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

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

A high-resolution understanding of the antibody response to SARS-CoV-2 is important for the design of effective diagnostics, vaccines and therapeutics. However, SARS-CoV-2 antibody epitopes remain largely uncharacterized, and it is unknown whether and how the response may cross-react with related viruses. Here, we use a multiplexed peptide assay (‘PepSeq’) to generate an epitope-resolved view of reactivity across all human coronaviruses. PepSeq accurately detects SARS-CoV-2 exposure and resolves epitopes across the Spike and Nucleocapsid proteins. Two of these represent recurrent reactivities to conserved, functionally-important sites in the Spike S2 subunit, regions that we show are also targeted for the endemic coronaviruses in pre-pandemic controls. At one of these sites, we demonstrate that the SARS-CoV-2 response strongly and recurrently cross-reacts with the endemic virus hCoV-OC43. Our analyses reveal new diagnostic and therapeutic targets, including a site at which SARS-CoV-2 may recruit common pre-existing antibodies and with the potential for broadly-neutralizing responses.