VIrtual SARS-CoV-2, Influenza, and Other respiratory viruses Network (VISION) is an electronic health record-based network that performs real-world evaluations of VE for respiratory viruses. This study included acute respiratory illness (ARI)-associated medical encounters among individuals aged ≥6 months. Seven sites in 8 states contributed encounter data (Kaiser Permanente Northern California, Kaiser Permanente Southern California, UCHealth in Colorado, Regenstrief Institute in Indiana, HealthPartners in Minnesota and Wisconsin, Kaiser Permanente Northwest in Oregon and Washington, and Intermountain Healthcare in Utah). The study sampled ARI-associated encounters between October 15, 2023 and April 30, 2024.

As previously described [9], we used a test-negative design to evaluate influenza VE by comparing the odds of influenza vaccination in influenza-positive cases versus influenza-negative controls. We included children and adolescents (aged 6 months-17 years) and adults (aged ≥18 years) with ARI-associated ED/UC encounters or hospitalizations of ≥24 hours duration. ARI was defined by International Classification of Diseases, Tenth Revision (ICD-10) codes for acute respiratory clinical diagnoses or acute respiratory signs or symptoms at the encounter (Supplementary Table 1). All patients received molecular testing for influenza as well as SARS-CoV-2 within 10 days before or up to 72 hours after the ED/UC visit or admission date. An individual could contribute more than one encounter; multiple ED and/or UC encounters within a 7-day period were combined into a single ED/UC encounter and hospitalizations within 30 days combined into a single hospitalization.

Baseline patient demographic and clinical information, including underlying medical conditions (Supplementary Table 2), was extracted from electronic health records (EHRs), along with in-hospital outcomes. Influenza vaccination status was ascertained from EHRs, state immunization information systems, and/or claims data. When available, information on vaccine type was collected. A patient was classified as vaccinated if they received ≥1 dose of a 2023–2024 influenza vaccine on or after August 1, 2023 and ≥14 days prior to the encounter index date (the earliest date of the most recent influenza test or the date of the ED/UC visit or hospital admission). A patient was considered unvaccinated if 2023–2024 influenza vaccination was not documented before the encounter index date. Certain children aged 6 months-8 years required 2 doses of influenza vaccine for the season based on their vaccination history [4]; partial versus full vaccination was not assigned for these children due to incomplete capture of vaccination history for past seasons.

Exclusion criteria are shown in Supplementary Figure 1A and 1B. Encounters with no influenza molecular test result, a diagnosis of influenza without a confirmatory positive laboratory test, or that occurred 1–13 days after influenza vaccination were excluded. We also excluded encounters with a SARS-CoV-2 positive test or COVID-19 ICD-10 discharge diagnostic code to reduce potential bias in influenza VE estimates due to correlation between influenza and COVID-19 vaccination [10].

Baseline patient characteristics were described using counts and percentages or medians and interquartile ranges. Standardized mean differences (SMDs) were calculated to compare patient characteristics by influenza vaccination status and case/control status. An SMD >0.20 was interpreted as a meaningful difference in distribution between groups. VE against influenza-associated hospitalizations and ED/UC encounters was estimated from logistic regression models comparing the odds of influenza vaccination between cases and controls, adjusting for pre-specified potential confounders used in prior VISION analyses: site, calendar day, patient age (in years), sex, and race/ethnicity reported in the EHR [11, 12]. VE was calculated as (1 – adjusted odds ratio) × 100. Calendar day and age were modeled as natural cubic splines with 4 degrees of freedom.

We estimated VE separately for children and adolescents and for adults by encounter setting (ED/UC encounters or hospitalizations). Results were further stratified by age group (6 months-4 years, 5–17 years, 18–49 years, 50–64 years, ≥65 years), by influenza virus type (A or B), by time since vaccination in a model with 4 exposure groups (unvaccinated and 14–59 days, 60–119 days, ≥120 days since vaccination), and by presence or absence of ≥1 likely immunocompromising conditions. Intervals for waning models were selected based on distribution of time since vaccination and seasonal influenza circulation patterns for most influenza seasons where most infections occur over several months in the fall and winter. Among ARI-associated hospitalizations, we evaluated VE against critical in-hospital outcomes, defined as intensive care unit (ICU) admission and/or death. For this analysis, cases included patients hospitalized with influenza who experienced a critical outcome, and controls were all hospitalized controls [13]. We also estimated VE against ED and UC encounters separately. Finally, because of differences by care setting in the proportion of influenza A and B cases and timing of vaccination across age groups, we stratified type-specific VE by age group and time since vaccination.

SAS version 9.4 (SAS Institute, Inc.) or R version 4.1.0 (R Foundation for Statistical Computing) were used to conduct analyses. These activities were reviewed and approved by institutional review boards (IRBs) at Kaiser Permanente Northern California and Kaiser Permanente Southern California (45 C.F.R. part 46.101(c); 21 C.F.R. part 56). The Westat IRB determined that the activities are non-research. Patient informed consent was not required.

A total of 79,374 ARI-associated hospitalizations and 308,389 ARI-associated ED/UC encounters were identified; 9,067 (11.4%) hospitalizations and 37,090 (12.0%) ED/UC encounters met ≥1 exclusion criterion (Supplementary Figure 1A and 1B). After exclusions, 70,307 (88.6%) hospitalizations and 271,299 (88.0%) ED/UC encounters were included in analyses. Among 70,307 hospitalizations, 3,500 individuals had >1 hospitalization during the study period. Among 271,299 ED/UC encounters, 15,707 individuals had >1 ED/UC encounter.

Influenza activity peaked in late December to early January (Supplementary Figures 2A–2D). Of influenza cases, 48,757 (75.7%) were influenza-A-positive, 15,862 (24.6%) were influenza-B-positive, with 172 (0.3%) mixed A and B infections. The proportion of influenza B cases was higher in children and adolescents (34.4% of cases) than in adults (20.9% of cases).

Of 3,479 ARI-associated hospitalizations in children and adolescents, 340 (9.8%) were influenza cases and 3,139 (90.2%) were test-negative controls; influenza positivity was 5.3% among children aged 6 months-4 years and 16.6% among those aged 5–17 years. Proportions of hospitalizations among patients with ≥1 documented underlying medical condition were similar for influenza cases (63.8%) and controls (65.1%) [Table 1]. Overall, 1,270 (36.5%) hospitalized patients had received influenza vaccination (18.5% of cases vs 38.5% of controls, SMD = 0.45). Among vaccinated patients, median time since vaccination was 96 days; 91 days for those aged 6 months-4 years and 110 days for those aged 5–17 years.

Among 70,521 ARI-associated ED/UC encounters in children and adolescents, 17,493 (24.8%) were cases and 53,028 (75.2%) were controls; influenza positivity was 14.8% among children aged 6 months-4 years and 32.9% among those aged 517 years (Table 1). Overall, 19,728 (28.0%) had received influenza vaccination prior to the encounter. Children aged 6 months-4 years were more likely to be vaccinated than those aged 517 years (34.3% vs 22.9%, SMD = 0.28). Cases were less likely to be vaccinated than controls (15.4% vs 32.1%, SMD = 0.40). Among vaccinated patients, median time since vaccination was 91 days; 86 days for those aged 6 months-4 years and 98 days for those aged 5–17 years.

Across care settings, 90.0% of vaccinated children with known vaccine product received standard-dose, egg-based inactivated vaccine, 6.8% received cell-culture-based vaccine, 2.9% live-attenuated influenza vaccine, and 0.2% another product type (Supplementary Table 3).

VE against pediatric influenza-associated hospitalization was 58% (95% confidence interval [95% CI]: 44–69%); 71% (95% CI: 51–83%) for children aged 6 months-4 years and 49% (95% CI: 27–65%) for those aged 5–17 years (Figure 1). VE against influenza B viruses (85% [95% CI: 72–93%]) was higher than against influenza A viruses (44% [95% CI: 23–60%]). VE against ICU admission was 43% (95% CI: −6–70%).

Estimates of VE against influenza-associated ED/UC encounters were consistent with VE against hospitalization and ICU admission. Overall VE against ED/UC encounters was 58% (95% CI: 56–60%); 65% (95% CI: 62–68%) for children aged 6 months-4 years and 54% (95% CI: 51–57%) for children aged 5–17 years (Figure 1). VE against influenza B-associated ED/UC encounters (74% [95% CI: 72–77%]) was higher than against influenza A-associated illness (49% [95% CI: 46–51%]). VE in ED and UC settings was similar (59% and 58%, respectively).

Of 66,828 ARI-associated hospitalizations in adults, 5,721 (8.6%) were influenza cases and 61,107 (91.4%) were controls; influenza positivity was 11.3% among adults aged 18–64 years and 7.2% among adults aged ≥65 years (Table 2). Median age was 67 years for cases and 72 years for controls, and most patients had ≥1 documented underlying medical condition (86.4% of cases and 92.0% of controls). Among hospitalized adults, 32,455 (48.6%) were vaccinated, including 35.1% of cases versus 49.8% of controls (SMD = 0.30). Of those vaccinated, median time since vaccination was 107 days; 103 days for those aged 18–49 years, 103 days for those aged 50–64 years, and 109 days for those aged ≥65 years. Of hospitalized cases, 824 (14.4%) were admitted to an ICU and 190 (3.3%) died during hospitalization.

Among 200,778 ARI-associated ED/UC encounters in adults, 40,893 (20.4%) were influenza cases and 159,885 (79.6%) were controls; influenza positivity was 24.5% among adults aged 18–64 years and 11.4% among adults aged ≥65 years. Cases were younger on average than controls (median age 42 vs 54 years) and less likely to have ≥1 documented underlying medical condition (20.5% of cases vs 36.1% of controls, SMD = 0.35; Table 2). Overall, 76,988 (38.3%) were vaccinated (23.5% of cases vs 42.1% of controls, SMD = 0.40). Among vaccinated adults, median time since vaccination was 103 days; 98 days for those aged 18–49 years, 101 days for those aged 50–64 years, and 106 days for those aged ≥65 years.

Across sites, most (85.5%) vaccinated adults aged 18–64 years with known vaccine type received standard-dose, egg-based inactivated vaccine (Supplementary Table 3). Most (90.3%) older adults received a high-dose inactivated or adjuvanted vaccine, which are preferentially recommended products for older adults [14].

VE against influenza-associated hospitalization in adults was 39% (95% CI: 35–43%); 51% (95% CI: 42–60%) for adults aged 18–49 years, 40% (95% CI: 32–48%) for adults aged 50–64 years, and 36% (95% CI: 31–41%) for adults aged ≥65 years (Figure 2). VE against influenza B viruses (67% [95% CI: 54–76%]) was higher than against influenza A viruses (37% [95% CI: 32–41%]). VE against critical illness (ICU admission and/or death) was 41% (95% CI: 30–49%); 41% (95% CI: 31–50%) against ICU admission and 50% (95% CI: 31–65%) against in-hospital death.

As observed for pediatric patients, VE against ED/UC encounters was similar to VE against hospitalization and ICU admission among adult age groups. VE against influenza-associated ED/UC encounters was 47% (95% CI: 46–49%); 54% (95% CI: 53–56%) for ages 18–49 years, 44% (95% CI: 40–47%) for ages 50–64 years, and 37% (95% CI: 34–40%) for adults aged ≥65 years (Figure 2). VE against influenza -associated ED/UC encounters among adults was 75% (95% CI: 72–77%) for influenza B versus 41% (95% CI: 39–42%) for influenza A.

In analyses of time since vaccination, vaccination provided significant protection against hospitalizations and ED/UC visits through ≥120 days after vaccination (Figure 1–3, Supplementary Table 4). Among children, we observed no significant differences in VE against hospitalization at 14–59 days (50% [95% CI: 18–71%]) versus ≥120 days versus (67% [95% CI: 45–81%]) after vaccination (Figure 1). VE against ED/UC encounters was 63% (95% CI: 60–66%) at 14–59 days versus 56% (95% CI: 53–59%) at 60–119 and 57% (95% CI: 53–60%) ≥120 days after vaccination. Type-specific VE estimates stratified by age group and time since vaccination are shown in Figure 3B and Supplementary Table 4. For children and adolescents, VE against influenza A-associated encounters trended downward with greater time since vaccination, with most difference observed for encounters ≥60 days since vaccination, although no consistent trend was observed against influenza B-associated encounters.

Among hospitalized adults, VE at 14–59 days after vaccination (49% [95% CI: 42–55%]) was higher than at 60–119 and ≥120 days after vaccination (Figure 2). Against influenza-associated ED/UC encounters, VE was lower with increased time since vaccination (e.g., 57% [95% CI: 55–60%] at 14–59 days vs 48% [95% CI: 45–50%] at ≥120 days since vaccination). Within strata of time since vaccination, VE against influenza A- and B-associated encounters tended to be lower in older compared to younger adults (Figure 3, Supplementary Table 4).