Cross-protection against highly pathogenic avian influenza H5N1 virus from seasonal influenza vaccines: a systematic review and meta-analysis of ferret studies

Clinical Snapshot

Key Findings

• P Value: p = 0.52 (comparison with H5N1 vaccines), p = 0.009 (vs seroprotective H5N1 vaccines)

• Effect Size: VE 73% for N1-containing seasonal vaccines vs 14.8% for non-N1 seasonal vaccines

• Primary Outcome: Vaccine efficacy against H5N1-related mortality

• Nnt Or Sensitivity: Seroprotection defined as neutralizing antibody titre ≥1:40; N1-containing vaccines achieved comparable efficacy to non-seroprotective H5N1 vaccines (63%, p = 0.29)

• Confidence Interval: 95% CI 54-84% for N1-containing seasonal vaccines

Clinical Application

High feasibility as seasonal influenza vaccines are widely available and routinely administered Relevant to Australian pandemic preparedness given TGA-approved seasonal vaccines contain N1 components; could inform ATAGI recommendations for high-risk populations pending human validation studies Potentially applicable to human populations at risk of H5N1 exposure, particularly those receiving N1-containing seasonal vaccines

Abstract

The recent surge in spillover events of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b to humans and mammals in North America has raised urgent pandemic concerns. Human H5N1 vaccines are unavailable in most countries. We synthesized data from ferret challenge trials to evaluate whether widely available seasonal influenza vaccines confer cross-protection against lethal H5N1 infection. We systematically searched PubMed, Embase, and Web of Science for ferret studies of lethal H5N1 challenge published up to 5 July 2025 (PROSPERO #CRD42024520346). Random-effects meta-analyses were conducted to compare vaccine efficacy (VE) of seasonal influenza vaccines and H5N1 vaccines against H5N1-related mortality. Seroprotection was defined as a neutralizing antibody titre of ≥1:40. We identified 35 studies (157 trials). Seasonal influenza vaccines without N1 did not confer significant cross-protection (five trials; VE 14.8%, 95% CI -3.6 to 30.0). In contrast, VE was 73% for N1-containing seasonal influenza vaccines (19 trials; 95% CI 54-84) and 77% for H5N1 vaccines overall (133 trials; 95% CI 72-82) (p = 0.52). The VE of N1-containing seasonal influenza vaccines was modestly lower than that of H5N1 vaccines with seroprotection (88%; 66 trials; 95% CI 84-91; p = 0.009), but comparable to H5N1 vaccines that did not achieve seroprotection (63%; 67 trials; 95% CI 52-71; p = 0.29). The VE of seasonal influenza vaccines against H5N1 was robust across sensitivity analyses, with no evidence of publication bias (p = 0.99). Seasonal influenza vaccines significantly reduce H5N1-associated mortality in ferret trials, suggesting the cross-protection potential of currently available vaccines. Human studies are warranted.

References

1. 1.Tseng, I., Huang, Y. C., Shih, W. L., Chou, C. H., Vermund, S. H., & Fang, C. T. (2026). Cross-protection against highly pathogenic avian influenza H5N1 virus from seasonal influenza vaccines: a systematic review and meta-analysis of ferret studies. Emerging Microbes & Infections. https://doi.org/10.1080/22221751.2026.2654278