Single-component multilayered self-assembling protein nanoparticles displaying extracellular domains of matrix protein 2 as a pan-influenza A vaccine

The development of a cross-protective pan-influenza A vaccine remains a significant challenge. Here, we designed and characterized single-component, self-assembling protein nanoparticles (1c SApNPs) presenting the conserved extracellular domain of matrix protein 2 (M2e) from influenza A viruses of human and other hosts. Vaccination with tandem repeats of M2e (M2ex3) displayed on 1c-SApNPs demonstrated higher survival and lower weight loss compared to the soluble M2ex3 antigen against lethal challenges of H1N1 and H3N2 in mice. The mechanism of vaccine-induced adaptive immunity was also investigated in mice. Compared with the soluble M2ex3 antigen, the M2ex3 I3-01v9a 1c-SApNP formulated with a squalene-based adjuvant showed 672 times longer follicular retention, 31 times greater exposure within follicular dendritic cell networks, and up to 2.5 times stronger germinal center reactions in lymph nodes. By inducing robust and durable M2e specific functional antibody and T cell responses, the M2ex3-presenting I3-01v9a 1c-SApNP provides a promising pan-influenza A vaccine candidate. ONE-SENTENCE SUMMARY Protein nanoparticles displaying tandem M2e elicit robust and durable immunity that may protect against influenza A viruses of diverse origins.

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