Altered germinal center outputs to SARS-CoV-2 mRNA vaccination in inflammatory bowel disease patients treated with anti-TNF biologics 2707

Abstract Description The impact of anti-cytokine therapies on vaccine-induced immunity is incompletely understood. The IMmune resPonse After Covid-19 vaccination during maintenance Therapy (IMPACT) study investigated the immunogenicity of the SARS-CoV-2 mRNA vaccines in patients with inflammatory bowel disease (IBD), treated with anti-TNF or anti-IL-12/23. Blood was collected pre and post 1-4 doses of BNT162b2 or mRNA-1273 vaccines. IBD patients showed greater waning of cellular and humoral immunity by 3 months post dose 2 compared to healthy controls (HC). Booster doses prolonged responses, albeit anti-TNF treated IBD patients showed reduced antibody titers across 4 vaccine doses. Spike (S)-specific memory B cells (MBCs) from HC, anti-TNF and anti-IL-12/23 treated IBD patients revealed predominant extrafollicular responses in anti-TNF treated patients, as indicated by higher proportions of marginal zone-like B cells and atypical MBCs, and lower proportions of classical MBCs. Anti-TNF treated patients also had lower plasma IgG:IgM ratios. MBCs from anti-TNF patients had less somatic hypermutation and their plasma IgG responses were of lower avidity. Thus, anti-TNF biologics impair humoral immunity to SARS-CoV-2 as revealed by low S-specific Ig titers, decreased affinity maturation, and extrafollicular-skewed memory responses, consistent with the inhibition of germinal center responses by TNF blockade. In contrast, treatment with anti-IL-12/23 had minimal impact on humoral immunity to vaccination. Funding Sources Supported by the Canadian Graduate Scholarship Doctoral Award (MWC), Canadian Institutes of Health research grants VR-1 172 711, GA2-177716 (to THW and ACG) and by a donation from Juan and Stefania Speck. THW holds the Canada Research Chair in Anti-viral Immunity at the University of Toronto; ACG is the Canada Research Chair in Functional Proteomics. Topic Categories Immune Mechanisms of Human Disease (HUM)