Homologous and Variant-Specific Memory B-Cell and Antibody Responses after SARS-CoV-2 mRNA Vaccination

Abstract Importance A better understanding of the immune memory and functional humoral immunity directed at the emerging Variants of Concern (VoC) strains after SARS-CoV-2 vaccination is essential for predicting the longevity of heterotypic protection. Objective The aim of our study was to characterize functional humoral immunity (including memory B cell response) after COVID-19 mRNA vaccination and to determine/compare the reactivity of COVID-19 vaccine-induced memory B cells to the emerging SARS-CoV-2 Variants of Concern (VoC). Design, setting, participants and interventions We designed an exploratory longitudinal observational (convenience sample-based) study at Mayo Clinic, Rochester, MN that enrolled and followed naive subjects and recovered COVID-19 subjects from Olmsted County, MN and surrounding areas after COVID-19 vaccination in January-June 2021. The study enrolled 17 relatively healthy subjects, 59% females and 94% White/Non-Hispanic or Latino with median age at enrollment 41 years. The subjects received either the BNT162b2 (Pfizer/BioNtech) or mRNA-1273 (Moderna) vaccine (n=3) and provided a blood sample at baseline, at ∼3 weeks after their first vaccine dose/before the second dose, and at ∼2 weeks after the receipt of their second vaccine dose. Main outcomes and measures Spike-specific humoral and memory B cells responses were assessed over time after vaccination against the original Wuhan-Hu-1/vaccine and against emerging VoC strains/antigens. Results We observed a robust neutralizing antibody response after COVID-19 mRNA vaccination, but a reduction in the functional antibody activity to several of the emerging SARS-CoV-2 VoC. Consistent with this, we also found differences in the number of isotype-switched/IgG+ MBCs responding to homologous and variant receptor-binding domain/RBDs after vaccination. We found a reduction of MBCs reactive to RBDs of Beta, Gamma and Delta SARS-CoV-2 VoC strains. Conclusion and relevance In this exploratory study in subjects following receipt of COVID-19 mRNA vaccine, we found differences in antibody titers observed for VoCs after vaccination that are accompanied with, and can partially be explained by, decreased MBC reactivity against the VoCs. This can further attenuate the generated recall humoral immune response upon exposure to these variants. Key Points Question What is the reactivity of COVID-19 vaccine-induced memory B cells to the emerging SARS-CoV-2 Variants of Concern (VoC)? Findings In this longitudinal cohort study of subjects receiving COVID-19 mRNA vaccine we assessed memory B cell response and functional antibody titers. We found statistically significant differences between the frequencies of memory B cells responding to homologous and VoC receptor-binding domain/RBDs after vaccination. Meaning In concert with the lowered antibody response, the reduced memory B-cell response to VoC could translate to an increased susceptibility to the emerging SARS-CoV-2 variant strains in the face of waning immunity.