Reduced antibody activity against SARS-CoV-2 B.1.617.2 Delta virus in serum of mRNA-vaccinated patients receiving TNF-α inhibitors

Although vaccines effectively prevent COVID-19 in healthy individuals, they appear less immunogenic in individuals with chronic inflammatory diseases (CID) and/or under chronic immunosuppression, and there is uncertainty of their activity against emerging variants of concern in this population. Here, we assessed a cohort of 74 CID patients treated as monotherapy with chronic immunosuppressive drugs for functional antibody responses in serum against historical and variant SARS-CoV-2 viruses after immunization with Pfizer mRNA BNT162b2 vaccine. Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with TNF-α inhibitors, and this pattern appeared worse against the B.1.617.2 Delta virus. Within five months of vaccination, serum neutralizing titers of the majority of CID patients fell below the presumed threshold correlate for antibody-mediated protection. Thus, further vaccine boosting or administration of long-acting prophylaxis ( e . g ., monoclonal antibodies) likely will be required to prevent SARS-CoV-2 infection in this susceptible population. ### Competing Interest Statement M.S.D. is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, and Emergent BioSolutions. F.K. is a coinventor on a patent application for serological assays and SARS-CoV-2 vaccines (international application numbers PCT/US2021/31110 and 62/994,252). A.H.J.K. participated in consulting, advisory board, or speaker's bureau for Alexion Pharmaceuticals, Aurinia Pharmaceuticals, Exagen Diagnostics, Inc., and GlaxoSmithKline, and received unrelated funding support under a sponsored research agreement from GlaxoSmithKline. The Ellebedy laboratory received funding under sponsored research agreements that are unrelated to current study from Emergent BioSolutions and from AbbVie. A.H.E. is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting LLC. A.H.E., M.S.D., and J.S.T. are recipients of a licensing agreement with Abbvie Inc., for commercial development of a SARS-CoV-2 mAb not described in this study. J.S.T. is a consultant for Gerson Lehrman Group. S.C. received research funding from Biogen and received speaking and/or consulting fees from Biogen, Novartis, Sanofi Genzyme, Genentech and Bristol Myers Squibb. P.D. has participated in consulting, advisory board, or speaker's bureau for Janssen, Pfizer, Prometheus Biosciences, Boehringer Ingelheim, AbbVie, and Arena Pharmaceuticals and received funding under an unrelated sponsored research agreement from Takeda Pharmaceutical, Arena Pharmaceuticals, Bristol Myers Squibb-Celgene, and Boehringer Ingelheim. G.F.W. has received honoraria for consulting from Novartis and Genentech, Inc., and research funding from Biogen, EMD Serono and Roche. F. K. has consulted for Merck, Curevac and Pfizer in the past and is currently consulting for Pfizer, Seqirus and Avimex. The Krammer laboratory is collaborating with Pfizer on animal models of SARS-CoV-2. G.A. is the founder of SeromYx Systems Inc., and an equity holder of Leyden Labs. ### Clinical Trial Longitudinal observational study of vaccine responses ### Funding Statement This study was supported by grants and contracts from NIH (R01 AI157155, R01AI151178, HHSN75N93019C00074, NIAID Centers of Excellence for Influenza Research and Response (CEIRR) contracts HHSN272201400008C and 75N93021C00014, and the Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051). The Alter laboratory was supported by the Ragon Institute, the Massachusetts Consortium on Pathogen Readiness (MassCPR), the NIH (3R37AI080289-11S1, R01AI146785, U19AI42790, U19AI135995, U19AI42790, 1U01CA260476, CIVIC75N93019C00052), the Gates foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650), and the Musk Foundation. M.P. was supported by the Scientist Development Award from the Rheumatology Research Foundation. P.D. is supported by a Junior Faculty Development Award from the American College of Gastroenterology and IBD Plexus of the Crohn's & Colitis Foundation. A.H.J.K. is supported by the Rheumatology Research Foundation, NIH/NIAMS P30 AR073752, and PCORI SDM2017C28224. G.F.W. was supported by grant funding from the NIH (R01 NS106289) and the NMSS (RG-1802-30253). The COVaRiPAD study was supported by The Leona M. and Harry B. Helmsley Charitable Trust, Washington University Digestive Disease Research Core Center (NIDDK P30DK052574), Washington University Rheumatic Diseases Research Resource-Based Center (NIAMS P30AR073752), the Judy Miniace Research Fund for the Washington University Lupus Clinic, the Siteman Cancer Center grant P30CA091842 from the NIH/NCI, and the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the NIH/NCATS. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All individuals were enrolled at Washington University School of Medicine in studies that had received Institutional Review Board approval (202012081 (WU368) and 202012084 (COVaRiPAD). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data supporting the findings of this study are available within the paper and are available from the corresponding author upon request.