Influenza Vaccine and Associated Infection and Death in California, 2024 to 2025

Case-control analysis

N= 1,106,628

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

Case individuals with laboratory-confirmed influenza (n= 234,715)

Control individuals without influenza (n= 871,913)

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

Persons with documented vaccination 0 to 13 days before the test result date

Electronic influenza test results from the California Reportable Disease Information Exchange were probabilistically linked to vaccination records from the California Immunization Registry. Vaccination was defined as ≥1 documented 2024-2025 influenza vaccine dose received ≥14 days before testing; persons without a vaccination record or vaccinated after testing were classified as unvaccinated. Laboratory-confirmed cases had a positive polymerase chain reaction or viral culture, whereas controls had only negative tests. Influenza-associated death was defined as death ≤30 days after a positive test with influenza or an influenza-related ICD-10 code recorded on the death certificate. Mixed-effects logistic regression evaluated vaccination in influenza-positive versus influenza-negative persons and in fatal versus nonfatal influenza cases.

October 1, 2024, to May 31, 2025

Primary: Association between 2024-2025 influenza vaccination and laboratory-confirmed influenza; association between vaccination and influenza-associated death among persons with laboratory-confirmed influenza

Secondary: Vaccine effectiveness against laboratory-confirmed influenza by age, influenza virus type and subtype, vaccine type, and calendar month

Cases (n= 234,715)

28 (10-52)

Age, years

0.5-17

18-49

50-64

≥65

92,148 (39.3%)

80,176 (34.1%)

28,556 (12.2%)

33,835 (14.4%)

205,502 (23.6%)

297,806 (34.2%)

133,691 (15.3%)

234,914 (26.9%)

Race

White

Asian

Black or African American

91,041 (38.8%)

19,714 (8.4%)

13,651 (5.8%)

385,092 (44.2%)

71,775 (8.2%)

47,771 (5.5%)

Ethnicity

Hispanic or Latino

Not Hispanic or Latino

65,761 (28.0%)

123,819 (52.8%)

205,243 (23.5%)

493,210 (56.6%)

Female

Among 234,715 patients with laboratory-confirmed influenza, 801 influenza-associated deaths occurred, including 586 (73.2%) among adults aged ≥65 years.

Vaccination was documented in 244 patients with influenza-associated death (30.4%) and 45,197 patients with nonfatal influenza (19.3%); after adjustment, vaccination was associated with lower odds of influenza-associated death overall (adjusted odds ratio [aOR] 0.73; 95% confidence interval [CI] 0.62-0.85).

Among adults aged ≥65 years, 210 of 586 patients who died (35.8%) and 13,536 of 33,249 patients with nonfatal infection (40.7%) were vaccinated, corresponding to an aOR of 0.71 (95% CI 0.60-0.84).

Associations were not statistically significant among adults aged 18 to 49 years (aOR 0.46; 95% CI 0.18-1.17) or 50 to 64 years (aOR 0.96; 95% CI 0.62-1.46), and an adjusted estimate was not reported for patients aged <18 years because of the small sample size.

Not applicable

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 large, population-based data set and linkage of laboratory, immunization, and vital-statistics records permitted assessment of the rare outcome of influenza-associated death across pediatric and adult age groups. However, the observational design was susceptible to residual confounding and vaccination-status misclassification; clinical comorbidities were unavailable, mortality rates by vaccination status were not calculated, and vaccine hesitancy and immunocompromised populations were not specifically evaluated.

The Effectiveness of Four Quadrivalent, Inactivated Influenza Vaccines Administered Alone or in Combination with Pneumococcal and/or SARS-CoV-2 Vaccines: A Population-Wide Cohort Study

Retrospective cohort study

N= 105,527

To evaluate the effectiveness of quadrivalent influenza vaccines, offered alone or in combination with pneumococcal and/or SARS-CoV-2 vaccines, in preventing all-cause mortality and hospital admissions for influenza and/or pneumonia

Vaccinated (n= 46,355)

Unvaccinated (n= 59,172)

Vaccinated subgroups:

Influenza vaccine only (n= 34,549)

Influenza and pneumococcal vaccines (n= 3,431)

Influenza and SARS-CoV-2 vaccines (n= 7,268)

All 3 vaccines (n= 1,107)

Permanent or temporary residents in the province of Pescara, Italy, aged ≥60 years, on 10 October 2023

Immunization, demographic, co-payment exemption, SARS-CoV-2 testing, mortality, and hospitalization data were obtained from official National Healthcare System databases. Influenza-vaccinated individuals received 1 intramuscular 0.5-mL dose of an inactivated quadrivalent vaccine and were considered vaccinated ≥14 days after administration. Outcomes were compared between influenza-vaccinated and unvaccinated individuals and among vaccine coadministration groups using Cox proportional hazards models adjusted for age, gender, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), kidney disease, cancer, and previous SARS-CoV-2 infection. Analyses were also stratified by age, gender, influenza vaccine type, and receipt of pneumococcal and/or SARS-CoV-2 vaccines. Vaccine hesitancy was not assessed.

October 2023 to September 2024

All-cause mortality; hospital admissions for influenza and/or pneumonia

Vaccinated (n= 46,355)

45.2%

76.0 ± 9.0

41.8%

22.6%

15.5%

7.9%

5.3%

14.0%

35.8%

Among 105,527 adults aged ≥60 years, 3,188 (3.02%) died from any cause during follow-up.

Crude mortality was similar among influenza-vaccinated and unvaccinated individuals (3.07% [1,423/46,355] vs 2.98% [1,765/59,172]); however, after adjustment for demographic characteristics, comorbidities, and previous SARS-CoV-2 infection, influenza vaccination was associated with a lower risk of all-cause mortality versus no vaccination (adjusted hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.49–0.56; p< 0.001), consistently across age and gender groups.

Compared with no vaccination, adjusted mortality HRs were 0.60 (95% CI 0.56–0.65) with influenza vaccination alone 0.43 (95% CI 0.37–0.49) with influenza plus SARS-CoV-2 vaccination, and 0.02 (95% CI 0.00–0.11) with all 3 vaccines; no deaths occurred among recipients of influenza plus pneumococcal vaccines.

Influenza vaccination was also associated with a lower adjusted risk of hospitalization for influenza and/or pneumonia compared with no vaccination (adjusted HR 0.55; 95% CI 0.48–0.62; p< 0.001).

Not explicitly stated

In the elderly population of an Italian province, during the influenza season 2023–2024, all the administered quadrivalent, inactivated influenza vaccines were able to effect a substantial and significant decrease in the risk of death or hospitalization due to influenza and/or pneumonia. The co-administration of a pneumococcal and/or SARS-CoV-2 vaccine further reduced the risk of both outcomes, while no significant differences were observed by gender, age-class, and between enhanced and standard vaccines. Head-to-head, randomized trials are required to confirm the specific benefits of co-administration with other vaccines and to compare the different types of quadrivalent influenza vaccine formulations.

This population-wide study included a large elderly cohort and adjusted for several important demographic and clinical confounders; however, its observational design remains susceptible to healthy-vaccinee bias, confounding by indication, and residual differences between vaccination groups. Mortality was measured as all-cause rather than influenza- or pneumonia-specific mortality, and the study did not assess vaccine hesitancy; therefore, it informs the elderly vaccination-versus-no-vaccination mortality comparison but does not directly establish disease-specific mortality or the effect of hesitancy on mortality.

Effect of Influenza Vaccination in Solid Organ Transplant Recipients: A Nationwide Population-Based Cohort Study

Nationwide population-based cohort study

N= 5745

To investigate the effects of seasonal influenza vaccination on the incidence of all-cause pneumonia admission, influenza-related admission, intensive care unit (ICU) admission, and all-cause mortality in solid organ transplant recipients

Vaccinated (n= 2790)

Non-vaccinated (n= 2955)

Solid organ transplant recipients aged ≥18 years living in Denmark from December 1, 2007 to April 1, 2016

Nationwide Danish administrative registers were linked using unique personal registration numbers to identify vaccination status, transplant characteristics, comorbidities, prescribed medications, socioeconomic factors, hospital admissions, ICU admissions, and deaths. For each season, patients were considered vaccinated if they had received an influenza vaccine during the preceding 4 months and were followed from December 1 through April 1; patients could contribute data to multiple seasons. Cox proportional hazards models were stratified by season, accounted for repeated observations within patients, and adjusted for age, sex, transplant type, time since transplantation, comorbidities, household income, education, prescribed medications, and vaccination during the previous season. 

December 1, 2007 to April 1, 2016

Primary: All-cause pneumonia admission

Secondary: Influenza-related admission, ICU admission, all-cause mortality

All patients (n= 5745)

Mean age, years

Age group

18–34

35–49

50–64

≥65

951 (16.5%)

1725 (30%)

2236 (39%)

833 (14.5%)

654 (22.1%)

1012 (34.2%)

1001 (33.9%)

288 (9.7%)

297 (25.6%)

713 (21.0%)

1235 (44.3%)

545 (19.5%)

Male

Kidney transplant

Heart transplant

Lung transplant

Heart and lung transplant

Liver transplant

All-cause pneumonia admission

Influenza-related admission

ICU admission

All-cause mortality

In the off-season mortality sensitivity analysis, 305 deaths occurred; vaccination was associated with a nonsignificant reduction in adjusted mortality risk (adjusted hazard ratio [aHR] 0.76; 95% confidence interval [CI] 0.55–1.06; p= 0.103). The authors stated that the large adjusted in-season mortality association suggested some residual confounding.

No specific adverse events reported

Influenza vaccination of SOT recipients was associated with a reduced risk of hospitalization due to all‐cause pneumonia and a reduced risk of all‐cause mortality during the same influenza season. Vaccination coverage was low, indicating that efforts to increase vaccine coverage are needed and that there are major opportunities for improvements in preventing this disease.

The nationwide register-based design, inclusion of all eligible Danish adult solid organ transplant recipients, evaluation across nine influenza seasons, and adjustment for multiple clinical and socioeconomic factors strengthened the analysis. However, the observational design, season-level exposure classification, nonspecific mortality outcome, unavailable vaccine formulation and immunosuppressive-treatment data, possible exposure or outcome misclassification, and residual confounding limit causal interpretation of the large adjusted mortality association. The study mentioned vaccine hesitancy as one possible explanation for low coverage but did not directly measure hesitancy or quantify its effect on mortality.

Influenza Vaccine Effectiveness Against Pediatric Death in the United States: 2016–2025

Case-cohort analysis

N= 1234

To estimate influenza vaccine effectiveness (VE) against pediatric death from 2016 to 2017 through 2024 to 2025

Children with underlying medical conditions (n= 530)

Children without known conditions (n= 556)

Children aged 6 months to 17 years with laboratory-confirmed influenza-associated deaths reported from October 2016 through September 2025

Children younger than 6 months on November 1 of the influenza season

Influenza-associated pediatric deaths reported to the US Influenza-Associated Pediatric Mortality Surveillance System were evaluated for demographics, underlying medical conditions, influenza characteristics, and current-season vaccination status. Children were fully vaccinated if they received all age-appropriate current-season doses at least 14 days before illness onset; children vaccinated only in previous seasons were classified as unvaccinated. Each death was assigned a comparison cohort based on age group, state, influenza season, and the calendar month preceding illness onset using National Immunization Survey-Flu vaccination-coverage estimates, adjusted using National Health Interview Survey data for children with high-risk medical conditions. 

October 2016 through September 2025

Primary: Influenza VE against pediatric death

Secondary: VE among children with and without underlying medical conditions

All patients (n= 1234)

Age

6 months to 4 years

5 to 12 years

13 to 17 years

459 (37%)

554 (45%)

221 (18%)

649 (53%)

579 (47%)

Race

White

Black

702 (57%)

251 (20%)

No known high-risk condition

≥1 high-risk condition

Immunocompromising condition

Mean duration of fatal illness, days

Median duration of fatal illness, days (IQR)

Abbreviations: IQR, interquartile range.

Among 1,086 influenza-associated pediatric deaths included in the vaccine-effectiveness analysis, 194 (18%) occurred in fully vaccinated children and 892 (82%) in unvaccinated children, compared with an average vaccination coverage of 49% in the comparison cohorts.

Influenza vaccine effectiveness against death was 80% (95% confidence interval [CI] 75%–84%) overall, 77% (95% CI 71%–82%) among children with high-risk medical conditions, and 87% (95% CI 84%–89%) among those without known high-risk conditions.

Vaccine effectiveness was 68% (95% CI 61%–74%) against influenza A-associated death and 77% (95% CI 72%–81%) against influenza B-associated death.

During the 2024–2025 season, 252 influenza-associated pediatric deaths were reported; among deaths with known vaccination status, 22 (9%) occurred in fully vaccinated children and 211 (91%) in children who were not fully vaccinated.

Not applicable

Influenza vaccination reduced risk of fatal influenza among children with or without known underlying medical conditions.

This national analysis included eight influenza seasons and used age-, state-, season-, and month-specific comparison coverage, with sensitivity analyses addressing unknown vaccination status and possible survey overestimation. However, the surveillance design may have missed deaths without laboratory confirmation, vaccination status could have been misclassified, and the study estimated VE using external coverage cohorts rather than directly measuring mortality incidence in prospectively followed vaccinated and unvaccinated groups; vaccine hesitancy was not evaluated.

Prior Pneumococcal Vaccination Improves In-Hospital Mortality Among Elderly Population Hospitalized Due to Community-Acquired Pneumonia

Nationwide cross-sectional study

N= 4515

To assess the effects of prior pneumococcal vaccination in elderly pneumonia patients

Pneumococcal vaccinated (n= 1609)

Unvaccinated (n= 2906)

Patients aged ≥65 years; had at least one diagnosis code of pneumonia (J11.x ∼ J18.x); treated with at least 3 days of intravenous (IV) antibiotics

Hospital acquired pneumonia, ventilator-associated pneumonia, pneumonia during postoperative period, transferred from other facilities, hospitalized for more than 2 days in the 90 days prior to admission, not treated with IV antibiotics first, delayed treatment due to emergent operation, recent malignant cancer diagnosis, recent chemo- or radiation therapy, taking immunosuppressants, high dose steroids

Data were obtained from the South Korean Health Insurance Review and Assessment Service Quality Assessment database. Patients hospitalized for community-acquired pneumonia (CAP) were classified as ever vaccinated with PCV13 or PPV23 or unvaccinated based on vaccination histories obtained during admission; the specific vaccine and timing of vaccination could not be determined. Demographics, smoking status, CURB score, Charlson Comorbidity Index (CCI), admission location, antibiotic treatment, hospital length of stay, and mortality were evaluated. Cox proportional hazards analysis assessed 30-day mortality, and logistic regression assessed in-hospital mortality, with multivariable models including age, sex, vaccination status, CURB score, and CCI.

Data reported from the 3rd QA (October 2017 ∼ December 2017)

In-hospital mortality, 30-day mortality

Pneumococcal vaccinated (n= 1609)

76.0 [71.0; 82.0]

907 (56.4%)

104 (6.8%)

1571 (97.6%)

42 (2.6%)

3.0 [2.0; 5.0]

1,534 (95.3%)

75 (4.7%)

278 (18.4%)

1,117 (73.9%)

653 (40.6%)

Pneumococcal vaccinated (n= 1609)

2.4%

2.6%

97.6%

The vaccinated group also demonstrated significantly better 30-day survival than the unvaccinated group by log-rank testing (P<0.05). The study did not evaluate vaccine hesitancy or its relationship with mortality.

Not applicable

Prior pneumococcal vaccination in elderly populations is effective in improving in-hospital and 30-day mortalities among those hospitalized for pneumonia, however, it does not affect the length of admission duration.

This nationwide study directly compared mortality among vaccinated and unvaccinated adults aged ≥65 years hospitalized with CAP and found significantly lower in-hospital and 30-day mortality associated with prior pneumococcal vaccination after multivariable adjustment. Interpretation is limited by the observational design, 2017 three-month data collection period, baseline differences in age and ICU admission, self-reported vaccination history without vaccine type or timing, absence of propensity-score matching, lack of influenza vaccination and causative-pathogen data, and exclusion of patients receiving immunosuppressants or recent cancer therapy; therefore, it informs the elderly pneumonia population but does not address pediatric or immunocompromised populations, influenza vaccination, or vaccine hesitancy.

Retrospective study

N= 8,649

PPSV23-vaccinated (n= 3,247)

Unvaccinated (n= 5,402)

Primary: All-cause mortality

Secondary: Cardiovascular disease-related mortality, pneumonia-related mortality, cancer mortality

During the 5-year follow-up, 1,557 all-cause deaths occurred, including 573 cardiovascular disease-related, 163 pneumonia-related, and 329 cancer-related deaths. PPSV23 vaccination was significantly associated with lower all-cause, cardiovascular disease-related, and pneumonia-related mortality compared with no PPSV23 vaccination; exploratory analyses also showed an association with lower cancer mortality. After inverse probability weighting, the estimated average treatment effect associated with universal PPSV23 vaccination was −11.4% for all-cause mortality, −4.0% for cardiovascular disease-related mortality, −0.8% for pneumonia-related mortality, and −1.9% for cancer mortality.

Change in influenza vaccine uptake among adults in the United States from May 2020 to October 2024

Two discrete, cross-sectional national surveys

N= 1500 (Survey 1: n= 672, Survey 2: n= 828)

To assess changes in influenza vaccine uptake among US adults from May 2020 to October 2024, and to identify demographic groups with significant changes in uptake

Survey 1 (n= 672)

Survey 2 (n= 828)

US adults aged 18 and over, recruited from CloudResearch's pre-existing survey panels

Not specified

Two distinct census-matched samples of US adults completed online Qualtrics surveys administered by CloudResearch. Respondents reported whether they had recently received an influenza vaccine or intended to receive one later in the season; these responses were combined to define vaccine uptake. Results were stratified by demographic characteristics and weighted using 2022 American Community Survey estimates for age, sex, and race. Weighted proportions, 95% CIs, and P values were calculated using STATA SE 18.5, with P≤0.05 considered statistically significant.

Survey 1 was administered May 6–7, 2020, and Survey 2 was administered September 20–27, 2024, representing an approximately 4-year comparison. The article refers to the second assessment as October 2024 in its title and results. No intervention was administered.

Self-reported influenza vaccine uptake, defined as having recently received or planning to receive an influenza vaccine, overall and stratified by age, gender, race, ethnicity, and education. Mortality and vaccine hesitancy were not measured.

The study included two distinct, census-matched samples of US adults aged ≥18 years: 672 respondents surveyed in May 2020 and 828 surveyed in September 2024. The samples were recruited according to demographic quotas proportional to the US Census, and analyses were weighted using 2022 American Community Survey estimates for age, sex, and race; however, the distributions of demographic characteristics within each survey sample were not reported.

Self-reported influenza vaccine uptake, defined as recent vaccination or intention to receive vaccination, decreased from more than 60% in 2020 to 54% in 2024.

Significant declines occurred among adults aged ≥55 years (74% vs 62%; change, −11%; p= 0.004), males (65% vs 51%; −13%; p= 0.001), White respondents (61% vs 54%; −7%; p= 0.030), non-Hispanic respondents (61% vs 56%; −5%; p= 0.050), and respondents with graduate or professional education (71% vs 55%; −16%; p= 0.021).

The study did not assess mortality or directly measure vaccine hesitancy.

Not applicable

Our study documented an overall decrease in flu vaccine uptake in the years of the COVID-19 pandemic. US adults who are male, over 35 years of age, White, non-Hispanic, and had achieved graduate and professional-level education, reported the most significant decreases in uptake. As such, these groups may benefit from targeted behavioral interventions to improve vaccination rates.

The census-matched sampling and survey weighting improve the national relevance of the observed changes in influenza vaccine uptake. However, the study combined actual vaccination with future vaccination intention, used separate cross-sectional samples and self-reported responses, and did not measure vaccine hesitancy or mortality; therefore, it does not directly establish whether hesitancy affected influenza-related deaths.