Background: Pre-existing antibody reactivity against SARS-CoV-2 in unexposed people is a potentially important consideration for COVID-19 severity and vaccine responses. However, it has been difficult to quantify due to a lack of reliable defined background titers in unexposed individuals.

Methods: We measured IgG against multiple SARS-CoV-2 antigens, SARS-CoV and other circulating coronavirus spike proteins using a highly sensitive multiplex assay, and total SARS-CoV-2 spike-specific antibodies (IgG/M/A) using a commercial CLIA assay in 276 adults from the Vancouver area, Canada between May 17th and June 19th 2020. Reactivity threshold in unexposed individuals were defined comparing to pre-pandemic sera and to sera from infants under 6 months of age.

Results: The seroprevalence from a SARS-CoV-2 exposure, adjusted for false-positive and false-negative test results, was 0.60% in our adult cohort. High antibody reactivity to circulating endemic coronaviruses was observed in all adults and was about 10-fold lower in infants under 6 months. Consistent with a waning of maternal antibodies, reactivity in infants decreased more than 50-fold eight months later. SARS-CoV-2 Spike, RBD, NTD or nucleocapsid antibody reactivity >100-fold above that of older infants was detected in the vast majority of unexposed adults and pre-pandemic sera. This antibody reactivity correlated with titers against circulating coronaviruses, but not with age, sex, or whether adults were healthcare workers.

Conclusion: A majority of unexposed adults have pre-existing antibody reactivity against SARS-CoV-2. The lack of similar antibody reactivity in infants where maternal antibodies have waned suggests that this cross-reactivity is acquired, likely from repeated exposures to circulating coronaviruses.