Synergistic effect of non-neutralizing antibodies and interferon-γ for cross-protection against influenza

Current influenza vaccines do not typically confer cross-protection against antigenically mismatched strains. To develop vaccines conferring broader cross-protection, recent evidence indicates the crucial role of both cross-reactive antibodies and viral-specific CD4⁺ T cells; however, the precise mechanism of cross-protection is unclear. Furthermore, adjuvants that can efficiently induce cross-protective CD4⁺ T cells have not been identified. Here we show that CpG oligodeoxynucleotides combined with aluminum salts work as adjuvants for influenza vaccine and confer strong cross-protection in mice. Both cross-reactive antibodies and viral-specific CD4⁺ T cells contributed to cross-protection synergistically, with each individually ineffective. Furthermore, we found that downregulated expression of Fcγ receptor IIb on alveolar macrophages due to IFN-γ secreted by viral-specific CD4⁺ T cells improves the activity of cross-reactive antibodies. Our findings inform the development of optimal adjuvants for vaccines and how influenza vaccines confer broader cross-protection.