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J Exp Med
. 2025 Dec 1;222(12):e20251146.
doi: 10.1084/jem.20251146. Epub 2025 Oct 9. Common cold embecovirus imprinting primes broadly neutralizing antibody responses to SARS-CoV-2 S2
Siriruk Changrob 1 , Atsuhiro Yasuhara 1 , Suncheol Park 2 , Sandhya Bangaru 2 , Lei Li 1 , Chloe A Troxell 1 , Peter J Halfmann 3 , Steven A Erickson 4 , Nicholas J Catanzaro 5 , Meng Yuan 2 , Panpan Zhou 6 , Min Huang 1 , G Dewey Wilbanks 1 , Joshua J C McGrath 1 , Gagandeep Singh 7 , Sean A Nelson 1 , Yanbin Fu 1 , Nai-Ying Zheng 1 , Sofia M Carayannopoulos 1 , Haley L Dugan 4 , Dustin G Shaw 4 , Christopher T Stamper 4 , Maria Lucia L Madariaga 8 , Florian Krammer 7 9 10 , Raiees Andrabi 6 , Dennis R Burton 6 11 , Andrew B Ward 2 , Ian A Wilson 2 12 , Yoshihiro Kawaoka 3 13 14 , Patrick C Wilson 1
Affiliations
The S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is highly conserved across coronavirus strains and therefore is a potential pan-coronavirus vaccine target. However, antibodies targeting this region are typically non-neutralizing. We report herein that S2-targeting antibodies from patients who recovered from SARS-CoV-2 infection bound only closely related sarbecovirus subgenus strains and, like most known S2 antibodies, none of these were neutralizing. In contrast, first-exposure, severe acutely infected COVID-19 patients predominantly induced back-boosted antibody-secreting cells imprinted against past common cold coronavirus strain OC43 that were cross-reactive to as many as five subgenera of betacoronavirus strains and gave rise to antibodies that were neutralizing and protective. The antibodies targeted two different sites: one defined by competition with stem helix antibodies, and the second to an underdescribed epitope at the apex of S2. These findings suggest that S2-targeted vaccines could strategically exploit controlled OC43 priming followed by SARS-CoV-2 boosting to enhance the breadth and quality of protective antibody responses.
. 2025 Dec 1;222(12):e20251146.
doi: 10.1084/jem.20251146. Epub 2025 Oct 9. Common cold embecovirus imprinting primes broadly neutralizing antibody responses to SARS-CoV-2 S2
Siriruk Changrob 1 , Atsuhiro Yasuhara 1 , Suncheol Park 2 , Sandhya Bangaru 2 , Lei Li 1 , Chloe A Troxell 1 , Peter J Halfmann 3 , Steven A Erickson 4 , Nicholas J Catanzaro 5 , Meng Yuan 2 , Panpan Zhou 6 , Min Huang 1 , G Dewey Wilbanks 1 , Joshua J C McGrath 1 , Gagandeep Singh 7 , Sean A Nelson 1 , Yanbin Fu 1 , Nai-Ying Zheng 1 , Sofia M Carayannopoulos 1 , Haley L Dugan 4 , Dustin G Shaw 4 , Christopher T Stamper 4 , Maria Lucia L Madariaga 8 , Florian Krammer 7 9 10 , Raiees Andrabi 6 , Dennis R Burton 6 11 , Andrew B Ward 2 , Ian A Wilson 2 12 , Yoshihiro Kawaoka 3 13 14 , Patrick C Wilson 1
Affiliations
- PMID: 41066082
- DOI: 10.1084/jem.20251146
The S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is highly conserved across coronavirus strains and therefore is a potential pan-coronavirus vaccine target. However, antibodies targeting this region are typically non-neutralizing. We report herein that S2-targeting antibodies from patients who recovered from SARS-CoV-2 infection bound only closely related sarbecovirus subgenus strains and, like most known S2 antibodies, none of these were neutralizing. In contrast, first-exposure, severe acutely infected COVID-19 patients predominantly induced back-boosted antibody-secreting cells imprinted against past common cold coronavirus strain OC43 that were cross-reactive to as many as five subgenera of betacoronavirus strains and gave rise to antibodies that were neutralizing and protective. The antibodies targeted two different sites: one defined by competition with stem helix antibodies, and the second to an underdescribed epitope at the apex of S2. These findings suggest that S2-targeted vaccines could strategically exploit controlled OC43 priming followed by SARS-CoV-2 boosting to enhance the breadth and quality of protective antibody responses.