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Sci Transl Med
. 2025 Jun 11;17(802):eadn5651.
doi: 10.1126/scitranslmed.adn5651. Epub 2025 Jun 11. Nonstabilized SARS-CoV-2 spike mRNA vaccination induces broadly neutralizing antibodies in nonhuman primates
R Dilshan Malewana 1 2 , Victoria Stalls 1 3 , Aaron May 1 4 , Xiaozhi Lu 1 3 , David R Martinez 5 6 , Alexandra Schäfer 5 , Dapeng Li 1 3 , Maggie Barr 1 3 , Laura L Sutherland 1 3 , Esther Lee 1 3 , Robert Parks 1 3 , Whitney Edwards Beck 1 3 , Amanda Newman 1 3 , Kevin W Bock 7 , Mahnaz Minai 7 , Bianca M Nagata 7 , C Todd DeMarco 1 3 , Thomas N Denny 1 3 , Thomas H Oguin 3rd 1 3 , Wes Rountree 1 3 , Yunfei Wang 1 3 , Katayoun Mansouri 1 3 , Robert J Edwards 1 3 , Lena Smith 1 3 , Gregory D Sempowski 1 3 , Amanda Eaton 1 3 , Hiromi Muramatsu 8 , Rory Henderson 1 3 , Ying Tam 9 , Christopher Barbosa 9 , Juanjie Tang 10 , Derek W Cain 1 3 , Sampa Santra 11 , Ian N Moore 7 , Hanne Andersen 12 , Mark G Lewis 12 , Hana Golding 10 , Robert Seder 13 , Surender Khurana 10 , David C Montefiori 1 14 , Norbert Pardi 8 , Drew Weissman 15 , Ralph S Baric 5 , Priyamvada Acharya 1 4 14 , Barton F Haynes 1 2 3 , Kevin O Saunders 1 2 14 16
Affiliations
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.
. 2025 Jun 11;17(802):eadn5651.
doi: 10.1126/scitranslmed.adn5651. Epub 2025 Jun 11. Nonstabilized SARS-CoV-2 spike mRNA vaccination induces broadly neutralizing antibodies in nonhuman primates
R Dilshan Malewana 1 2 , Victoria Stalls 1 3 , Aaron May 1 4 , Xiaozhi Lu 1 3 , David R Martinez 5 6 , Alexandra Schäfer 5 , Dapeng Li 1 3 , Maggie Barr 1 3 , Laura L Sutherland 1 3 , Esther Lee 1 3 , Robert Parks 1 3 , Whitney Edwards Beck 1 3 , Amanda Newman 1 3 , Kevin W Bock 7 , Mahnaz Minai 7 , Bianca M Nagata 7 , C Todd DeMarco 1 3 , Thomas N Denny 1 3 , Thomas H Oguin 3rd 1 3 , Wes Rountree 1 3 , Yunfei Wang 1 3 , Katayoun Mansouri 1 3 , Robert J Edwards 1 3 , Lena Smith 1 3 , Gregory D Sempowski 1 3 , Amanda Eaton 1 3 , Hiromi Muramatsu 8 , Rory Henderson 1 3 , Ying Tam 9 , Christopher Barbosa 9 , Juanjie Tang 10 , Derek W Cain 1 3 , Sampa Santra 11 , Ian N Moore 7 , Hanne Andersen 12 , Mark G Lewis 12 , Hana Golding 10 , Robert Seder 13 , Surender Khurana 10 , David C Montefiori 1 14 , Norbert Pardi 8 , Drew Weissman 15 , Ralph S Baric 5 , Priyamvada Acharya 1 4 14 , Barton F Haynes 1 2 3 , Kevin O Saunders 1 2 14 16
Affiliations
- PMID: 40498855
- DOI: 10.1126/scitranslmed.adn5651
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.