Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses

Jason T. Ladner, Sierra N. Henson, Annalee S. Boyle, Anna L. Engelbrektson, Zane W. Fink, Fatima Rahee, Jonathan D'ambrozio, Kurt E. Schaecher, Mars Stone, Wenjuan Dong, Sanjeet Dadwal, Jianhua Yu, Michael A. Caligiuri, Piotr Cieplak, Magnar Bjørås, Mona H. Fenstad, Svein A. Nordbø, Denis E. Kainov, Norihito Muranaka, Mark S. CheeSergey A. Shiryaev, John A. Altin

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


The SARS-CoV-2 proteome shares regions of conservation with endemic human coronaviruses (CoVs), but it remains unknown to what extent these may be cross-recognized by the antibody response. Here, we study cross-reactivity using a highly multiplexed peptide assay (PepSeq) to generate an epitope-resolved view of IgG reactivity across all human CoVs in both COVID-19 convalescent and negative donors. PepSeq resolves epitopes across the SARS-CoV-2 Spike and Nucleocapsid proteins that are commonly targeted in convalescent donors, including several sites also recognized in some uninfected controls. By comparing patterns of homologous reactivity between CoVs and using targeted antibody-depletion experiments, we demonstrate that SARS-CoV-2 elicits antibodies that cross-recognize pandemic and endemic CoV antigens at two Spike S2 subunit epitopes. We further show that these cross-reactive antibodies preferentially bind endemic homologs. Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous CoV exposures and which have the potential to raise broadly neutralizing responses.

Original languageEnglish (US)
Article number100189
JournalCell Reports Medicine
Issue number1
StatePublished - Jan 19 2021


  • SARS-CoV-2
  • antibody response
  • cross-reactivity
  • endemic CoVs
  • highly multiplexed serology

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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