Background. Autoimmune disease patients on immunosuppressants exhibit reduced humoral responses to primary COVID-19 vaccination. Booster vaccine responses and the effects of holding immunosuppression around vaccination are less studied. We evaluated the efficacy and safety of additional vaccination in mycophenolate mofetil/mycophenolic acid (MMF/MPA)-, methotrexate (MTX)-, and B cell-depleting therapy (BCDT)-treated autoimmune disease patients, including the impact of withholding MMF/MPA and MTX.

Methods. In this open-label, multicenter, randomized trial, 22 MMF/MPA-, 26 MTX-, and 93 BCDT-treated autoimmune disease patients with negative or suboptimal antibody responses to initial COVID-19 vaccines (BNT162b2, mRNA-1273, or AD26.COV2.S) received a homologous booster. MMF/MPA and MTX participants were randomized (1:1) to continue or withhold treatment around vaccination. The primary outcome was the change in anti-Wuhan-Hu-1 receptor-binding domain (RBD) concentrations at 4 weeks post-additional vaccination. Secondary outcomes included adverse events, COVID-19 infections, and autoimmune disease activity through 48 weeks.

Results. Additional vaccination increased anti-RBD concentrations in MMF/MPA and MTX patients, irrespective of whether immunosuppression was continued or withheld. BCDT-treated patients also demonstrated increased anti-RBD concentrations, albeit lower than MMF/MPA- and MTX-treated cohorts. COVID-19 infections occurred in 30-46% of participants, were predominantly mild, and included only two non-fatal hospitalizations. Additional vaccination was well-tolerated, with low frequencies of severe disease flares and adverse events.

Conclusion. Additional COVID-19 vaccination is effective and safe in immunosuppressant-treated autoimmune disease patients, regardless of whether MMF/MPA or MTX is withheld.

Trial Registration. ClinicalTrials.gov (NCT#05000216)

JAC received personal compensation for consulting for Astoria, Atara, Biogen, Bristol-Myers Squibb, Convelo, and Viatris. ASP received equity, payments, research funding, and patent royalties from Cabaletta Bio and provided consulting to Janssen, Sanofi, and Avilar. JAS has received research support from Boehringer Ingelheim, Bristol Myers Squibb, Johnson & Johnson, and Sonoma Biotherapeutics unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius Kabi, Gilead, Inova Diagnostics, Johnson & Johnson, Merck, MustangBio, Novartis, Optum, Pfizer, ReCor, Sana, Sobi, and UCB unrelated to this work. YMD has served as a consultant and/or received grant support from Biogen Idec, Celgene/Bristol Myers Squibb, EMD Serono, Sanofi-Genzyme, Roche-Genentech, Novartis, Questor, Janssen, and Teva Neuroscience. JAJ has received consulting funds from GSK and has IP with OMRF licensed to Progentec Biosciences. All other authors have no conflicts of interest to disclose.

NCT05000216

The study was supported by awards from the Autoimmunity Centers of Excellence, a research network funded by the National Institute of Allergy and Infectious Diseases (NIAID/NIH) (U19AI144306, U19AI082714, U19AI110483, UM1AI110494, UM1AI144292, UM1AI144295, UM1AI144288, UM1AI144298, UM1AI110557) and to Rho, the statistical and clinical coordinating center (UM2AI117870; U19AI110483-08S4; 75N93022C00003).

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Participants were recruited from 19 US centers, and all provided written informed consent before participation. The study was approved by a central institutional review board (Advarra, Columbia, MD), reviewed by institutional review boards at each site, and conducted following the Declaration of Helsinki. An independent Data and Safety Monitoring Board reviewed the progress of the study and safety data twice per year.

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