Lower magnitude and faster waning of antibody responses to SARS-CoV-2 vaccination in anti-TNF-a-treated IBD patients are linked to lack of activation and expansion of cTfh1 cells and impaired B memory cell formation

Background Patients with inflammatory bowel disease (IBD) and healthy controls received primary SARS-CoV-2-mRNA vaccination and a booster after six months. Anti-TNF-alpha-treated patients showed significantly lower antibody (Ab) levels and faster waning than alpha 4 beta 7-integrin-antagonist recipients and controls. This prospective cohort study aimed to elucidate the underlying mechanisms on the basis of circulating T-follicular helper cells (cTfh) and B memory cells. Methods We measured SARS-CoV-2- Wuhan and Omicron specific Abs, B- and T-cell subsets at baseline and kinetics of Spike (S)-specific B memory cells along with distributions of activated cTfh subsets before and after primary and booster vaccination. Findings Lower and faster waning of Ab levels in anti-TNF-alpha treated IBD patients was associated with low numbers of total and naive B cells vs. expanded plasmablasts prior to vaccination. Along with their low Ab levels against Wuhan and Omicron VOCs, reduced S-specific B memory cells were identified after the 2nd dose which declined to non-detectable after 6 months. In contrast, IBD patients with alpha 4 beta 7-integrin-antagonists and controls mounted and retained high Ab levels after the 2nd dose, which was associated with a pronounced increase in S-specific B memory cells that were maintained or expanded up to 6 months. Booster vaccination led to a strong increase of Abs with neutralizing capacity and S-specific B memory cells in these groups, which was not the case in anti-TNF-alpha treated IBD patients. Of note, Ab levels and S-specific B memory cells in particular post-booster correlated with the activation of cTfh1 cells after primary vaccination. Interpretations The reduced magnitude, persistence and neutralization capacity of SARS-CoV-2 specific Abs after vaccination in anti-TNF-alpha-treated IBD patients were associated with impaired formation and maintenance of S-specific B memory cells, likely due to absent cTfh1 activation leading to extra-follicular immune responses and diminished B memory cell diversification. These observations have implications for patient-tailored vaccination schedules/vaccines in anti-TNF-alpha-treated patients, irrespective of their underlying disease. Copyright (c) 2023 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Patients with inflammatory bowel disease (IBD) receiving anti-TNF-alpha treatment showed lower and faster waning antibody levels after SARS-CoV-2 vaccination, likely due to impaired formation and maintenance of S-specific B memory cells. In contrast, IBD patients receiving alpha 4 beta 7-integrin antagonists and controls had higher and more persistent antibody levels, which correlated with the increased levels of S-specific B memory cells.