The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a serious health crisis (1, 2). COVID-19 infections vary from asymptomatic or mild through to severe disease, with lethal complications such as progressive pneumonia, acute respiratory distress syndrome, and BACKGROUND. Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID).METHODS. This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Ab and T cell responses to SARS-CoV-2, including neutralization against SARS-CoV-2 variants, were determined before and after 1 and 2 vaccine doses. RESULTS.We prospectively followed 150 subjects, 26 healthy controls, 9 patients with IMID on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Ab and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in patients with IMID compared with healthy controls. Ab levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF-treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. CONCLUSIONS.Our findings support the need for a third dose of the mRNA vaccine and for continued monitoring of immunity in these patient groups.FUNDING. Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (to THW and ACG), CIHR FDN-143250 (to THW), GA2-177716 (to VC, ACG, and THW), and GA1-177703 (to ACG) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to ACG).

Previous studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in patients with immune-mediated inflammatory diseases (IMIDs), particularly those treated with anti-TNF biologics. We previously reported that IMID patients diagnosed with inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, or rheumatoid arthritis exhibited greater waning of Ab and T cell responses than healthy control subjects after SARS-CoV-2 vaccine dose 2. Fewer data are available on the effects of third and fourth doses. This observational cohort study collected plasma and PBMCs from healthy control subjects and untreated or treated patients with IMIDs prevaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2–specific Ab levels, neutralization, and T cell cytokine release were measured against wild-type and Omicron BA.1 and BA.5 variants of concern. Third vaccine doses substantially restored and prolonged Ab and T cell responses in patients with IMIDs and broadened responses against variants of concern. Fourth-dose effects were subtle but also prolonged Ab responses. However, patients with IMIDs treated with anti-TNF, especially patients with inflammatory bowel disease, exhibited lower Ab responses even after the fourth dose. Although T cell IFN-γ responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3–4 mo postvaccination. Our study demonstrates that third and fourth doses of the SARS-CoV-2 mRNA vaccines sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in patients with IMIDs.

Background Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). This study investigated antibody and T cell responses to SARS-CoV-2 mRNA vaccines in IMID patients undergoing immunomodulatory maintenance therapy. Methods This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis or psoriatic disease, with or without maintenance immunosuppressive therapies. T cell and antibody responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined pre-vaccination and after 1 and 2 vaccine doses. Findings We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Most patients showed increased antibody responses from dose 1 to dose 2, with decreases apparent by 3 months post dose 2, albeit with considerable variability within groups. Overall, T cell responses were not consistently different between groups; however, antibody levels and neutralization efficacy in the anti-TNF treated group was lower than controls and waned substantially by 3 months post-dose 2. Implications These findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity over time.

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BackgroundPrevious studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in immunocompromised patients with immune-mediated inflammatory diseases (IMID), particularly those treated with anti-tumor necrosis factor (TNF) biologics. We previously reported that IMID patients exhibited greater waning of antibody and T cell responses compared to healthy controls after dose 2. Fewer data are available on the effects of third and fourth doses.MethodsThis observational cohort study collected plasma and peripheral blood mononuclear cells from healthy controls and untreated or treated IMID patients, pre-vaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2- specific antibody levels, neutralization, and T cell cytokine responses were measured against Wildtype (WT) and BA.1 and BA.5 variants of concern (VOCs).ResultsThird vaccine doses substantially restored and prolonged antibody and T cell responses in IMID patients and broadened responses against VOCs. Fourth dose effects were subtle but also prolonged antibody responses. However, IMID patients treated with anti-TNF, especially inflammatory bowel disease (IBD) patients, exhibited lower antibody responses even after the fourth dose. Although T cell IFNγ responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3-4 months post-vaccination.ConclusionOur study demonstrates that third and fourth doses of the SARS-CoV-2 vaccine sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in IMID patients.FundingCOVID-19 Immunity Task Force and Speck family donationConflict-of-Interest StatementsAnne-Claude Gingras has received research funds from a research contract with Providence Therapeutics Holdings, Inc., for other projects, participated in the COVID-19 Immunity Task Force (CITF) Immune Science and Testing working party, chaired the CIHR Institute of Genetics Advisory Board, and chairs the SAB of the National Research Council of Canada Human Health Therapeutics Board. Vinod Chandran has received research grants from AbbVie, Amgen, and Eli Lilly and has received honoraria for advisory board member roles from AbbVie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, and UCB. His spouse is an employee of AstraZeneca. Vincent Piguet has no personal financial ties with any pharmaceutical company. He has received honoraria for speaker and/or advisory board member roles from AbbVie, Celgene, Janssen, Kyowa Kirin Co. Ltd, LEO Pharma, Novartis, Pfizer, Sanofi, UCB, and Union Therapeutics. In his role as Department Division Director of Dermatology at the University of Toronto, Dr. Piguet has received departmental support in the form of unrestricted educational grants from AbbVie, Bausch Health, Celgene, Janssen, LEO Pharma, Lilly, L’Oréal, NAOS, Novartis, Pfizer, Sandoz and Sanofi in the past 36 months. Vincent Piguet has received research grants from Sanofi, Abbvie and Novartis. Mark Silverberg has received research support, consulting fees and speaker honoraria from AbbVie, Janssen, Takeda, Pfizer, Gilead, and Amgen. All other authors have no conflicts to declare.Graphical Abstract