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.

目前的流感疫苗通常不能针对抗原不匹配的毒株提供交叉保护。为了开发具有更广泛交叉保护的疫苗，最近的证据表明交叉反应抗体和病毒特异性 CD4 ⁺ T 细胞的关键作用；然而，交叉保护的确切机制尚不清楚。此外，尚未鉴定出能够有效诱导交叉保护性CD4 ⁺ T细胞的佐剂。在这里，我们证明 CpG 寡脱氧核苷酸与铝盐组合可作为流感疫苗的佐剂，并在小鼠中赋予强大的交叉保护作用。交叉反应抗体和病毒特异性 CD4 ⁺ T 细胞协同促进交叉保护，但各自无效。此外，我们发现，由于病毒特异性 CD4 ⁺ T 细胞分泌的 IFN-γ，肺泡巨噬细胞上 Fcγ 受体 IIb 的表达下调，从而提高了交叉反应抗体的活性。我们的研究结果为疫苗最佳佐剂的开发以及流感疫苗如何提供更广泛的交叉保护提供了信息。