Importance  Influenza continues to cause significant mortality and morbidity in the US. Seasonal influenza vaccines reduce the severity of disease and prevent hospitalizations and death, especially among individuals at high risk.Objective  To identify and summarize the most recently published research spanning several influenza seasons reporting on the epidemiology of influenza in the US and the effectiveness and safety of US-licensed seasonal influenza vaccines, updating a prior evidence review through August 2025.Evidence Review  This systematic review searched Medline (PubMed), Embase, Cochrane CENTRAL, and Scopus from August 1, 2025, through June 30, 2026, for all English-language studies. Eligible publications reported on the epidemiology of influenza in the US or vaccine effectiveness and safety for any influenza vaccine formulation approved for use in the US. Data extraction included effectiveness and safety estimates reported among older adults; adults; during pregnancy; infants, children, and young adults; and persons who were immunocompromised. Risk of bias assessment was conducted.Findings  The search identified 69 eligible studies: 21 randomized clinical trials (RCTs) and 23 observational studies with a comparator group, 7 product safety studies without a comparator group, and 18 descriptive studies of disease burden. Across multiple seasons, influenza vaccines were associated with reduced risk of influenza-related hospitalization (vaccine effectiveness [VE] ranging from 19.0%; 95% CI, 0.0%-34.0% to 43.0%; 95% CI, 30.0%-53.0%) and mortality (VE ranging from 29.0%; 95% CI, 16.0%-40.0% to 65.8%; 95% CI, 54.6%-76.9%) among older adults. Vaccines were also associated with reduced risk of severe influenza among infants, children, adolescents, and young adults; a case-cohort analysis of national surveillance data over 8 seasons (2016-2020 and 2021-2025) among infants, children, and adolescents aged 6 months to 17 years reported that VE was 80.0% (95% CI, 75.0%-84.0%) against laboratory-confirmed influenza-associated deaths. Vaccination during pregnancy was associated with a VE against symptomatic disease in infants of 44.4% (95% CI, 31.4%-54.9%) based on a retrospective cohort study from 2011 to 2022. RCT data published in 2025 for seasons 2022 to 2025 reported higher efficacy against hospitalization with the high-dose compared with standard-dose vaccine among older adults (relative VE, 43.6%; 95% CI, 27.5%-56.3%). A large self-controlled case series among 9 973 703 individuals receiving vaccines found no association with increased risk of serious adverse events, including Guillain-Barré syndrome, after the seasonal influenza vaccine was administered alone or when coadministered with respiratory syncytial virus or COVID-19 immunizations. Another self-controlled case series reported no association with increased risk of febrile seizure during the interval 0 to 7 days after vaccination.Conclusions and Relevance  This systematic review found that evidence published August 1, 2025, through June 30, 2026, continued to demonstrate that influenza vaccines were associated with reduced risk of severe disease and hospitalization, especially among older adults, infants, children, and young adults. No new safety concerns were identified.

CDC Reports 18 Million Flu Illnesses, 9,300 Deaths.

IMPORTANCE  Effectiveness of seasonal influenza vaccine must be assessed annually as influenza viruses evolve, requiring updated vaccine components. Evidence is limited for direct vaccine benefit in lowering risk of death following influenza virus infection.OBJECTIVE  To evaluate the association between current-season influenza vaccination and laboratory-confirmed influenza virus infection and, among persons with laboratory-confirmed influenza, the association with influenza-associated death.DESIGN, SETTING, AND PARTICIPANTS  A case-control analysis of California residents aged 6 months or older with influenza diagnostic testing ordered between October 1, 2024, and May 31, 2025, with data on diagnostic test result and 2024 to 2025 influenza vaccination. Influenza-associated deaths within 30 days of testing among persons with laboratory-confirmed influenza were identified from vital statistics records.EXPOSURES  Influenza vaccination from October 1, 2024, to May 31, 2025.MAIN OUTCOMES AND MEASURES  Associations were evaluated between 2024 to 2025 influenza vaccination and (1) laboratory-confirmed influenza, in which case individuals tested positive and control individuals tested negative for laboratory confirmed influenza; and (2) influenza-associated death, in which deaths were compared with surviving cases among persons with laboratory-confirmed influenza. Associations were assessed with mixed-effects logistic regression.RESULTS  Among 1 106 628 persons tested for laboratory-confirmed influenza (610 093 female participants [55.1%]), 234 715 were case individuals with laboratory-confirmed influenza (median [IQR] age, 28 [10-52] years) and 871 913 were control individuals (median [IQR] age, 42 [19-67] years); 45 441 influenza cases (19.4%) and 255 605 control individuals (29.3%) had received 2024 to 2025 influenza vaccination. Vaccination was significantly associated with decreased likelihood of laboratory-confirmed influenza (estimated vaccine effectiveness, 40%; 95% CI, 39%-41%). Among persons with laboratory confirmed influenza, there were 801 influenza-associated deaths. Influenza-associated death among persons aged 65 years or older was associated with lower likelihood of influenza vaccination (adjusted odds ratio, 0.71; 95% CI, 0.60-0.84) compared with persons with nonfatal infection.CONCLUSIONS AND RELEVANCE  In this case-control study of estimated vaccine effectiveness, influenza vaccination was associated with decreased likelihood of laboratory-confirmed influenza and influenza-associated deaths among those with laboratory-confirmed influenza. Electronic laboratory reporting linked to immunization registry and vital statistics provide tools to assess vaccine effectiveness and risk of death, a rare influenza-associated outcome.

The US Centers for Disease Control and Prevention recently removed annual influenza vaccination from its childhood recommendations,1 citing concerns about lack of contemporaneous randomized data to support annual influenza vaccination and historical reliance on observational data to support vaccine efficacy (ie, annual comparisons of influenza vaccination rates among individuals with influenza-like illnesses testing positive vs negative for influenza), which may be confounded.2,3 One way to use observational data to assess annual influenza vaccine efficacy in children that is less susceptible to confounding is to identify instances in which some children are, by chance, vaccinated while others are not—a natural experiment.4 Get Access