Analysis of Serologic Cross-Reactivity Between Common Human Coronaviruses and SARS-CoV-2 Using Coronavirus Antigen Microarray

Saahir Khan; Rie Nakajima; Aarti Jain; Rafael Ramiro de Assis; Al Jasinskas; Joshua M. Obiero; Oluwasanmi Adenaiye; Sheldon Tai; Filbert Hong; Donald K. Milton; Huw Davies; Philip L. Felgner

This pilot study yields several insights into cross-reactivity of common human coronavirus antibodies for SARS-CoV-2 antigens. The antibodies to the S1 and RBD domains of spike protein are highly subtype-specific, consistent with the high variability in these sequences between different human coronaviruses. Conversely, the S2 domain of spike protein and NP protein are more cross-reactive, consistent with these sequences being highly conserved across coronaviruses. SARS-CoV-2 has caused a worldwide pandemic despite likely pre-existing cross-reactive antibodies to S2 domain and NP protein in most people, indicating that these antibodies are likely not protective, whereas antibodies to S1 and RBD domains are more likely to be protective. This observation favors a vaccination strategy based on S1 or RBD domains of spike protein over a vaccination strategy that also includes S2 domain or NP protein. In addition, S1 and RBD domains are more likely to generate subtype-specific serologic tests for population surveillance studies. In addition, a key unexplained finding during the SARS-CoV-2 epidemic has been the low incidence of infection in children aged 15 and younger. This observation generates two related hypotheses: adults may have pre-existing antibodies against antigenically distinct coronaviruses that produce an ineffective humoral response to SARS-CoV-2 infection (antibody-dependent enhancement as demonstrated for dengue virus), or children younger than 15 may have initially encountered a coronavirus that is more closely related to SARS-CoV-2 so are more protected against this infection (immunologic imprinting or original antigenic sin as demonstrated for influenza virus). Both of these hypotheses would be informed by comparing the level of cross-reactive coronavirus antibodies in pediatric and adult cohorts and correlating these antibodies with incidence of severe disease.