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Published February 9, 2024 | Submitted
Discussion Paper Open

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

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 sarbecovirus response breadths elicited by mosaic-8b, admix-8b (8 homotypics), and homotypic SARS-CoV-2, finding greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate-mapping in which antibodies derived 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 with mosaic-8b boosting, 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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Acknowledgement

We thank Jesse Bloom (Fred Hutchinson) and Tyler Starr (University of Utah) for RBD libraries and help setting up DMS at Caltech, Noor Youssef (Harvard Medical School) and Ziyan Wu (Caltech) for radar plot Python scripts, Jost Vielmetter, Luisa Segovia, Annie Lam, and the Caltech Beckman Institute Protein Expression Center for protein production, Igor Antoshechkin and the Caltech Millard and Muriel Jacobs Genetics and Genomics Laboratory for Illumina sequencing, S. Alison Arnold, Connor Bowen, Sharon Versteeg, Jack E. Kay, Joseph Moores-Poole, and Vasilis Tsakonitis (Ingenza, Ltd.) for expressing and purifying Bacillus mi3 and Pichia RBDs, Marta Murphy for help making figures, the Viral Vector Core Facility (Oxford University) for ChAdOx1 nCoV-19, Helix Biotech for Pfizer-like WA1 and BA.5 mRNA-LNP, Jeffrey Ravetch (Rockefeller University) for the Moderna WA1 mRNA-LNP vaccine, Labcorp Drug Development (Denver, PA) for performing BALB/c mouse immunizations for the mRNA-LNP and ChAdOx1 nCoV-19 experiments, T. Kurosaki and T. Okada (U. Osaka, RIKEN-Yokohama) for S1pr2-CreERT2 BAC-transgenic mice, and Alain Townsend and Jack T. K. Tan (Oxford), Andrew DeLaitsch and Magnus Hoffmann (Caltech), and Bjorkman lab members for helpful discussions. These studies were funded by Wellcome Leap (P.J.B.), the National Institutes of Health: [P01-AI165075 (P.J.B.), R01AI119006 and R01AI173086 (G.D.V.), R01AI153064 (N.P.)], Bill and Melinda Gates Foundation INV-034638 (P.J.B.), the Coalition for Epidemic Preparedness Innovations (CEPI) (P.J.B., I.F.), the Merkin Institute for Translational Research (Caltech), and the Stavros Niarchos Foundation Institute (Rockefeller).

Conflict of Interest

P.J.B. and A.A.C. are inventors on a US patent application (17/523,813) filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work. A.I.R. and J.D.P. are inventors on a US patent (11,780,888) that covers the chimeric sequence of RBD fused to the HA2 stem of influenza hemagglutinin. A.J.G. is an inventor on a Fred Hutchinson Cancer Center-optioned technology related to DMS of the RBD of SARS-CoV-2 spike protein. L.M., S.B., R.C., C.S-A., and I.G.F. are inventors on U.S. Patent Applications (16/952,983) and (17/651,476) filed by Ingenza Ltd. that cover Bacillus and Pichia strains established to manufacture endotoxin-free vaccine products. J.H.E. is an employee of HDT Bio that provided the repRNA-LION vaccine. D.H.F. is a co-founder of Orlance, Inc. that is developing gene gun delivery of DNA and repRNA vaccines. S.B., R.C., M.Q.-A., E.R., C.S.-A., L.M., and I.G.F. are employees of Ingenza, LTD. P.J.B. and G.D.V. are scientific advisors for Vaccine Company, Inc, and P.J.B. is a scientific advisor for Vir Biotechnology. N.P. is named on patents describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022 and the mRNA technology advisory board of Pfizer in 2023 and is a member of the Scientific Advisory Board of AldexChem and Bionet-Asia. P.J.C.L. is an employee of Acuitas Therapeutics, a company developing LNP delivery systems for RNA therapeutics.

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Additional details

Created:
May 3, 2024
Modified:
May 3, 2024