Antigenic structure of the human coronavirus OC43 spike reveals exposed and occluded neutralizing epitopes
Chuyan Wang1, Emma L. Hesketh2, Tatiana M. Shamorkina3, Wentao Li1,*, Peter J. Franken1, Dubravka Drabek4,5, Rien van Haperen4,5, Sarah Townend2, Frank J.M. van Kuppeveld1, Frank Grosveld4,5, Neil A. Ranson2, Joost Snijder3, Raooul J. de Groot1, Daniel L. Hurdiss1,#, Berend-Jan Bosch1,#
1. Virology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
2. Astbury Centre Structural Molecular Biology, School Molecular and Cellular Biology, Faculty Biological Sciences, University of Leeds, Leeds, UK
3. Biomolecular Mass Spectrometry & Proteomics, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands
4. Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands
Harbour BioMed, Rotterdam, The Netherlands
# Corresponding author
Human coronavirus OC43 is a globally circulating common cold virus sustained by recurrent reinfections. How it persists in the population and defies existing herd immunity is unknown. Here we focus on viral glycoprotein S, the target for neutralizing antibodies. In this work we studied the antigenic structure of the human coronavirus OC43 spike protein by characterizing the neutralizing capacity, binding sites and binding breadth of a panel of anti-OC43-S monoclonal antibodies using structural (cryo-EM and HDX-MS) and functional approaches.
We defined multiple vulnerable sites on the OC43 spike protein recognized by neutralizing monoclonal antibodies. Neutralizing antibodies are directed to the sialoglycan-receptor binding site in S1A domain, but, remarkably, also to S1B. The latter block infection yet do not prevent sialoglycan binding. While two distinct neutralizing S1B epitopes are readily accessible in the prefusion S trimer, other sites are occluded such that their accessibility must be subject to conformational changes in S during cell-entry. While non-neutralizing antibodies were broadly reactive against a collection of natural OC43 variants, neutralizing antibodies generally displayed restricted binding breadth. Collectively, these results provide a structural basis for understanding humoral immunity and adaptive evolution for this endemic human coronavirus.
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