Common cold embecovirus imprinting primes broadly neutralizing antibody responses to SARS-CoV-2 S2
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.
Authors
- Pan-Pan Zhou (ORCID: https://orcid.org/0000-0001-5740-4303)
- Ian A. Wilson (ORCID: https://orcid.org/0000-0002-6469-2419)
- Patrick C. Wilson (ORCID: https://orcid.org/0000-0002-3537-1245)
- Atsuhiro Yasuhara (ORCID: https://orcid.org/0000-0002-7781-0197)
- Sandhya Bangaru (ORCID: https://orcid.org/0000-0001-7994-4693)
- Meng Yuan (ORCID: https://orcid.org/0000-0001-9754-4503)
- Steven A. Erickson (ORCID: https://orcid.org/0000-0002-5260-9286)
- Joshua J.C. McGrath (ORCID: https://orcid.org/0000-0002-9267-5501)
- Christopher T. Stamper (ORCID: https://orcid.org/0000-0002-5568-8880)
- Siriruk Changrob (ORCID: https://orcid.org/0000-0002-1826-4333)
- Maria Lucia L. Madariaga (ORCID: https://orcid.org/0000-0002-2950-7230)
- G. Dewey Wilbanks
- Raiees Andrabi (ORCID: https://orcid.org/0000-0001-8837-7520)
- Nicholas Catanzaro (ORCID: https://orcid.org/0000-0002-0210-8440)
- Dennis R. Burton (ORCID: https://orcid.org/0000-0001-6711-9864)
- Gagandeep Singh (ORCID: https://orcid.org/0000-0001-5848-2741)
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Peter Halfmann (ORCID: https://orcid.org/0000-0002-1648-1625)
- Dustin G. Shaw (ORCID: https://orcid.org/0000-0003-3961-7588)
- Yoshihiro Kawaoka (ORCID: https://orcid.org/0000-0001-5061-8296)
- Yanbin Fu (ORCID: https://orcid.org/0000-0002-3424-4420)
- Chloe Troxell (ORCID: https://orcid.org/0009-0003-9647-324X)
- Lei Li (ORCID: https://orcid.org/0000-0002-8828-5199)
- Min Huang
- Sean A. Nelson (ORCID: https://orcid.org/0000-0002-9000-3496)
- Nai‐Ying Zheng
- Suncheol Park (ORCID: https://orcid.org/0000-0003-3910-6454)
- Sofia M. Carayannopoulos
- Haley L. Dugan
Institutions
- Semmelweis University (HU)
- University of North Carolina at Chapel Hill (US)
- Scripps Research Institute (US)
- International AIDS Vaccine Initiative (US)
- University of Wisconsin–Madison (US)
- Cornell University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Tokyo Health Care University (JP)
- University of Chicago (US)
- Children's Cancer and Blood Foundation (US)
- Institute of Virology of the Slovak Academy of Sciences (SK)
- Medical University of Vienna (AT)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1084/jem.20251146
- Citations
- 3
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 4.19