Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates
Author:
Malewana R. DilshanORCID, Stalls Victoria, May Aaron, Lu Xiaozhi, Martinez David R., Schäfer Alexandra, Li Dapeng, Barr Maggie, Sutherland Laura L., Lee Esther, Parks Robert, Beck Whitney Edwards, Newman Amanda, Bock Kevin W., Minai Mahnaz, Nagata Bianca M., DeMarco C. Todd, Denny Thomas N., Oguin Thomas H., Rountree Wes, Wang Yunfei, Mansouri Katayoun, Edwards Robert J., Sempowski Gregory D., Eaton Amanda, Muramatsu Hiromi, Henderson Rory, Tam Ying, Barbosa Christopher, Tang Juanjie, Cain Derek W., Santra Sampa, Moore Ian N., Andersen Hanne, Lewis Mark G., Golding Hana, Seder Robert, Khurana Surender, Montefiori David C., Pardi Norbert, Weissman Drew, Baric Ralph S., Acharya Priyamvada, Haynes Barton F., Saunders Kevin O.ORCID
Abstract
ABSTRACTImmunization 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.One Sentence SummaryNon-stabilized SARS-CoV-2 Spike mRNA vaccination activated B cells that target either conserved epitopes on SARS-CoV-2 Omicron variants of concern, or cross-neutralizing epitopes on pre-emergent Sarbecoviruses.
Publisher
Cold Spring Harbor Laboratory
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