Reduced vaccine-induced germinal center outputs in patients with inflammatory bowel disease treated with anti-TNF biologics
Michelle W. Cheung, Samantha Xu, Janna R. Shapiro, Freda Qi, Melanie Delgado-Brand, Karen Colwill, Roya M. Dayam, Ying Liu, Jenny D. Lee, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Michelle W. Cheung, Samantha Xu, Janna R. Shapiro, Freda Qi, Melanie Delgado-Brand, Karen Colwill, Roya M. Dayam, Ying Liu, Jenny D. Lee, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
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Clinical Research and Public Health Immunology Infectious disease

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

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 patients with inflammatory bowel disease (IBD) who were treated with anti-TNF biologics exhibited decreased Spike-specific antibody responses compared with patients with IBD treated with anti-IL-12/23 or healthy controls, even after 4 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 patients with IBD treated with anti-TNF or anti-IL-12/23 and from people in the healthy control group.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 patients with IBD treated with anti-TNF, compared with patients with IBD treated with anti-IL-12/23 or people in the healthy control group. This decreased somatic hypermutation in Spike-specific MBCs in patients treated with anti-TNF 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 M. Dayam, Ying Liu, Jenny D. Lee, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts

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Figure 4

Biased BCR heavy and light chain variable gene usage in S-specific memory B cells.

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Biased BCR heavy and light chain variable gene usage in S-specific memor...
BCR-sequencing of people in the healthy control group (n = 3), patients with IBD treated with anti-IL-12/23 (n = 4), and patients with IBD treated with anti-TNF (n = 5), 3–4 months after dose 2 and 3. (A) Diversity (D) curve of S-specific MBCs grouped by study group (after dose 2 and dose 3 pooled). Diversity is calculated over a range of diversity orders, q (q = 1 species richness; q = 2 Shannon entropy; q = 3 Simpson’s index). Shading represents confidence intervals. (B) Pie charts showing MBC clonal expansion indicated for each patient and timepoint. MBCs were binned into rare clones (n = 1 cell), small (n = 2 cells), medium (2 < n cells ≤ 5), or large (5 < n ≤ 10). (C) Frequency of heavy chain variable genes and light chain κ and λ variable genes in each study group compared to the CoV-AbDab database (filtered for SARS-CoV-2 specific entries). Only genes found in at least 3% of 1 of the 4 comparison groups are plotted.