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

Abstract

Summary 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.

Impact of adjuvant: Trivalent vaccine with quadrivalent-like protection against heterologous Yamagata-lineage influenza B virus

“…While much of vaccine development focuses on neutralizing antibody activity, it is becoming appreciated that nonneutralizing antibodies also can play a role in an effective immune response against viruses such as influenza (46)(47)(48)(49)(50). A number of studies have indicated the role of cross-reactive nonneutralizing antibodies in providing cross-protection against antigenically divergent heterologous influenza viral strains (47, 50, 51).…”

Envelope virus-mimetic nanovaccines by hybridizing bioengineered cell membranes with bacterial vesicles

“…CD4 + T cells subsets, which orchestrate the immune response and help prime B cells during infection ( Chen et al., 2020a ), performed a more significant proliferation ( Figures 3 G and 3H). It was worth mentioning that interferon-gamma (IFN-γ), produced primarily by activated natural killer cells, Th1 cells, and CD8 + cytotoxic cells, is a pivotal moderator of cellular immunity to fight multiple pathogens ( Shibuya et al., 2021 ). The percentages of IFN-γ-secreting cells in both CD4 + and CD8 + T cells subsets in mice primed with HMVs were notably higher than that in mice treated with PBS ( Figures 3 I and 3J), suggesting that HMVs could modulate IFN-γ-mediated immune responses.…”

Sustained vaccine exposure elicits more rapid, consistent, and broad humoral immune responses to multivalent influenza vaccines

“…The extensive antibody range induced by the adjuvanted PNP hydrogel platform against varied strains and subtypes, poorly immunogenic NA antigens, as well as historically difficult HA antigen regions is evidence that sustained delivery can increase the diversity and potency of humoral responses to influenza vaccination [20] . A breadth of anti-HA antibodies is known to be protective against infection by the virus [18, 72] and furthermore increases the chance of gaining immunity that will be maintained against future mutations. The ease of use of our adjuvanted PNP hydrogel system, shown in this work to readily admix with commercial Fluzone, provides a promising way to “supercharge” current influenza vaccination infrastructure to better protect our global populations against both annual influenza and pandemic risks.…”