Clinical Report: Evaluating the Common 40%–60% Estimate of Influenza Vaccine Effectiveness

Overview

This meta-analysis combined 18 end-of-season influenza vaccine effectiveness (VE) estimates from the US Influenza Vaccine Effectiveness Network for 2004–2005 through 2023–2024, representing 96,335 participants. Overall pooled VE was 41.3% (95% CI, 35.6%–46.5%), but season-to-season heterogeneity was substantial and the 95% prediction interval for one future season was 15.6%–59.3%. VE was within the commonly cited 40%–60% range in 9 of 18 seasons and below 40% in the other 9.

Background

The CDC has assessed seasonal influenza VE through the US Influenza Vaccine Effectiveness Network since 2004, using observational studies of medically attended influenza. VE is commonly described as 40%–60% when vaccine strains closely match circulating viruses, and this interval is widely used as a benchmark for expected performance. The analysis examined whether that heuristic characterizes performance across historical US seasons, including seasons with reported antigenic mismatch. The source reports that the network uses a standardized test-negative design.

Data Highlights

Key Findings

• The analysis included 18 published end-of-season estimates; estimates were unavailable for 2008–2009 and 2020–2021, and no final estimate after 2023–2024 had been published at the time described.
• Overall pooled VE was 41.3% (95% CI, 35.6%–46.5%), with substantial heterogeneity across seasons (I² = 82.8%; Cochran Q P < .001).
• The 95% prediction interval for VE in one future season was 15.6%–59.3%.
• Exactly half of the included seasons had VE estimates below 40%; the other half were within 40%–60%, and none exceeded 60%.
• Antigenic mismatch in at least one vaccine component was reported in 11 seasons (61%); in 10 of those seasons, the mismatch involved a predominant or codominant strain.
• Pooled VE was 36.2% in seasons with reported mismatch and 50.4% in seasons without reported mismatch; the subgroup difference was statistically significant (P = .001).

Clinical Implications

The authors’ analysis indicates that the 40%–60% interval did not encompass all historical season-specific estimates: half were below 40%, and the prediction interval extended from 15.6% to 59.3%. The source also reports lower pooled VE in seasons with reported antigenic mismatch than in seasons without reported mismatch; these estimates describe the included seasons and do not provide participant-level subgroup results.

Conclusion

Across 18 US Flu VE Network seasons, pooled VE was 41.3%, while substantial between-season variation meant that the commonly cited 40%–60% range did not describe every season. Reported antigenic mismatch was associated with lower pooled VE in the subgroup analysis.

Related Resources & Content

1. JAMA Network Open, Year not stated -- Evaluating the Common 40%–60% Estimate of Influenza Vaccine Effectiveness: A Meta-Analysis
2. CDC/ACIP, 2025 -- Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2025–26 Influenza Season
3. CDC, 2025 -- Interim Estimates of 2024–2025 Seasonal Influenza Vaccine Effectiveness — Four Vaccine Effectiveness Networks, United States, October 2024–February 2025
4. Kaiser Family Foundation (KFF) — Estimating Effectiveness of Influenza and COVID-19 Vaccines: The “Test-Negative” Design
5. The Journal of Infectious Diseases — Estimating Standard-Dose and High-Dose Fluzone Vaccine Efficacies for Influenza A Based on Hemagglutination Inhibition Titers
6. American Journal of Epidemiology — Assessing the Community-Level Indirect Impact of Influenza Vaccination: A Combined Approach Utilizing Mathematical Modeling and Bias Evaluation
7. Open Forum Infectious Diseases — Assessing the Efficacy of the 2023 Southern Hemisphere Influenza Vaccine Against Outpatient Influenza-Like Illness: Findings from a Multi-Nation Test-Negative Study
8. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2025–26 Influenza Season
9. Interim Estimates of 2024–2025 Seasonal Influenza Vaccine Effectiveness — Four Vaccine Effectiveness Networks, United States, October 2024–February 2025
10. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2025–26 Influenza Season
11. Testing the 40% to 60% Influenza Vaccine Effectiveness Heuristic: A Meta-Analysis | Infectious Diseases | JAMA Network Open | JAMA Network
12. Vaccine Effectiveness Against Influenza A(H1N1), A(H3N2), and B–Associated Hospitalizations — United States, September 1, 2023–May 31, 2024
13. Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025.