Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease.

OBJECTIVE: To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. METHODS: Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. RESULTS: Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. CONCLUSIONS: In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines. KEY MESSAGES: What is already known about this subject?: The impact of COVID-19 has been felt across the globe and new hope has arisen with the approval of mRNA vaccines against the SARS-CoV-2. Studies have shown immunogenicity and efficacy rates of over 90% in the immunocompetent adult population. However, there is a lack of knowledge surrounding the response of patients with immune-mediated inflammatory diseases (IMIDs) who may also be on immunomodulatory medications.Patients with IMID have been shown to have attenuated immune responses to seasonal influenza vaccination.What does this study add?: This study looks at the humoral and cellular immune response to two doses of BNT162b2 mRNA COVID-19 Vaccine in participants with IMID (on immunomodulators) compared with healthy controls.Individuals with IMID on methotrexate demonstrate up to a 62% reduced rate of adequate immunogenicity to the BNT162b2 mRNA vaccination. Those on anti-cytokine or non-methotrexate oral medications demonstrate similar levels of immunogenicity as healthy controls (greater than 90%).Similarly, vaccination did not induce an activated CD8+ T cell response in participants on background methotrexate, unlike healthy controls and patients with IMID not receiving methotrexate.How might this impact of clinical practice or future developments?: These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.