Mosaic display of stable hemagglutinin monomers induces broad immune responses

Kim, H.; Min, S. C.; Lee, D. B.; Jeong, J. H.; Kim, E. J.; Maeng, J. Y.; Seok, J. H.; Lee, J.-H.; Jang, Y.; Jang, U. S.; Ysenbaert, T.; Catani, J. P. P.; Lee, J.; Lee, Y.; Kim, Y. K.; Lee, G.; Mun, J. Y.; Jun, H. S.; Baek, Y. H.; Saelens, X.; Chung, M. S.; Song, M.-S.; Kim, K. H.

doi:10.1101/2024.04.10.588945

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bioRxiv · 10.1101/2024.04.10.588945

Mosaic display of stable hemagglutinin monomers induces broad immune responses

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Abstract

The nature of the interplay between immunity and viral variation is infinitely adaptive. Infection frequently induces immune responses against variation-prone epitopes, rather than against spatially hidden conserved epitopes. It thus remains a substantial challenge to elicit the immune responses to the conserved epitopes providing broad-spectrum immunity. We developed an approach of scaffold-mediated mosaic display to present monomeric influenza virus hemagglutinins (HAs), which exposes highly conserved stem and interface epitopes. Stable monomers were rationally engineered from H1 and H3 subtypes and B type HA trimers, with amino acid mutations at the monomer-monomer interface and for disulfide bond formation, and fused to a self-assembling scaffold, to generate a mosaic HA monomer-displaying nanoparticle, 3HA-np. Immunization with 3HA-np induced broadly neutralizing antibodies (bnAbs) in mice and ferrets and protected against challenges with H1N1 and H3N2 viruses. Competitive immunoassays revealed that 3HA-np induced high interface- and stem-binding Ab titers as compared to head Ab titers, indicating that the monomeric and mosaic nature of 3HA-np elicit cross-reactive Abs. Our results suggest that exposure of the hidden conserved epitope by monomer-displaying nanoparticles is a promising approach to generate a universal influenza vaccine.

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Kim, H., Min, S. C., Lee, D. B., Jeong, J. H., Kim, E. J., Maeng, J. Y., Seok, J. H., Lee, J.-H., Jang, Y., Jang, U. S., Ysenbaert, T., Catani, J. P. P., Lee, J., Lee, Y., Kim, Y. K., Lee, G., Mun, J. Y., Jun, H. S., Baek, Y. H., Saelens, X., Chung, M. S., Song, M.-S., Kim, K. H.. 2024-04-15. Mosaic display of stable hemagglutinin monomers induces broad immune responses. https://doi.org/10.1101/2024.04.10.588945

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