Abstract
OBJECTIVES: Enhanced inactivated influenza vaccines (eIIV) aim to increase immunogenicity and protection compared with the widely used standard IIV (S-IIV). METHODS: We tested four vaccines in parallel, FluZone high dose, FluBlok and FluAd versus S-IIV in a randomised controlled trial of older adults and in a mouse infection model to assess immunogenicity, protection from lethal challenge and mechanisms of action. RESULTS: In older adults, FluAd vaccination stimulated a superior antibody profile, including H3-HA antibodies that were elevated for up to 1 year after vaccination, higher avidity H3HA IgG and larger HA stem IgG responses. In a mouse model, FluAd also elicited an earlier and larger induction of HA stem antibodies with increased germinal centre responses and upregulation and long-term expression of B-cell switch transcription factors. Long-term cross-reactive memory responses were sustained by FluAd following lethal heterosubtypic influenza challenge, with reduced lung damage and viral loads, coinciding with increased T- and B-cell recall. Advantages were also noted for the high-dose FluZone vaccine in both humans and mice. CONCLUSION: The early, broadly reactive and long-lived antibody response of FluAd indicates a potential advantage of this vaccine, particularly in years when there is a mismatch between the vaccine strain and the circulating strain of influenza viruses.