Patients on Methotrexate Show T-Cell Response to Pfizer Vaccine

Tara Haelle

July 12, 2021

People taking methotrexate had low antibody responses after the first dose of the Pfizer–BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell-mediated immune responses, findings from a small study show.

The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.

The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in Lancet Rheumatology.

"These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice," write Satveer K. Mahil, MBBChir, PhD, from St John's Institute of Dermatology, Guy's and St. Thomas' NHS Foundation Trust, London, and her colleagues.

"When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population," they write. "Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved."

Mahil and her colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and South East England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer–BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor [TNF] inhibitor, 15 an interleukin [IL]-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer–BioNTech vaccine served as the control group.

Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion — producing measurable antibodies — as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rates.

Seroconversion Rates in Patients Taking Immunosuppression Therapy
Immunosuppressant Seroconversion Rate, %
Methotrexate 47
TNF inhibitor 79
IL-23 inhibitor 83
IL-17 inhibitor 100

Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.

All participants had low neutralizing titers against the alpha (B.1.1.7) variant.

The researchers also assessed cellular immunity, "defined as the presence of T-cells secreting interferon-γ, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein."

A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group, and in 69% of control subjects.

"Some Protection Is Better Than None"

These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University in Atlanta.

It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Mahil and her colleagues.

"The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided," Sanz told Medscape Medical News, adding that it would have been helpful to see CD8 T-cell response as well.

"My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced," he said. But, he noted, discussion of B-cells independent of their role in producing antibodies is missing.

"When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity," in the same way virus-specific memory B-cells do, he explained. "They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B-cells."

Temporarily Stopping Methotrexate

It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University School of Medicine, in an accompanying comment.

Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology (ACR) to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.

"Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups," Connolly and Paik explain. "During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies."

Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients — most commonly injection-site pain, headache, and fatigue — and by 94% of control subjects. No participants reported moderate or severe adverse effects.

However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.

This research was funded by the UK National Institute for Health Research. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Sanz, Connolly, and Paik have disclosed no relevant financial relationships

Lancet Rheumatol. Published online July 8, 2021. Full text, Comment

31st European Congress of Clinical Microbiology & Infectious Diseases (ECCMID): Abstract 2782-6. Presented July 11, 2021.

Tara Haelle is an independent science/health journalist based in Dallas.

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