Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans

Ng, Kevin W; Faulkner, Nikhil; Cornish, Georgina; Rosa, Annachiara; Harvey, Ruth; Hussain, Saira; Ulferts, Rachel; Earl, Christopher; Wrobel, Antoni; Benton, Donald; Roustan, Chloe; Bolland, William; Thompson, Rachael; Agua-Doce, Ana; Hobson, Philip; Heaney, Judith; Rickman, Hannah; Paraskevopoulou, Stavroula; Houlihan, Catherine F; Thomson, Kirsty; Sanchez, Emilie; Brealey, David; Shin, Gee Yen; Spyer, Moira J; Joshi, Dhira; Walker, Philip A; Kjaer, Svend; Riddell, Andrew; Moore, Catherine; Jebson, Bethany R; Marshall, Lucy R; Wilkinson, Meredyth G; Rosser, Elizabeth C; Radziszewska, Anna; Peckham, Hannah; Ciurtin, Coziana; Wedderburn, Lucy R; Beale, Rupert; Swanton, Charles; Gandhi, Sonia; Stockinger, Brigitta; McCauley, John; Gamblin, Steve; McCoy, Laura E; Cherepanov, Peter; Nastouli, Eleni; Kassiotis, George

Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections1. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19), is a recent zoonotic infection that has quickly reached pandemic proportions2,3. Zoonotic introduction of novel coronaviruses is thought to occur in the absence of pre-existing immunity in the target human population. Using diverse assays for detection of antibodies reactive with the SARS-CoV-2 spike (S) glycoprotein, we demonstrate the presence of pre-existing humoral immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. These were predominantly of the IgG class and targeted the S2 subunit. In contrast, SARS-CoV-2 infection induced higher titres of SARS-CoV-2 S-reactive IgG antibodies, targeting both the S1 and S2 subunits, as well as concomitant IgM and IgA antibodies, lasting throughout the observation period of 6 weeks since symptoms onset. SARS-CoV-2-uninfected donor sera also variably reacted with SARS-CoV-2 S and nucleoprotein (N), but not with the S1 subunit or the receptor binding domain (RBD) of S on standard enzyme immunoassays. Notably, SARS-CoV-2-uninfected donor sera exhibited specific neutralising activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes, according to levels of SARS-CoV-2 S-binding IgG and with efficiencies comparable to those of COVID-19 patient sera. Distinguishing pre-existing and de novo antibody responses to SARS-CoV-2 will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.