Pre-existing and <i>de novo</i> humoral immunity to SARS-CoV-2 in humans

TLDR

Human coronaviruses are endemic and cause mild respiratory illness, but the zoonotic emergence of SARS‑CoV‑2, which lacks pre‑existing immunity in humans, led to a rapid global pandemic. The study aims to differentiate pre‑existing from de‑novo humoral responses to SARS‑CoV‑2 to better understand susceptibility and disease course. Researchers employed multiple antibody assays—including flow cytometry, enzyme immunoassays, and neutralization tests—to detect spike‑protein‑reactive antibodies in uninfected and infected individuals. Pre‑existing IgG antibodies targeting the S2 subunit were common in uninfected children and adolescents, while infection induced higher IgG titers against both S1 and S2, plus IgM/IgA, and uninfected sera displayed neutralizing activity comparable to patient sera.

Abstract

Abstract Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections 1 . 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 proportions 2,3 . 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.