Reduced vaccine-induced germinal center outputs in inflammatory bowel disease patients treated with anti-TNF biologics

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Abstract

Background: Anti-TNF biologics are widely used to treat patients with immune-mediated inflammatory diseases. In mouse models, the complete absence of TNF impairs germinal center (GC) responses. Less is known about the impact of anti-TNF therapy on specific immune responses in humans. Widespread vaccination against SARS-CoV-2 offered an unprecedented opportunity to investigate the effects of biological therapies on responses to specific immunization. Previous work demonstrated that inflammatory bowel disease (IBD) patients treated with anti-TNF biologics exhibit decreased Spike-specific antibody responses compared to IBD patients treated with anti-IL-12/23 or healthy controls, even after four doses of mRNA vaccine. Methods: Here we analyzed humoral responses to SARS-CoV-2 immunization using single-cell RNA-Sequencing and flow cytometry of Spike-specific memory B cells (MBC), as well as avidity measurements of plasma antibodies from IBD patients treated with anti-TNF or anti-IL-12/23 or from healthy controls. Results: We observed decreased somatic hypermutation in the B cell receptors of Spike-specific MBCs and decreased antigen-specific MBC accumulation following SARS-CoV-2 mRNA vaccination in anti-TNF treated IBD patients, compared to IBD patients treated with anti-IL-12/23 or healthy controls. This decreased somatic hypermutation in Spike-specific MBCs in anti-TNF treated patients correlated with decreased and delayed antibody affinity maturation and reduced neutralization activity. Conclusion: These data provide in vivo evidence that anti-TNF, but not anti-IL-12/23, therapy impairs the quantity and quality of antigen-specific GC outputs in humans. Funding: Juan and Stefania Speck (donation) and by Canadian Institutes of Health Research (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711, VS1-175545, GA2-177716, GA1-177703 and CIHR FDN 143301 &143350.

Authors

Michelle W. Cheung, Samantha Xu, Janna R. Shapiro, Freda Qi, Melanie Delgado-Brand, Karen Colwill, Roya Dayam, Ying Liu, Jenny Choi, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts