 to 0.99 for race, and 0.88 to 0.99 for ethnicity. Sensitivity ranged from 0.70 to 0.97 across age strata, 0.76 to 0.97 across sex, 0.85 to 0.99 across race, and 0.85 to 0.989 across ethnicity. Lower sensitivity and F1-scores were consistently observed in strata with greater missingness or discordance, particularly in Newborn Screening and Social Security Administration Death Master File. Race and ethnicity exhibited the highest missingness and lowest informational diversity, coinciding with the largest declines in accuracy. Shannon entropy and distinct value ratio varied across demographic groups and were strongly associated with performance, indicating that both low and excessively high informational diversity can impair matching. Conclusions Probabilistic patient matching accuracy is not uniform across demographics and is strongly influenced by data quality and completeness. Although overall matching performance, as assessed by the F1-score, remained above 0.8, it varied across datasets when stratified by sociodemographic characteristics. Sociodemographic data missingness is associated with lower matching accuracy, raising equity and ethical concerns for clinical, research, and public health applications. Routine demographic-stratified evaluations of matching accuracy, improved standardization of sociodemographic data, and fairness-aware linkage methods are essential to prevent the amplification of structural inequities in linked health datasets.

Importance:Antigenically drifted influenza A(H3N2) J.2.4.1 (subclade K) viruses predominated during the 2025-2026 Northern Hemisphere influenza season. Objective:To describe influenza activity and burden, characterize subclade K, evaluate susceptibility to influenza antivirals and postinfluenza vaccination antibodies, and estimate vaccine effectiveness. Design, Setting, and Participants:This surveillance study used multiple data sources, including (1) national surveillance of influenza-positive respiratory specimens collected by approximately 300 clinical laboratories and 100 public health laboratories from October 1, 2025, through March 14, 2026, a subset of which were further characterized; (2) serologic data of people who received 2025-2026 influenza vaccines; (3) influenza admissions data from the Influenza Hospitalization Surveillance Network (ie, 10% of US population) and the associated estimates of US burden; and (4) test-negative, case-control vaccine effectiveness estimates from the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network. Exposures:Influenza infection, hospitalization, and vaccination. Main Outcomes and Measures:Outcomes included influenza virus type, subtype, and clade; antiviral susceptibility; immunogenicity; influenza-associated outpatient and emergency department visits, hospitalizations, and mortality; estimated influenza illnesses, hospitalizations, and death; and estimated vaccine effectiveness. Results:As of March 14, 2026, of the 55 318 influenza-positive respiratory specimens tested by public health laboratories, most (50 291 specimens [90.9%]) were influenza A, of which 40 779 (81.1%) were subtyped and 35 801 (87.8%) were A(H3N2). Of the 1754 characterized A(H3N2) viruses, most (1626 specimens [92.7%]) were subclade K. Postinfluenza vaccination neutralizing geometric mean antibody titers against subclade K were reduced 1.62 (95% CI, 1.29-2.02)-fold compared with the vaccine virus. All 1729 tested A(H3N2) viruses were sensitive to antivirals. Of the 27 881 recorded influenza hospitalizations, 15 426 (54.7%) were among female patients, and 15 051 (54.0%) were among patients aged 65 years or older. The estimated cumulative influenza-associated hospitalization rate was 80.0 per 100 000 which would correlate with estimates of between 28 000 000 to 49 000 000 illnesses, 360 000 to 740 000 hospitalizations, and 22 000 to 74 000 deaths in the US during the 2025-2026 season. Adjusted interim vaccine effectiveness estimates against influenza-associated emergency department or urgent care encounters and hospitalizations were 35% (95% CI, 33%-38%) and 27% (95% CI, 21%-34%), respectively. Conclusions and Relevance:This surveillance study found that while antigenically drifted viruses predominated and caused substantial morbidity and mortality, influenza vaccines were associated with a reduced risk of influenza among those who were vaccinated, and recommended antivirals remained effective.

On June 26, 2024, the CDC updated respiratory syncytial virus (RSV) vaccine recommendations to a single dose of RSV vaccine for all adults aged ≥ 75 years and adults aged 60-74 years with increased risk of severe RSV disease. Using electronic health record (EHR) data from the VISION platform, we described characteristics of patients testing negative for RSV who did and did not receive an RSV vaccine and assessed factors associated with RSV vaccine receipt.Figure 1:Characteristics associated with receipt of respiratory syncytial virus (RSV) vaccination among test-negative patients with an emergency department (ED) encounter for RSV-like illness (RLI) during the 2024-2025 season in the VISION network, N=23,403 patientsFigure 2:Characteristics associated with receipt of respiratory syncytial virus (RSV) vaccine among test-negative patients with an inpatient encounter for RSV-like illness (RLI) during the 2024-2025 season in the VISION network, N=25,020 patients Patients with ≥ 1 emergency department (ED) or inpatient encounter at any of 6 participating health systems in 8 states with RSV-like illness (RLI) during October 1, 2024-March 31, 2025 were included. Vaccination status was ascertained from EHR, state and city immunization information systems, and medical claims. Patients who tested positive for SARS-CoV-2 or influenza viruses at the same RLI encounter were excluded. Patient age, sex, race and ethnicity, Medicaid status, number of underlying medical conditions, month of medical encounter, and documented receipt of COVID-19 or influenza vaccines were evaluated as covariates when assessing the odds of vaccination. The best fitting multivariable logistic regression models using Bayesian Information Criterion were chosen. Among 48423 included patients, 2113 (4.4%) had documented RSV vaccine receipt. The odds of RSV vaccination differed by site and increased with calendar time and age. Compared to patients aged 60-64 years, those aged ≥ 75 years were more likely to have received an RSV vaccine (ED: aOR: 3.6, 95%CI: 2.7-4.8, Figure 1; inpatient: aOR: 2.3, 95%CI: 1.7-3.0, Figure 2). Receipt of both influenza and COVID-19 vaccine within the same season had the strongest association with RSV vaccination in both the ED (aOR: 14.88, 95%CI: 11.87-18.89, Figure 1) and hospital setting (aOR: 20.04, 95%CI: 16.20-25.03, Figure 2). Receipt of other respiratory viral vaccines was the strongest indicator of RSV vaccination in the 2024-2025 RSV season in patients testing negative for RSV among all demographic and clinical characteristics considered. RSV vaccination was lower among those aged 60-64 years than older patients. These findings inform future methods to estimate vaccine effectiveness and inform policy implementation. Gabriela Vazquez-Benitez, PhD, MSc, AbbVie: research funding not related to this study|Sanofi: Grant funding for other research not related to this study Stephanie Irving, MHS, Westat: Grant/Research Support Nicola P. Klein, MD, PhD, AstraZeneca: Grant/Research Support|Centers for Disease Control and Prevention: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Janssen: Grant/Research Support|Merck: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Grant/Research Support|Seqirus: Grant/Research Support Shaun J. Grannis, MD, MS, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health NCATS: Grant/Research Support|National Institutes of Health NIMH: Grant/Research Support Toan Ong, PhD, Centers for Disease Control and Prevention via Westat: Grant/Research Support|Patent Title: Systems and Methods For Record Linkage: Patent Number: PCT/US2018/047961|PCORI: Travel Support|Regenstrief Institute: Advisor/Consultant|Regenstrief Institute: Travel Support Sarah W. Ball, MPH, ScD, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support|Centers for Disease Control and Prevention, Contract #75D30121D12779: Grant/Research Support|Novavax: Grant/Research Support Jingran Cao, MS, Sanofi Pasteur: Grant/Research Support Charlene E. McEvoy, MD, MPH, Astra Zeneca: Grant/Research Support|Centers for Disease Control and Prevention: Grant/Research Support|Department of Defense: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|National Institutes of Health: Grant/Research Support|PCORI: Grant/Research Support Ousseny Zerbo, PhD, Centers for Disease Control and Prevention: Grant/Research Support|Moderna: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer: Grant/Research Support John R. Hansen, MPH, Centers for Disease Control and Prevention: Grant/Research Support Lawrence Block, MPH, MPA, Centers for Disease Control and Prevention: Grant/Research Support Karen B. Jacobson, MD, MPH, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer: Grant/Research Support William F. Fadel, PhD, Centers for Disease Control and Prevention: Grant/Research Support Catia Chavez, MPH, Westat: Grant/Research Support Karthik Natarajan, PhD, Centers for Disease Control and Prevention: Grant/Research Support Ryan E. Wiegand, PhD, Merck & Co., Inc.: Stocks/Bonds (Public Company)|Sanofi S.A.: Stocks/Bonds (Public Company)

Background:The 2024-2025 influenza season was the most severe in the United States (US) since 2017-2018, with co-circulation of both influenza A virus subtypes (H1N1 and H3N2). Influenza vaccine effectiveness (VE) has varied by season, setting, and patient characteristics. Methods:Using electronic healthcare encounter data from 7 VISION sites in 8 US states, we evaluated influenza VE against influenza-associated hospitalizations and emergency department or urgent care (ED/UC) encounters from October 2024 to April 2025 among children aged 6 months-17 years and adults aged ≥18 years. Using a test-negative, case-control design, we compared the odds of influenza vaccination between acute respiratory illness encounters with a positive (cases) versus negative (controls) test for influenza by molecular assay, adjusting for confounders. Results:Analyses included 108 618 encounters (5764 hospitalizations and 102 854 ED/UC encounters) among children and 309 483 encounters (76 072 hospitalizations and 233 411 ED/UC encounters) among adults. Among children across care settings, 17.0% (6097/35 765) of cases versus 29.4% (21 449/72 853) of controls were vaccinated. Among adults, 28.2% (21 832/77 477) of cases versus 44.2% (102 560/232 006) of controls were vaccinated. VE was 51% (95% confidence interval [95% CI]: 41%-60%) against influenza-associated hospitalizations and 54% (95% CI: 52%-55%) against influenza-associated ED/UC encounters among children. VE was 43% (95% CI: 41%-46%) against influenza-associated hospitalizations and 49% (95% CI: 47%-50%) against influenza-associated ED/UC encounters among adults. Conclusions:Influenza vaccination provided protection against influenza-associated hospitalizations and ED/UC encounters among children and adults in the US during the severe 2024-2025 influenza season. These findings support influenza vaccination as an important tool to reduce influenza.

During the 2023-2024 and 2024-2025 respiratory virus seasons, two products, a maternal vaccine (Abrysvo, by Pfizer) and an infant monoclonal antibody (nirsevimab), were recommended in the United States to protect infants against severe respiratory syncytial virus (RSV) disease during their first RSV season. We estimated product effectiveness (PE) against RSV-associated emergency department (ED) encounters and hospitalizations among infants in their first RSV season during these seasons.Table 1.Nirsevimab effectiveness against RSV-associated ED encounters and hospitalization among infants in their first RSV season, VISION, 2023-2024 and 2024-2025 RSV seasonsRSV = respiratory syncytial virus; ED = emergency department; IQR = interquartile range; CI = confidence interval; Ref = reference group; PE = product effectiveness; VISION = Virtual SARS-CoV-2, Influenza, and Other respiratory viruses Network*Encounters included those among infants aged <8 months as of October 1 with a diagnosis of RSV-like illness (RLI), excluding infants with evidence of maternal RSV vaccination and infants who received nirsevimab <7 days prior to the index date for the encounter. RLI was defined as ≥1 International Classification of Disease 10th Revision discharge diagnosis code corresponding to one or more of the following: COVID-19 pneumonia, influenza pneumonia, other viral pneumonia, influenza disease, bacterial pneumonia, acute respiratory distress syndrome, asthma exacerbation, respiratory failure, other acute lower respiratory tract infection, sinusitis, acute upper respiratory tract infections, acute respiratory illness signs and symptoms, viral illness not otherwise specified, sepsis, respiratory failure, irritable/fussy infant, respiratory distress of newborn, congenital pneumonia, interstitial emphysema and related conditions, other respiratory conditions originating in the perinatal period, congenital viral diseases, bacterial sepsis of newborn, or other infections specific to the perinatal period.†Encounters with a positive molecular or antigen RSV test 10 days prior to 3 days after the date of the ED encounter or hospital admission were considered RSV-positive.‡PE was calculated as (1 – adjusted odds ratio) x 100%, with adjusted odds ratio estimated using logistic regression, adjusting for age, race and ethnicity, sex, calendar day, and geographic region.Table 2.Maternal RSV vaccine product effectiveness against RSV-associated ED encounters and hospitalization among infants in their first RSV season, VISION, 2023-2024 and 2024-2025 RSV seasonsRSV = respiratory syncytial virus; ED = emergency department; IQR = interquartile range; CI = confidence interval; Ref = reference group; PE = product effectiveness; VISION = Virtual SARS-CoV-2, Influenza, and Other respiratory viruses Network*Encounters included those among infants in their first RSV season with a diagnosis of RSV-like illness (RLI), excluding infants with evidence of nirsevimab receipt and infants born <14 days after maternal RSV vaccine receipt. RLI was defined as ≥1 International Classification of Disease 10th Revision discharge diagnosis code corresponding to one or more of the following: COVID-19 pneumonia, influenza pneumonia, other viral pneumonia, influenza disease, bacterial pneumonia, acute respiratory distress syndrome, asthma exacerbation, respiratory failure, other acute lower respiratory tract infection, sinusitis, acute upper respiratory tract infections, acute respiratory illness signs and symptoms, viral illness not otherwise specified, sepsis, respiratory failure, irritable/fussy infant, respiratory distress of newborn, congenital pneumonia, interstitial emphysema and related conditions, other respiratory conditions originating in the perinatal period, congenital viral diseases, bacterial sepsis of newborn, or other infections specific to the perinatal period.†Days since maternal vaccination included the number of days between maternal RSV vaccine dose receipt and birth and the number of days since birth.‡Encounters with a positive molecular or antigen RSV test 10 days prior to 3 days after the date of the ED encounter or hospital admission were considered RSV-positive.§PE was calculated as (1 – adjusted odds ratio) x 100%, with adjusted odds ratio estimated using logistic regression, adjusting for age, race and ethnicity, sex, calendar day, and geographic region.¶A minimum of 14 days between maternal vaccination and birth was required; infants aged 0-6 days were excluded from this analysis. VISION includes integrated health record data with linkages to state and local immunization information systems from 127 EDs and 107 hospitals. We conducted a test-negative analysis using data from 6 VISION sites, including children with ED encounters and hospitalizations with a diagnosis of RSV-like illness (RLI) during October 2023–March 2024 and October 2024–March 2025 among infants in their first RSV season. PE was estimated for each product, comparing the odds of immunization versus no immunization among RSV-positive cases and RSV-negative controls, adjusting for age, race and ethnicity, sex, calendar day, and geographic region. Of the 8,404 RLI ED encounters and 1,395 RLI hospitalizations among infants in their first RSV season without exposure to maternal RSV vaccine, 2,981 (35%) and 771 (55%) were RSV-positive and 1,448 (17%) and 208 (15%) had evidence of nirsevimab receipt, respectively. Nirsevimab effectiveness was 67% (95% CI: 61-72%) against RSV-associated ED encounters and 92% (95% CI: 87-95%) against RSV-associated hospitalization (Table 1). In 1,508 RLI ED encounters and 421 RLI hospitalizations among infants in their first RSV season without receipt of nirsevimab, 480 (32%) and 222 (53%) were RSV-positive and 261 (17%) and 62 (15%) had evidence of maternal RSV vaccination, respectively. Maternal RSV vaccine PE was 70% (95% CI: 57-79%) against RSV-associated ED encounters and 79% (95% CI: 58-89%) against RSV-associated hospitalization among infants in their first RSV season (Table 2). Both RSV prevention products were effective in preventing RSV-associated ED encounters and hospitalizations among infants in their first RSV season in the United States. It is important to continue monitoring RSV PE during future RSV seasons. Steph Battan-Wraith, PhD, Novavax, Inc.: Grant/Research Support Sara Y. Tartof, PhD, MPH, Centers for Disease Control and Prevention: Grant/Research Support Karthik Natarajan, PhD, Centers for Disease Control and Prevention: Grant/Research Support Stephanie Irving, MHS, Westat: Grant/Research Support Shaun J. Grannis, MD, MS, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health NCATS: Grant/Research Support|National Institutes of Health NIMH: Grant/Research Support Sean M. Chickery, DHSc, Centers for Disease Control and Prevention: Grant/Research Support Gabriela Vazquez-Benitez, PhD, MSc, AbbVie: research funding not related to this study|Sanofi: Grant funding for other research not related to this study S. Bianca Salas, MPH, Centers for Disease Control and Prevention: Grant/Research Support|Pfizer: Grant/Research Support Cassandra Bezi, MPH, Centers for Disease Control and Prevention: Grant/Research Support Lina S. Sy, MPH, AstraZeneca: Grant/Research Support|Dynavax: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support Bruno Lewin, MD, Centers for Disease Control and Prevention: Grant/Research Support|National Institutes of Health: Grant/Research Support William F. Fadel, PhD, Centers for Disease Control and Prevention: Grant/Research Support Sarah W. Ball, MPH, ScD, Centers for Disease Control and Prevention, Contract #200-2019-F-06819: Grant/Research Support|Centers for Disease Control and Prevention, Contract #75D30121D12779: Grant/Research Support|Novavax: Grant/Research Support Jingran Cao, MS, Sanofi Pasteur: Grant/Research Support Charlene E. McEvoy, MD, MPH, Astra Zeneca: Grant/Research Support|Centers for Disease Control and Prevention: Grant/Research Support|Department of Defense: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|National Institutes of Health: Grant/Research Support|PCORI: Grant/Research Support Ryan E. Wiegand, PhD, Merck & Co., Inc.: Stocks/Bonds (Public Company)|Sanofi S.A.: Stocks/Bonds (Public Company)

In the United States, annual influenza vaccination has been recommended for all persons aged ≥6 months, including during the 2025-26 season. Interim influenza vaccine effectiveness (VE) estimates were calculated for patients with acute respiratory illness-associated outpatient visits and hospitalizations from three U.S. respiratory virus VE networks during the 2025-26 influenza season, using a test-negative case-control design. Among children and adolescents aged <18 years, VE was 38%-41% against influenza outpatient visits and 41% against influenza-associated hospitalization. Among adults aged ≥18 years, VE was 22%-34% against influenza outpatient visits and 30% against influenza-associated hospitalization. Among children and adolescents, VE against influenza A ranged from 37% (against outpatient visits) to 42% (against hospitalization) across settings; among adults, VE against influenza A ranged from 30% (against hospitalization) to 34% (against outpatient visits) across settings. Among children and adolescents, VE against influenza A(H3N2)-associated outpatient visits was 35% and against influenza A(H3N2)-associated hospitalization was 38%. VE against influenza B outpatient visits ranged from 45%-71% among children and adolescents and was 63% among adults. Other estimates of VE were not statistically significant or were not reportable. Although interim influenza VE is lower during the 2025-26 influenza season than it was during recent influenza seasons, these findings demonstrate that influenza vaccination still provides protection against influenza. CDC recommends influenza vaccination; U.S. influenza vaccines remain available for persons aged ≥6 months.

Importance:Vaccine effectiveness (VE) estimates are needed to monitor the effect of updated COVID-19 vaccinations. Objective:To assess the effectiveness of 2024-2025 COVID-19 vaccines against medically attended COVID-19 among adults 18 years and older in the US. Design, Setting, and Participants:This case-control study with a test-negative design included patient encounters with a COVID-19-like illness discharge diagnosis code and a molecular or antigen SARS-CoV-2 test within 10 days before to 3 days after the encounter date, from September 5, 2024, to September 2, 2025. Encounters were captured in VISION (Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network), a multisite, electronic medical record-based network of health care systems, including 381 emergency department/urgent care (ED/UC) departments and 246 hospitals in 6 states. Exposure:Vaccination with a 2024-2025 COVID-19 vaccine formulation (approved by the US Food and Drug Administration in August 2024) in the previous 7 to 299 days. Main Outcomes and Measures:Outcomes were COVID-19-associated ED/UC encounters, COVID-19-associated hospitalization, and COVID-19-associated critical illness (hospitalization with an intensive care unit admission or in-hospital death). Encounters with a positive molecular or antigen SARS-CoV-2 test result were classified as cases, and encounters with a negative molecular SARS-CoV-2 test result were classified as controls. The odds of 2024-2025 COVID-19 vaccination were compared among cases and controls, adjusting for confounders, with estimated VE calculated as (1 - adjusted odds ratio) × 100%. Results:In 333 262 eligible ED/UC encounters (median [IQR] age of patients, 54 [35-72] years; 60% female) and 97 663 eligible hospitalizations among immunocompetent adults 18 years and older (median [IQR] age of patients, 72 [59-81] years; 53% female), estimated VE was 26% (95% CI, 23%-29%) against COVID-19-associated ED/UC encounters, 35% (95% CI, 30%-40%) against COVID-19-associated hospitalization, and 41% (95% CI, 28%-51%) against COVID-19-associated critical illness 7 to 299 days after vaccination. Among immunocompetent adults 65 years and older (122 663 ED/UC encounters and 63 958 hospitalizations), estimated VE was 26% (95% CI, 22%-30%) against COVID-19-associated ED/UC encounters, 35% (95% CI, 29%-40%) against COVID-19-associated hospitalization, and 41% (95% CI, 28%-52%) against COVID-19-associated critical illness 7 to 299 days after vaccination. Among 32 629 hospitalizations in immunocompromised adults 18 years and older, estimated VE against COVID-19-associated hospitalization was 24% (95% CI, 13%-34%). VE estimates waned with more time since vaccination. Conclusions and Relevance:In this test-negative case-control study, 2024-2025 COVID-19 vaccination was associated with reduced likelihood of medically attended COVID-19-associated outcomes among immunocompetent and immunocompromised adults, highlighting the importance of adults receiving recommended COVID-19 vaccinations.

Pregnant women are at higher risk of severe coronavirus disease 2019 (COVID-19) compared with nonpregnant women of reproductive age. During 2023-2024, the Centers for Disease Control and Prevention recommended COVID-19 vaccination for everyone aged 6 months or older, including pregnant women. Using a test-negative design, we assessed the effectiveness of 2023-2024 COVID-19 vaccines against COVID-19-associated emergency department (ED) and urgent care setting encounters among pregnant women aged 18-45 years presenting for care with COVID-19 symptoms from September 2023 to August 2024. Vaccine effectiveness against COVID-19-associated ED and urgent care encounters of one 2023-2024 COVID-19 vaccine dose was 58% (95% CI, 24-77%) among pregnant women and 37% (95% CI, 29-44%) among nonpregnant women of the same age. The 2023-2024 COVID-19 vaccines were associated with a decrease in COVID-19-associated ED and urgent care encounters among pregnant women and nonpregnant women of reproductive age.

Influenza vaccination is particularly important for pregnant women. Using a test-negative, case-control design, we estimated the effectiveness of 2023-2024 seasonal influenza vaccination against influenza-associated emergency department and urgent care (ED/UC) encounters among pregnant and non-pregnant women of reproductive age using data from seven healthcare systems. Eligible encounters were among individuals aged 18-49 years with documented female sex. Vaccine effectiveness (VE) was estimated by comparing the odds of vaccination among influenza-positive cases versus influenza-negative controls, adjusting for site, age, race/ethnicity, calendar time, and gestational age at encounter (in pregnant women). Among pregnant women (N = 3539), VE against influenza-associated ED/UC encounters was 46 % (95 % CI: 36-55) and did not differ by gestational age at vaccination. Among non-pregnant women (N = 57,709), VE against influenza-associated ED/UC encounters was 54 % (95 % CI: 51-56). Influenza vaccination during the 2023-2024 season was similarly effective in both pregnant and non-pregnant women and by timing of vaccine receipt during pregnancy.

Abstract Background In September 2023, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccines for use in persons ≥6 months for prevention of COVID-19, including severe disease. Understanding how well updated COVID-19 vaccines work in the context of high population immunity due to prior infection, vaccination, or both, is important for future vaccine policy decisions, as well as informing patient/provider discussions, and increasing vaccine confidence. Effectiveness of updated (2023-2024) COVID-19 vaccination against laboratory-confirmed COVID-19-associated emergency department/urgent care encounters and hospitalization among immunocompetent adults aged ≥18 years — VISION Network, September 2023–March 2024 Methods VISION, an electronic health record (EHR)-based network including emergency departments/urgent care clinics (ED/UCs) and hospitals including 6 health systems, uses clinician-ordered testing data to estimate vaccine effectiveness (VE) for respiratory viruses. COVID-19 VE was estimated using the test-negative design, comparing the odds of vaccination with a single updated 2023-2024 COVID-19 vaccine dose between patients who tested positive versus those who tested negative for SARS-CoV-2 by molecular assay, adjusting for potential confounders. Effectiveness of updated 2023–2024 (monovalent XBB.1.5) COVID-19 vaccination against laboratory-confirmed COVID-19–associated hospitalization among immunocompromised adults aged ≥18 years — VISION network, September 2023–March 2024 Results A total of 198,345 ED/UC encounters and 59,777 hospitalizations between September 2023-March 2024 among immunocompetent adults ≥18 years with symptoms of COVID-19 were included. VE against COVID-19-associated ED/UC encounters comparing receipt of an updated dose to no receipt of an updated dose was 50% (95% CI: 46-53%) in the 7-59 days and 0 (95% CI: -14 to 12) in the 120-179 days after receipt of an updated dose (Table 1). VE against COVID-19-associated hospitalization was 50% (95% CI: 44-56%) in the 7-59 days and 23 (95% CI: 2-39) in the 120-179 days after receipt of an updated dose (Table 1). A total of 17,417 hospitalizations among immunocompromised adults ≥18 years with symptoms of COVID-19 were included, with a VE of 38% (95% CI: 23-50%) in the 7-59 days and 14 (95% CI: -33 to 44) in the 120-179 days after receipt of an updated dose after an updated dose (Table 2). Conclusion Receipt of an updated COVID-19 vaccine dose provided protection against COVID-19-associated ED/UC encounters and hospitalizations among immunocompetent and immunocompromised adults, although waning was evident. Disclosures Nicola P. Klein, MD, PhD, GlaxoSmithKline: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Grant/Research Support|Seqirus: Grant/Research Support Toan Ong, PhD, Patent Title: Systems and Methods For Record Linkage: PCT/US2018/047961 Patent Title: Systems and Methods For Record Linkage|PCORI: Travel support to attend the PCORI Annual meeting in Washington DC, 2023|Regenstrief Institute: Advisor/Consultant|Regenstrief Institute: Travel support to attend the OHIE 23 meeting in Malawi. Brian E. Dixon, PhD, Elsevier: Honoraria

The concept of a Learning Health System (LHS) has been widely discussed in academic literature, yet its practical implementation remains a challenge. This paper describes the institutional journey, leadership structure, data governance policies, and technical innovations that together support a scalable and sustainable Research-Oriented LHS. Additionally, we propose an expanded data vision that aligns with interdisciplinary and translational research needs. Supplementary materials provide technical details for those interested in implementing such a model.

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.

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.