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Patients on immunomodulators need 2 COVID-19 vaccinations before seroconversion

Presented by
Dr Ali Al-Janabi, University of Manchester, UK
PFGC 2021
Encouraging results of 2 recent studies found that almost all patients on immunomodulating treatment for immune-mediated inflammatory diseases (IMID) show antibody positivity after full vaccination. However, in contrast to healthy persons, up to 17% of them do not seroconvert after their first shot of a COVID-19 vaccine. In addition, cellular immune responses are lower in these patients, questioning the durability of antibody response in this patient population.

The results of vaccine trials led to a robust knowledge of immune-response in healthy subjects, but less is established about patients on immunomodulatory treatment [1]. “We know that healthy subjects have close to a 100% seroconversion 15–35 days after the first vaccine dose, and if we consider seroconversion as a potential surrogate of vaccine efficacy, we could investigate whether this is the case in patients on immunomodulatory drugs,” Dr Ali Al-Janabi (University of Manchester, UK) pointed out.

The current study included 357 patients on immunomodulators for IMID, among them a great majority with psoriasis (n=290), followed by psoriatic arthritis (n=79), and rheumatoid arthritis (n=48). Some patients had more than 1 diagnosis. Samples were collected ≥10 days after vaccine administration and analysed with immunoassays for antibodies against spike protein S1 to assess the vaccine-induced antibody formation. Further, a second immunoassay was performed to exclude participants with antibodies against nucleocapsid antigen, originating from a preceding infection.

After the first dose of any of the available vaccines, 17% did not demonstrate a positive antibody response. “If we look at some of the baseline variables, we see that as age increases, the percentage of participants with a positive antibody response decreases and this is statistically significant,” Dr Al-Janabi noted. Regarding different drug classes, the group of patients on biologics had the greatest rate of positive responses (73%), while 69% of the group treated with oral immunomodulators were positive for antibodies, and 61% of participants receiving a combination of both. A logistic regression analysis that took biologic therapy as a reference and adjusted for age, sex, and disease found significantly reduced odds for mounting a positive antibody response, with an adjusted odds ratio (OR) of 0.21 (95% CI 0.05–0.87) only for the cohort of participant with combination treatment of biologic plus immunotherapy. In further exploring the sub-categories of IMID treating drugs, methotrexate was associated with a significant reduction in the likelihood of seroconversion (adjusted OR 0.09; 95% CI 0.02–0.56) compared with tumour necrosis factor (TNF) inhibition.

After the second vaccination, 192 out of 194 patients were positive for anti-spike antibodies. So, reassuringly, 99% of IMID patients on immunomodulation had a positive antibody response after their second vaccination.

“By now, there is an argument to minimise the interval between vaccine doses, since almost everybody seroconverts after the second vaccine dose. There is also an argument for methotrexate in particular that we should pause treatment either before or after the vaccine,” Dr Al-Janabi commented on the results.

Reduced T-cell responses in a third of patients taking therapeutic immunosuppression

A second study presented in the COVID session also dealt with COVID-19 vaccine immunogenicity in people receiving therapeutic immunosuppression [2]. “There is emerging research but this has largely focused on seroconversion alone, which may not be representative of the complex and multifaceted immune response to vaccinations,” said Dr Satveer Mahil (Guy’s and St Thomas’ NHS Foundation Trust and King´s College London, UK). In his study, he assessed the impact of monotherapy with methotrexate or biologics targeting TNF, IL-17, and IL-23 on both humoral and cellular immunogenecity to the COVID-19 vaccine BNT162b2 [2]. They took blood samples at day 0 and day 28 post-dose 1, and day 14 post-dose 2. The researchers performed 2 immunogenicity assays, a humoral assessing seroconversion and neutralisation, and a cellular, assessing T helper 1 (Th1; i.e. IFNy, IL-2) and T follicular helper cell (Tfh; i.e. IL-21) responses.

In total, blood samples were analysed of 82 patients with a median age of 44 years (67 receiving immunosuppressants and 15 controls). Similar to the study by Dr Al-Janabi, seroconversion rates following the first vaccine dose were lower in patients receiving immunosuppressants than in controls (78% vs 100%), and lowest in those taking methotrexate. Reassuringly, all patients seroconverted on the second dose. Moreover, the functional capacity of plasma to neutralise wild-type, alpha and delta SARS-CoV-2 variants was similar after the second dose in patients receiving immunosuppression and controls. However, the neutralisation activity against wild-type SARS-CoV-2 and the alpha variant was lower in methotrexate-treated patients but still above the response threshold after the second dose.

Moving on to cellular responses, researchers assessed Th1 responses and were also interested in T follicular helper cell responses, which is important to maintain long-term antibody-mediated immunity. T-cell response rates following the first vaccine dose were similar in patients receiving methotrexate, biologics, and controls. However, T cell response rates following the second dose were lower in patients receiving immunosuppression compared with controls. “29% of individuals taking therapeutic immunosuppression had no evidence of T-cell response following the second vaccine dose,” Dr Mahil said. The durability of antibody response in the context of absent cellular responses is uncertain and merits further study. Thus, she concluded that larger and longer-term cohort studies analysing immunogenicity of further vaccine doses including vaccines against novel variants of concern are vital. Immune correlates of vaccine effectiveness remain to be determined.


    1. Al-Janabi A. Antibody responses to SARS-CoV-2 vaccination in patients receiving immunomodulators for immune-mediated inflammatory disease. FC17, Psoriasis from Gene to Clinic 2021, 9–11 December.
    2. Mahil S. The impact of methotrexate and targeted immunosuppression on humoral and cellular immunogenicity of the COVID-19 vaccine BNT162b2 in people with psoriasis: a prospective longitudinal cohort study. FC18, Psoriasis from Gene to Clinic 2021, 9–11 December.

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