Mosaic sarbecovirus vaccination elicits cross-reactive responses in pre-immunized animals

Cohen, A. A.; Keeffe, J. R.; Schiepers, A.; Dross, S. E.; Greaney, A. J.; Rorick, A. V.; Gao, H.; Gnanapragasam, P. N. P.; Fan, C.; West, A. P.; Ramsingh, A. I.; Erasmus, J. H.; Pata, J. D.; Muramatsu, H.; Pardi, N.; Lin, P. J. C.; Baxter, S.; Cruz, R.; Quintanar-Audelo, M.; Robb, E.; Serrano-Amatriain, C.; Magneschi, L.; Fotheringham, I. G.; Fuller, D. H.; Victora, G. D.; Bjorkman, P. J.

doi:10.1101/2024.02.08.576722

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bioRxiv · 10.1101/2024.02.08.576722

Mosaic sarbecovirus vaccination elicits cross-reactive responses in pre-immunized animals

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Abstract

Immunization with mosaic-8b [60-mer nanoparticles presenting 8 SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs)] elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate-mapping in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19 vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.

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Cohen, A. A., Keeffe, J. R., Schiepers, A., Dross, S. E., Greaney, A. J., Rorick, A. V., Gao, H., Gnanapragasam, P. N. P., Fan, C., West, A. P., Ramsingh, A. I., Erasmus, J. H., Pata, J. D., Muramatsu, H., Pardi, N., Lin, P. J. C., Baxter, S., Cruz, R., Quintanar-Audelo, M., Robb, E., Serrano-Amatriain, C., Magneschi, L., Fotheringham, I. G., Fuller, D. H., Victora, G. D., Bjorkman, P. J.. 2024-02-09. Mosaic sarbecovirus vaccination elicits cross-reactive responses in pre-immunized animals. https://doi.org/10.1101/2024.02.08.576722

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