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Immunocompromised patients treated with immunosuppressive drugs are at increased risk of adverse outcomes following SARS-CoV-2 infection.1 There is limited information on the effect of immunomodulatory therapies on the quality of SARS-CoV-2 vaccine-induced immunity in these populations.2 In a cohort of patients with immune-mediated inflammatory diseases (IMIDs) not treated with B-cell depleting agents or corticosteroids, we recently demonstrated that antibody levels and T cell responses showed greater waning by 3 months following the second dose of SARS-CoV-2 mRNA vaccine compared with healthy controls, emphasising the need for third doses of the vaccine.3 Here, we investigated immune responses in uninfected patients with IMID following a third dose of the Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273 mRNA vaccine.
We collected blood samples 2–4 weeks after the third dose of vaccine from 62 patients (median (range) age 40 (22–70) years, 34 females) enrolled in our ongoing study (figure 1A) and diagnosed with one or more of the following IMIDs: inflammatory bowel disease (37 patients), psoriasis (11), psoriatic arthritis (10), ankylosing spondylitis (2), rheumatoid arthritis (2) or hidradenitis suppurativa (1). The patients analysed included 6 healthy controls, 5 patients with IMID not on treatment, 18 patients on anti-TNF, 9 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 6 on anti-IL-17, 10 on anti-IL-12/23, 6 on anti-IL-23 and 2 on MTX/AZA. IgG responses against coronavirus S protein (spike) and receptor binding domain (RBD) were measured by automated ELISA.3 PBMCs were stimulated for 48 hours with SARS-CoV-2 Wildtype or Omicron B.1.1.529 spike peptide pools. T cell responses were analysed by measuring the release of IL-2 and IL-4 in cell culture supernatants using a bead-based immunoassay (see reference Dayam et al for details).3
Anti-spike and anti-RBD antibody levels increased following the third dose (T5, figure 1A), with 92% of patients showing relative ratios greater than the medians of the convalescents for spike and RBD (figure 1B). T cell responses showed significant variation in IL-2 and IL-4 production (figure 1C). We previously reported significant waning of IL-2 and IL-4 responses by 3 months postdose 2 (T4, figure 1A).3 Pooled analysis of all study subjects revealed that the third dose of vaccination (T5) corrects the waning immunity, significantly boosting IL-2 and IL-4 responses (figure 1C; median IL-2 sqrt(Δpg/mL) at T4: 4.65 vs T5: 13.73 *p<0.0001; median IL-4 sqrt(Δpg/ml) at T4: 0.05 vs T5: 1.65 *p<0.0001). IL-2 responses were stronger after a third dose of vaccination compared with after the second dose (figure 1C; median IL-2 sqrt(Δpg/ml) at T3: 6.40 vs T5: 13.73 *p<0.0001) while IL-4 responses were similar after the second and third dose of vaccination (figure 1C; median IL-4 sqrt(Δpg/ml) at T3: 1.32 vs T5: 1.65 p=0.42). We additionally assessed T cell responses against Omicron B.1.1.529, and observed no difference in IL-2 and IL-4 responses compared with wild-type (figure 1C,D) in agreement with similar studies in healthy individuals.4 5
Thus, we observed robust serological and cellular responses in patients with IMID following the third dose of SARS-CoV-2 mRNA vaccine. Importantly, the third dose rescues waning of T cell-mediated and antibody-mediated immunity in patients with IMID observed by 3 months after the second dose. Additionally, patients with IMID retain T cell immunity to Omicron B.1.1.529. Our results agree with a recent systematic review and meta-analysis.6 Future studies will analyse additional cellular and humoral readouts, durability of the responses and effect of additional doses in this cohort.
Patient consent for publication
This study was approved by the ethics boards of the University of Toronto (REB 7673), Sinai Health System (REB 21-0022-E), University Health Network (REB 21-5096) and Women’s College Hospital (REB 2021-0023-E). Participants gave informed consent to participate in the study before taking part.
VP, MSS, THW, A-CG and VC are joint senior authors.
Contributors MWC conducted T cell assays, analysed data and edited manuscript. RMD analysed antibody data, conducted statistical analysis, prepared figures and edited the manuscript. JCL designed and assisted with T cell assays. RLG contributed to study conception and design. GYCC provided overall project management including patient recruitment and validation of data records. JMS and DP contributed to project management and patient recruitment. NF, DC, LA, SR, JDL and DG contributed to patient recruitment. RL assisted with PBMC preparation. MD-B and GM handled samples and conducted ELISA assays. A-CG and THW contributed to study design, supervised the laboratory assays, analyzed data, acquired funding and edited the manuscript. VP and MSS contributed to study design, acquisition of funding, supervised clinical coordinators, contributed to data interpretation and manuscript editing. VC contributed to study design, acquisition of funding, supervision of patient recruitment, data analysis and wrote the manuscript.
Funding Funded by Canadian Institutes of Health (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172 711 and vs1-175545 (to THW and ACG), CIHR FDN-143250 (to THW), GA2-177716 (to VC, A-CG and THW) and GA1-177703 (to ACG) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to ACG) as well as a donation from Juan and Stefania Speck.
Competing interests VP has no personal financial ties with any pharmaceutical company but has received honoraria for speaker and/or advisory board member roles from AbbVie, Almirall, Celgene, Janssen, Kyowa Kirin, LEO Pharma, Novartis, Pfizer, Sanofi, UCB and Union Therapeutics. In his role as Department Division Director of Dermatology at the University of Toronto, VP has received departmental support in the form of unrestricted educational grants from AbbVie, Bausch Health, Celgene, Janssen, LEO Pharma, Eli Lilly, L’Oréal, NAOS, Novartis, Pfizer, Pierre-Fabre, Sandoz and Sanofi in the past 36 months. MSS has received research support, consulting fees and speaker honoraria from AbbVie, Janssen, Takeda, Pfizer, Gilead, and Amgen. VC 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. None of the other authors have any conflicts of interest.
Provenance and peer review Not commissioned; externally peer reviewed.