Researchers may have uncovered the mechanisms contributing to lower COVID-19 vaccine responses among patients receiving tumor necrosis factor (TNF) inhibitors, according to a new study published by Garner-Spitzer et al in eBioMedicine. In the prospective study, researchers enrolled patients with inflammatory bowel disease (IBD) and healthy controls; both groups received COVID-19 vaccines and subsequent booster shots after 6 months. They then analyzed the antibodies, baseline B-cell and T-cell subsets, kinetics of Spike-specific B memory cells, and the distributions of activated circulating T-follicular helper cell subsets prior to and following receipt of the booster shots. The researchers found that the patients with IBD who were treated with anti–TNF-α therapies demonstrated lower antibody levels and quicker waning of antibody response compared to patients with IBD who were treated with α4β7-integrin antagonists as well as controls. Patients receiving anti–TNF-α agents also had a lower number of naive B cells vs expanded plasmablasts at baseline; reduced and undetectable Spike-specific B memory cells after their second vaccine doses and 6 months, respectively; and absent circulating T-follicular helper cell activation—which led to extrafollicular immune responses and minimal B memory cell diversification. The researchers concluded that patients receiving anti–TNF-α therapies—such as etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab—may require personalized COVID-19 vaccination schedules to increase their antibody levels and antibody response durations.