In a recent study posted to the medRxiv* preprint server, researchers conducted a comparative study among a cohort of individuals on rheumatoid arthritis (RA) therapies vis-à-vis healthy controls to assess their responses to coronavirus disease 2019 (COVID-19) vaccines.
RA, an autoimmune disease, causes swelling, pain, and infirmity in people's joints. Drugs used to treat RA actively suppress people's immune systems, altering their response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Preliminary clinical trials showed that BNT162b2 and messenger ribonucleic acid (mRNA)-1273 vaccines have ~95% efficacy against COVID-19. However, these trials excluded immunocompromised patients, such as those on RA therapies.
Amid the emergence of SARS-CoV-2 variants that evade antibody-mediated protective immunity (e.g., Omicron), it is crucial to understand the response to COVID-19 vaccination in this high-risk population. The American College of Rheumatology has acknowledged that disease-modifying anti-rheumatic drugs (DMARDs) impair the effective COVID-19 vaccine-induced responses.
Methotrexate (MTX), the first-line treatment for RA, is an immunosuppressive drug thought to interfere with folate metabolism in RA-causing lymphocytes. Abatacept binds antigen-presenting cells, blocking costimulation to pathogenic autoreactive T cells causing RA. It also likely inhibits mRNA vaccine-induced neutralizing antibody responses in RA patients. Similarly, the RA drug rituximab is believed to deplete B cells, which, in turn, severely impairs the immune response to mRNA-based COVID-19 vaccines.
About the study
In the present multicenter study, researchers collected blood samples from RA subjects who had received a primary vaccination series of BNT162b2 or mRNA-1273 vaccines. The study cohorts comprised 40 subjects, 27 with RA and 13 age and gender-matched healthy controls. Of the 27 RA subjects, 11 received MTX, and the other 11 received abatacept treatments. The remaining five received rituximab therapy.
The team collected donor blood samples within one to three weeks, and in some cases, three months after vaccination for isolation of serum and PBMCs and humoral and cellular analyses. First, they measured antibody responses to the SARS-CoV-2 spike (S) in the patient's serum. Furthermore, they examined the amount, phenotype, and functionality of SARS-CoV-2-specific T cells and B cells.
In addition, the researchers performed a pseudovirus neutralization (pVNT) assay. It helped them assess whether serum from SARS-CoV-2 naïve and unvaccinated individuals on RA therapies effectively blocked infection of angiotensin-converting enzyme 2 (ACE-2).
Abatacept and MTX both reduce antibody production in response to SARS-CoV-2 mRNA vaccines. The T cell activator-induced marker (AIM) assay confirmed that MTX-treated RA subjects had a markedly lower magnitude of the SARS-CoV-2 S-specific cluster of differentiation (CD4)+ T cell response to COVID-19 mRNA vaccines. However, the number of phenotypically and functionally specific CD4+ T cells and RBD-specific B cells were comparable with healthy subjects. Conversely, most RA subjects receiving the B cell-depleting antibody rituximab had undetectable S-specific antibody responses in the serum.
Likewise, in abatacept-treated RA subjects, responses to CD4+ memory T cells, IgG+ memory B cells, and neutralizing antibodies to COVID-19 vaccination were impaired. Furthermore, the researchers noted a marked reduction in the magnitude of cytokines, such as interleukin ( IL) 2 & 21, and interferon-gamma (IFNγ). Additionally, they found that abatacept treatment diminished the number of T follicular helper (Tfh) cells, Tfh cells-related IL-12 levels, and impaired the transcription of T cell proliferation. Strikingly, ceasing the drug treatment reversed the effect of abatacept on the magnitude and transcriptional profile of Tfh cells almost instantaneously.
Another significant observation was that RA subjects on abatacept therapy had decreased serum neutralization activity. Although it was quantitatively impaired, the quality of antibodies produced in MTX- and abatacept-treated subjects were normal.
Vaccination-induced neutralizing antibody titers are an established correlate of protection against viral pathogens, including SARS-CoV-2. Thus, the observed substantially diminished anti-SARS-CoV-2 S antibodies in the abatacept cohort were clinically relevant. The authors advocated for ceasing the abatacept treatment of RA subjects for the duration of vaccination as it was beneficial. It could significantly improve response to the SARS-CoV-2 vaccines and defend the immunocompromised populations against future SARS-CoV-2 variants.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Samuel D Klebanoff, Lauren B Rodda, Chihiro Morishima, Mark H Wener, Susan L Fink, Andrew Bryan, Yevgeniy Yuzefpolskiy, Estelle Bettelli, Jane H Buckner, Cate Speake, Marion Pepper, Daniel J Campbell. (2023). Diminished responses to mRNA-based SARS-CoV-2 vaccines in individuals with rheumatoid arthritis on immune modifying therapies. medRxiv. doi: https://doi.org/10.1101/2023.01.03.23284167 https://www.medrxiv.org/content/10.1101/2023.01.03.23284167v1