Designed mosaic nanoparticles enhance cross-reactive immune responses in mice

Wang, E.; Cohen, A. A.; Caldera, L. F.; Keeffe, J. R.; Rorick, A. V.; Aida, Y. M.; Gnanapragasam, P. N. P.; Bjorkman, P. J.; Chakraborty, A. K.

doi:10.1101/2024.02.28.582544

bioRxiv · 10.1101/2024.02.28.582544

Designed mosaic nanoparticles enhance cross-reactive immune responses in mice

Wang, E.·Cohen, A. A.·Caldera, L. F.·Keeffe, J. R.·Rorick, A. V.·Aida, Y. M.·Gnanapragasam, P. N. P.·Bjorkman, P. J.·Chakraborty, A. K.

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Abstract

Using computational methods, we designed 60-mer nanoparticles displaying SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) by (i) creating RBD sequences with 6 mutations in the SARS-COV-2 WA1 RBD that were predicted to retain proper folding and abrogate antibody responses to variable epitopes (mosaic-2COMs; mosaic-5COM), and (ii) selecting 7 natural sarbecovirus RBDs (mosaic-7COM). These antigens were compared with mosaic-8b, which elicits cross-reactive antibodies and protects from sarbecovirus challenges in animals. Immunizations in naive and COVID-19 pre-vaccinated mice revealed that mosaic-7COM elicited higher binding and neutralization titers than mosaic-8b and related antigens. Deep mutational scanning showed that mosaic-7COM targeted conserved RBD epitopes. Mosaic-2COMs and mosaic-5COM elicited higher titers than homotypic SARS-CoV-2 Beta RBD-nanoparticles and increased potencies against some SARS-CoV-2 variants than mosaic-7COM. However, mosaic-7COM elicited more potent responses against zoonotic sarbecoviruses and highly mutated Omicrons. These results support using mosaic-7COM to protect against highly mutated SARS-CoV-2 variants and zoonotic sarbecoviruses with spillover potential.

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Wang, E., Cohen, A. A., Caldera, L. F., Keeffe, J. R., Rorick, A. V., Aida, Y. M., Gnanapragasam, P. N. P., Bjorkman, P. J., Chakraborty, A. K.. 2024-02-28. Designed mosaic nanoparticles enhance cross-reactive immune responses in mice. https://doi.org/10.1101/2024.02.28.582544

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