Preexisting cross-reactivity to SARS-CoV-2 occurs in the absence of prior viral exposure. However, this has been difficult to quantify at the population level due to a lack of reliably defined seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that about 0.6% of nontriaged adults from the greater Vancouver, Canada, area between May 17 and June 19, 2020, showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive and false-negative test results. Using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determined that more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-binding domain (RBD), N-terminal domain (NTD), or the nucleocapsid (N) protein from SARS-CoV-2. This seroreactivity was evenly distributed across age and sex, correlated with circulating coronaviruses’ reactivity, and was partially outcompeted by soluble circulating coronaviruses’ spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity broadly mapped to spike and to conserved nonstructural viral proteins. We conclude that most adults display preexisting antibody cross-reactivity against SARS-CoV-2, which further supports investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine responses.
The presence of preexisting SARS-CoV-2 antibody reactivity in uninfected individuals in the current study is consistent with the detection of T cell reactivity against SARS-CoV-2 in about 40% of uninfected individuals (3, 4). This raises an important question: what is the antigenic source of this antibody reactivity? Competition experiments and correlatives analyses indicate that it may, in part, be attributable to cross-reactivity against circulating coronaviruses. Most humans become infected with circulating coronaviruses by their second year of age (16). On the one hand, correlations between SARS-CoV-2 and antibody reactivity against either HKU1, N63L, or 229E, but not OC43, could reflect seasonal variations in recent exposure to common coronaviruses (10, 17). On the other hand, the high antibody reactivity to SARS-CoV in individuals in this study likely represents cross-reactivity due to the higher (>75%) sequence similarity between SARS-CoV and SARS-CoV-2 (18, 19), rather than a previous exposure to SARS-CoV.
In conclusion, this study reveals common preexisting, broadly reactive SARS-CoV-2 antibodies in uninfected adults. These findings warrant larger studies to understand how these antibodies affect the severity of COVID-19, as well as the quality and longevity of responses to SARS-CoV-2 vaccines.