Abstract
Current influenza vaccines provide limited protection against circulating influenza A viruses. A universal influenza vaccine will eliminate the intrinsic limitations of the seasonal flu vaccines. Here we report methodology to generate double-layered protein nanoparticles as a universal influenza vaccine. Layered nanoparticles are fabricated by desolvating tetrameric M2e into protein nanoparticle cores and coating these cores by crosslinking headless HAs. Representative headless HAs of two HA phylogenetic groups are constructed and purified. Vaccinations with the resulting protein nanoparticles in mice induces robust long-lasting immunity, fully protecting the mice against challenges by divergent influenza A viruses of the same group or both groups. The results demonstrate the importance of incorporating both structure-stabilized HA stalk domains and M2e into a universal influenza vaccine to improve its protective potency and breadth. These potent disassemblable protein nanoparticles indicate a wide application in protein drug delivery and controlled release.
Highlights
Current influenza vaccines provide limited protection against circulating influenza A viruses
We found that layered protein nanoparticle (PNp) composed of structure-stabilized HA stalk domains from both HA groups, and novel constructed matrix protein 2 ectodomain (M2e), are highly immunogenic to induce immune protection against homosubtypic and heterosubtypic influenza A virus challenges
We have shown that PNps with small sizes induce significant upregulation of the pro-inflammatory cytokine IL-1β from dendritic cells compared to soluble antigens, potentially enhancing specific immune responses[33]
Summary
The induced M2e antibodies showed strong cross-reactivity to diverse M2e peptides including A/California/7/2009 (H1N1, p09) M2e, A/Vietnam/1203/2004 (H5N1, Vtn) M2e and A/Shanghai/2/2013 (H7N9, SH) M2e (Supplementary Table 1 and Supplementary Fig. 4b). Both Uni4C1- and Uni4C3-elicited sera bound strongly to HA homologous to the vaccine strain but weakly to heterologous HA (Fig. 2a, b). Immunizations with Uni4C13 but neither Uni4C1 nor Uni4C3 provided universally complete protection against lethal viral challenges (Fig. 3c–f) Both challenge strains reassortant H5N1 (rVn) and H7N9 (rSH) bear internal genes from PR8 H1N1, including the same PR8 M2e sequence (Supplementary Table 1).
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