Designed mosaic nanoparticles enhance cross-reactive immune responses in mice

Eric Wang; Alexander A Cohen; Luis F Caldera; Jennifer R Keeffe; Annie V Rorick; Yusuf M Aida; Priyanthi N P Gnanapragasam; Pamela J Bjorkman; Arup K Chakraborty

doi:10.1101/2024.02.28.582544

Designed mosaic nanoparticles enhance cross-reactive immune responses in mice

bioRxiv [Preprint]. 2024 Feb 28:2024.02.28.582544. doi: 10.1101/2024.02.28.582544.

Authors

Eric Wang^{1

2}, Alexander A Cohen^{3

2}, Luis F Caldera^{3

2}, Jennifer R Keeffe³, Annie V Rorick³, Yusuf M Aida^{3

4}, Priyanthi N P Gnanapragasam³, Pamela J Bjorkman³, Arup K Chakraborty^{1

5

6

7

8

9}

Affiliations

¹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
² These authors contributed equally.
³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
⁴ Present address: School of Clinical Medicine, University of Cambridge, Hills Rd, Cambridge, CB2 0SP, UK.
⁵ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
⁶ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
⁷ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
⁸ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139.
⁹ Lead contact.

Abstract

1Using 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-2_COMs; mosaic-5_COM), and (ii) selecting 7 natural sarbecovirus RBDs (mosaic-7_COM). These antigens were compared with mosaic-8b, which elicits cross-reactive antibodies and protects from sarbecovirus challenges in animals. Immunizations in naïve and COVID-19 pre-vaccinated mice revealed that mosaic-7_COM elicited higher binding and neutralization titers than mosaic-8b and related antigens. Deep mutational scanning showed that mosaic-7_COM targeted conserved RBD epitopes. Mosaic-2_COMs and mosaic-5_COM elicited higher titers than homotypic SARS-CoV-2 Beta RBD-nanoparticles and increased potencies against some SARS-CoV-2 variants than mosaic-7_COM. However, mosaic-7_COM elicited more potent responses against zoonotic sarbecoviruses and highly mutated Omicrons. These results support using mosaic-7_COM to protect against highly mutated SARS-CoV-2 variants and zoonotic sarbecoviruses with spillover potential.

Keywords: RBD; SARS-CoV-2; antibody; computational methods; nanoparticle; protein design; sarbecovirus; vaccination.

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Preprint

Abstract

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