Kavli Affiliate: Robert Edwards
| Authors: R. Dilshan Malewana, Victoria Stalls, Aaron May, Xiaozhi Lu, David R Martinez, Alexandra Schafer, Dapeng Li, Maggie Barr, Laura L Sutherland, Esther Lee, Robert Parks, Whitney Edwards Beck, Amanda Newman, Kevin W Bock, Mahnaz Minai, Bianca M Nagata, C. Todd DeMarco, Thomas N Denny, Thomas H Oguin III, Wes Rountree, Yunfei Wang, Katayoun Mansouri, Robert J Edwards, Gregory D Sempowski, Amanda Eaton, Hiromi Muramatsu, Rory Henderson, Ying Tam, Christopher Barbosa, Juanjie Tang, Derek W Cain, Sampa Santra, Ian N Moore, Hanne Andersen, Mark G Lewis, Hana Golding, Robert Seder, Surender Khurana, David C Montefiori, Norbert Pardi, Drew Weissman, Ralph S Baric, Priyamvada Acharya, Barton F Haynes and Kevin O Saunders
| Summary:
Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.