Persistence of functional memory B cells recognizing SARS-CoV-2 variants despite loss of specific IgG

Summary While some COVID-19 patients maintain SARS-CoV-2-specific serum IgGs for more than 6 months post-infection, others, especially mild cases, eventually lose IgG levels. We aimed to assess the persistence of SARS-CoV-2-specific B cells in patients who have lost specific IgGs and analyzed the reactivity of the immunoglobulins produced by these B cells. Circulating IgG memory B cells specific for SARS-CoV-2 were detected in all 16 patients 1–8 months post-infection, and 11 participants had specific IgA B cells. Four patients lost specific serum IgG after 5–8 months but had SARS-CoV-2-specific-B-cell levels comparable to those of seropositive donors. Immunoglobulins produced after in vitro differentiation blocked receptor-binding domain (RBD) binding to the cellular receptor ACE-2, indicating neutralizing activity. Memory-B-cell-derived IgGs recognized the RBD of B.1.1.7 similarly to the wild-type, while reactivity to B.1.351 and P.1. decreased by 30% and 50%, respectively. Memory-B-cell differentiation into antibody-producing cells is a more sensitive method for detecting previous infection than measuring serum antibodies. Circulating SARS-CoV-2 IgG memory B cells persist, even in the absence of specific serum IgG; produce neutralizing antibodies; and show differential cross-reactivity to emerging variants of concern. These features of SARS-CoV-2-specific memory B cells will help to understand and promote long-term protection.