ABSTRACT
Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.
ABSTRACT
Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. We studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease and membranous nephropathy. The observed incidence during the vaccination campaign (Jan to Aug 2021) was not different from the expected incidence based on the years 2015 to 2019 (incidence rate ratio 0.86, 95%-credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients aged >18 years with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was 0.97 (95% CI 0.66-1.42, P=0.95) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within 4 weeks after vaccine did not differ clinically from the rest of the cohort. Results were consistent across all types of glomerulonephritis with the possible exception of minimal change disease. In conclusion, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies. Most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis are likely coincidental.