Nonstabilized SARS-CoV-2 spike mRNA vaccination induces broadly neutralizing antibodies in nonhuman primates

Immunization with messenger RNA (mRNA) or viral vectors encoding spike protein with diproline substitutions (S-2P) were shown to provide protective immunity, curbing the COVID-19 pandemic. However, in light of the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can cause COVID-19, it is essential that we understand how immunization with spike protein elicits neutralizing antibodies (nAbs). Here, we compared immunization of macaques with mRNA vaccines expressing ancestral spike protein with or without diproline substitutions, showing that 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 protein lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOC pseudotyped viruses including Omicron XBB.1.5 in vitro, but lacked cross-sarbecovirus neutralization. Structural analysis showed that the macaque nAbs that could broadly neutralize VOCs bound to the same epitope as a human nAb, DH1193. In contrast, 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 mRNA vaccines lacking proline substitutions can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human sarbecoviruses or neutralize recent Omicron VOCs. Thus, the use of a nonstabilized spike protein design in some COVID-19 vaccines does not preclude the elicitation of broad sarbecovirus and broad VOC nAbs.

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Publication Details

Journal
Science Translational Medicine
Published
2025-06-11
DOI
https://doi.org/10.1126/scitranslmed.adn5651
Citations
1
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
1.40
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article

Nonstabilized SARS-CoV-2 spike mRNA vaccination induces broadly neutralizing antibodies in nonhuman primates

Aaron May, Priyamvada Acharya, David C. Montefiori, Dapeng Li et al.
1 citations
Science Translational Medicine
SARS-CoV-2 and COVID-19 Research
1.40
article

Nonstabilized SARS-CoV-2 spike mRNA vaccination induces broadly neutralizing antibodies in nonhuman primates

Aaron May, Priyamvada Acharya, David C. Montefiori, Dapeng Li, Ian N. Moore, Juanjie Tang, Victoria Stalls, Sampa Santra, Thomas N. Denny, David R. Martinez, Xiaozhi Lu, Lena Smith, Ralph Steven Baric, Hana Golding, Laura L. Sutherland, Maggie Barr, Yunfei Wang, Amanda Eaton, Amanda Newman, Rory Henderson, Mark G. Lewis, Mahnaz Minai, C. Todd DeMarco, Barton F. Haynes, Derek W. Cain, Katayoun Mansouri, Wes Rountree, Robert A. Seder, Ying K. Tam, Thomas H. Oguin, Norbert Pardi, Drew Weissman, Surender Khurana, Goda Baddage Rakitha Malewana, Kevin O. Saunders, Bianca M. Nagata, Alexandra Schäfer, Hiromi Muramatsu, Robert Parks, Christopher Barbosa, Hanne Andersen Elyard, Gregory D. Sempowski, Kevin W. Bock, Robert J. Edwards, Esther Lee, Whitney Edwards Beck
article en
1 citations

Abstract

Immunization with messenger RNA (mRNA) or viral vectors encoding spike protein with diproline substitutions (S-2P) were shown to provide protective immunity, curbing the COVID-19 pandemic. However, in light of the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can cause COVID-19, it is essential that we understand how immunization with spike protein elicits neutralizing antibodies (nAbs). Here, we compared immunization of macaques with mRNA vaccines expressing ancestral spike protein with or without diproline substitutions, showing that 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 protein lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOC pseudotyped viruses including Omicron XBB.1.5 in vitro, but lacked cross-sarbecovirus neutralization. Structural analysis showed that the macaque nAbs that could broadly neutralize VOCs bound to the same epitope as a human nAb, DH1193. In contrast, 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 mRNA vaccines lacking proline substitutions can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human sarbecoviruses or neutralize recent Omicron VOCs. Thus, the use of a nonstabilized spike protein design in some COVID-19 vaccines does not preclude the elicitation of broad sarbecovirus and broad VOC nAbs.

Science Translational MedicineVol. 17(802)
University of North Carolina at Chapel Hill (US), National Institutes of Health (US), Beth Israel Deaconess Medical Center (US), Center for Biologics Evaluation and Research (US), Duke University (US), Yale University (US), Bioqual (US), National Institute of Allergy and Infectious Diseases (US), Acuitas Therapeutics (Canada) (CA), University of Pennsylvania (US)
Openalex Percentile: Top 20%
SARS-CoV-2 and COVID-19 Research
1.40
DOISourceOpenAlex
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