Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses

Moin, S. M.; Boyington, J. C.; Boyoglu-Barnum, S.; Gillespie, R. A.; Cerutti, G.; Cheung, C. S.-F.; Cagigi, A.; Gallagher, J. R.; Brand, J.; Prabhakaran, M.; Tsybovsky, Y.; Stephens, T.; Fisher, B. E.; Creanga, A.; Ataca, S.; Rawi, R.; Corbett, K. S.; Crank, M. C.; Gorman, J.; McDermott, A. B.; Harris, A. K.; Zhou, T.; Kwong, P. D.; Shapiro, L.; Mascola, J. R.; Graham, B. S.; Kanekiyo, M.

doi:10.1101/2022.02.11.480115

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bioRxiv · 10.1101/2022.02.11.480115

Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses

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Abstract

Current influenza vaccines predominantly induce immunity to the hypervariable viral hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, antigenic sites on the conserved HA stem are subdominant and harbor a supersite which is targeted by broadly neutralizing antibodies (bnAbs), making it a prime target for universal vaccines. Here, we show that co-immunization of two stem immunogens derived from influenza A group 1 and 2 HAs elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and conferred protection from viruses including H5N1 and H7N9. Genetic and structural analyses revealed a remarkable convergent evolution between macaque and human bnAbs, illustrating the biophysical constraints for acquiring immunoglobulins with cross-group specificity. Co-immunization of stem immunogens elicits not only group-specific protective immunity, but also cross-group bnAb responses, and represents a step towards broadly protective influenza vaccines.

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Moin, S. M., Boyington, J. C., Boyoglu-Barnum, S., Gillespie, R. A., Cerutti, G., Cheung, C. S.-F., Cagigi, A., Gallagher, J. R., Brand, J., Prabhakaran, M., Tsybovsky, Y., Stephens, T., Fisher, B. E., Creanga, A., Ataca, S., Rawi, R., Corbett, K. S., Crank, M. C., Gorman, J., McDermott, A. B., Harris, A. K., Zhou, T., Kwong, P. D., Shapiro, L., Mascola, J. R., Graham, B. S., Kanekiyo, M.. 2022-02-12. Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses. https://doi.org/10.1101/2022.02.11.480115

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