Immunogenicity of SARS-CoV-2 primary vaccination and boosters in patients with immune-mediated inflammatory diseases: Impact of immunosuppressive therapy

Introduction: Patients with immune-mediated inflammatory diseases (IMID) are at increased risk of severe COVID-19 infection. Their immunosuppressive treatment may lead to attenuated vaccine responses. In this study, we assessed the impact of specific immunosuppressive treatments on the immunogenicity of primary SARS-CoV-2 vaccination as well as booster vaccinations in IMID patients. Material and methods: We included participants with IMID from the Danish ENFORCE cohort with baseline sampling prior to SARS-CoV-2 vaccination. Participants were followed for two years, with scheduled visits prior to vaccine dose 2, day 90, 180, 365 and 730 as well as before and after each booster dose. At all visits, seroconversion rates and quantitative SARS-CoV-2 Spike IgG antibody levels were assessed. Vaccine hyporesponsiveness, defined as <2log₁₀ increase in SARS-CoV-2 Spike IgG levels from baseline, was evaluated at day 90 and again after the first booster. Results: We included 282 patients with IMID and 482 immunocompetent controls. At day 90, patients with IMID treated with anti-CD20 antibodies or fingolimod exhibited markedly reduced seroconversion rates (27 % and 60 %, respectively, vs 100 % for controls), significantly lower antibody levels (2251 AU/mL [95 % CI: 888–5703] and 1743 AU/mL [95 % CI:784–3873] vs 186,308 AU/mL [95 % CI, 171366–202,552]) and higher odds of vaccine hyporesponsiveness (odds ratio (OR) = 67.5 [95 % CI, 25.4–179.7] and 82.5 [95 % CI, 29.6–196.3]). This impaired response persisted throughout the follow-up period, and anti-CD20 antibodies and fingolimod treated patients never reached antibody titers comparable to day 90 titers in controls, despite repeated booster vaccinations. Conclusion: Anti-CD20 antibody treatment and fingolimod severely impair humoral vaccine responses in IMID patients. In contrast, IMID patients treated with Methotrexate, TNF-alpha inhibitors, or other immunosuppressants mounted efficient vaccine responses. These findings support that tailored vaccine schedules with early and frequent boosters are crucial to protect this high-risk population. Clinical Trial registration: EudraCT no, 2020–006003-42, NVK no. 1–10–72-337-20.