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 2

Transcriptomic analysis reveals altered proportions of S-specific memory B cell subsets in IBD patients treated with anti-TNF.

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Transcriptomic analysis reveals altered proportions of S-specific memory...
(A) UMAP of S-specific memory B cells (MBC). Clusters are colored by subtype: C1, classical MBC; C2, marginal zone–like (MZ) B cells; C3, atypical MBC. Total number of individuals: n = 12 (healthy controls n = 3, patients with IBD treated with anti-TNF n = 5, patients with IBD treated with anti-IL-12/23 n = 4); total cell count: n = 1,268. (B) UMAP of S-specific MBCs separated by timepoint: 3–4 months after dose 2 (n cells = 824) or 3–4 months post dose 3 (n cells = 444). (C) UMAP of S-specific MBCs separated by timepoint and by study group: MBC after vaccine dose 2 in patients with IBD treated with anti-IL-12/23 (n cells = 215); MBC after vaccine dose 3 in patients with IBD treated with anti-IL-12/23 (n cells = 256); MBC after vaccine dose 2 in IBD patients treated with anti-TNF (n cells = 252); MBC after vaccine dose 3 in patients with IBD treated with anti-TNF (n cells = 125); MBC after vaccine dose 2 in the healthy control group (n cells = 357); MBC after vaccine dose 3 in the healthy control group (n cells = 63). (D) DotPlot depicting the expression of selected genes. Dot size corresponds to the percentage of cells expressing the gene. Color intensity of the dots corresponds to the average expression across cells, where “0.0” represents the mean expression across the whole dataset. (E) Percentage of S-specific MBCs of each subset. Each dot represents one individual. Data represent median ± 95% CI. (F) Permutation tests were utilized to compare the proportion of S-specific MBCs classified as each MBC subset between study groups. The values colored in grey are nonsignificant; values colored in black are significant (FDR < 0.05 & absolute value of log2(fold difference) > 0.58. (A–F) Anti-IL-12/23 IBD, patients with IBD treated with anti-IL-12/23; anti-TNF IBD, patients with IBD treated with anti-TNF.