Targeted Biologics Did Not Affect Humoral Immunity to First Dose of COVID-19 Vaccine


Common immunosuppressant therapies for patients with rheumatic disease, such as methotrexate and targeted biologics, increase risk of serious infection, especially with respiratory pathogens. A recent study investigates the connection between these drugs and functional humoral immunity to the first dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech).

While functional humoral immunity to the first dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) is hindered by methotrexate (MTX), it is unaffected by targeted biologics, according to a study published in The Lancet.1 Further, the cellular responses were preserved.

MTX and biologics designed to target tumor necrosis factor (TNF), such as interleukin (IL)-17 and IL-23, are common immunosuppressant therapies for patients with rheumatic disease. However, they also increase risk of serious infection, especially with respiratory pathogens.

“Individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression were excluded from COVID-19 vaccine trials; therefore, characterization of vaccine efficacy in this vulnerable population is important,” explained investigators. “Given the roll-out of extended interval vaccination programs, the effect of immunosuppression on the immunogenicity of a single dose of vaccine is of major public, and personal, health importance.”

A total of 84 patients with a confirmed diagnosis of psoriasis who were being treated with either MTX or biologic monotherapy were entered in the cohort study between January 14 and April 4, 2021. Volunteers without psoriasis (n = 17) were included as the control cohort. To be eligible for inclusion, participants needed to be able to receive the BNT162b2 vaccine. Investigators collected blood samples, as well as clinical and safety data, at 3 visits: baseline, 28 days later, and 14 days after the second dose. Data included demographics, comorbidities, psoriasis details, and any adverse events that occurred after vaccination.

The primary endpoints were focused on humoral immunity to the SARS-CoV-2 spike glycoprotein and spike-specific T-cell responses 28 days after the first dose. Secondary endpoints included antibody seroconversion rates, the presence of T cells secreting IL-17A and IL-22, adverse events, and worsening psoriasis symptoms. Adverse events were categorized as local or systemic, and subcategorized as mild, moderate, or severe.

Humoral immunogenicity was calculated by seroconversion and the plasma’s ability to neutralize the prototypic strain of SARS-CoV-2 and the B.1.1.7 variant.

The 2 pre-determined hypotheses were that patients receiving MTX would have lower humoral or cellular immunogenicity to the first dose of the vaccine compared with healthy controls; and that patients receiving MTX would have lower humoral or cellular immunogenicity to the first dose compared with patients receiving targeted biologics.

Of the 84 patients in the psoriasis cohort, 17 were on MTX, 27 on TNF inhibitors, 15 were receiving IL-17 inhibitors, and 25 were taking IL-23 inhibitors. The average dose of MTX was 15 mg per week. The median age was 43 years, 56% were males, and 84% were White.

During the first 28 days, 75% (n = 63) patients in the psoriasis cohort reported mild adverse events, compared with 94% (n = 16) of controls. The most common effects were pain at injection site, fatigue, and headache.

Seroconversion rates were lower in the group receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in the healthy control group (17 [100%; 80–100] of 17), with the lowest rate in patients currently receiving MTX (7 [47%; 21–73] of 15).

Immune response was reported in all groups, regardless of immunosuppressant status. Positive T-cell responses were confirmed across the cohorts, and rates were similar.

Patients receiving MTX had lower median neutralization titers (129) against the wild-type SARS-CoV-2 when compared with both the healthy control cohort (317) and those receiving targeted biological therapy (269). Patients on IL-17 or IL-23 inhibitors had neutralization titers against wild-type SARS-CoV-2 that were comparable to the control group. However, neutralization activity against B.1.1.7 were low across all groups.

The study was limited by the number of participants and absence of immunogenicity data after the second dose. However, baseline demographics were well matched and immune responses were profiled, thus helping further research on this topic. Additionally, longer-term data is not available as the investigators focused on the immune efficacy of the first dose.

“While global mass COVID-19 vaccination programs are underway, there remains concern over vaccine efficacy in immunosuppressed patients,” concluded investigators. “Although our data indicating preserved cellular immunogenicity across biological classes and methotrexate, independent of neutralizing activity, are reassuring, ongoing pharmacovigilance studies will determine whether this finding translates into clinical effectiveness of vaccines.”


Mahil SK, Bechman K, Raharja A, et al. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study [published online ahead of print, 2021 Jul 8]. Lancet Rheumatol. 2021;10.1016/S2665-9913(21)00212-5. doi:10.1016/S2665-9913(21)00212-5

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