Prospective SARS-CoV-2 additional vaccination in immunosuppressant-treated individuals with autoimmune diseases in a randomized controlled trial

Abstract

Background: Individuals with autoimmune diseases (AD) on immunosuppressants often have suboptimal responses to COVID-19 vaccine. We evaluated the efficacy and safety of additional COVID-19 vaccines in those treated with mycophenolate mofetil/mycophenolic acid (MMF/MPA), methotrexate (MTX), and B cell-depleting therapy (BCDT), including the impact of withholding MMF/MPA and MTX.

Methods: In this open-label, multicenter, randomized trial, 22 participants taking MMF/MPA, 26 taking MTX, and 93 treated with BCDT who had suboptimal antibody responses to initial COVID-19 vaccines (2 doses of BNT162b2 or mRNA-1273 or 1 dose of AD26.COV2.S) received an additional homologous vaccine. Participants taking MMF/MPA and MTX were randomized (1:1) to continue or withhold treatment around vaccination. The primary outcome was the change in anti-Wuhan-Hu-1 receptor-binding domain (RBD) concentrations at 4 weeks post-additional vaccination. Secondary outcomes included adverse events, COVID-19 , and AD activity through 48 weeks.

Results: Additional vaccination increased anti-RBD concentrations in participants taking MMF/MPA and MTX , irrespective of immunosuppressant withholding. BCDT-treated participants also demonstrated increased anti-RBD concentrations, albeit lower than MMF/MPA- and MTX-treated cohorts. COVID-19 occurred in 33% of participants; infections were predominantly mild and included only three non-fatal hospitalizations. Additional vaccination was well-tolerated, with low frequencies of severe disease flares and adverse events.

Conclusion: Additional COVID-19 vaccination is effective and safe in individuals with ADs treated with immunosuppressants, regardless of whether MMF/MPA or MTX is withheld.

Clinicaltrials: gov (NCT05000216; registered August 6, 2021: https://clinicaltrials.gov/ct2/show/NCT05000216).

Keywords: Autoimmune diseases; Autoimmunity; COVID-19; Clinical practice; Rheumatology; Vaccines.

Figure 1. ACV01 trial profile.

MMF, mycophenolate mofetil; MPA, mycophenolic acid; MTX, methotrexate; BCDT, B cell–depleting therapy. *Samples were excluded from the humoral response analyses if the participant experienced COVID-19, monoclonal antibody use, or a COVID-19 vaccination off-study between the baseline and week 4 visit. Some individuals were rolled over to Stage 2 of this study to assess a booster with a nonhomologous vaccine; Stage 2 results are not reported here.

Figure 2. Anti-RBD concentrations and seropositivity in participants treated with mycophenolate mofetil/mycophenolic acid (MMF/MPA), methotrexate (MTX), or B cell–depleting therapy (BCDT) who received a third mRNA vaccine.

Concentrations of anti-RBD antibodies at baseline and 4 weeks after the third vaccination in participants in the (A) MMF/MPA, (B) MTX, or (C) BCDT cohorts. Box-and-whisker plots display the interquartile range (IQR), with the line within the box indicating median values. Geometric mean values are represented by triangles and connected across study visits. Whiskers extend to 1.5 × IQR, with circles indicating outliers. The dashed line represents the positivity cutoff, and numbers indicate the number of participants analyzed at each time point. The Wilcoxon signed-rank test was used to assess the change in antibody concentration from baseline to week 4 within each group. There was no significant difference in concentrations between those who continued or withheld immunosuppressants, as determined by van Elteren’s test. Seropositivity of anti-RBD antibodies at baseline and 4 weeks after the third vaccination in participants in the (D) MMF/MPA, (E) MTX, or (F) BCDT cohorts. Statistical significance was determined using McNemar’s test. **P < 0.01; ***P < 0.001; ****P < 0.0001.

Figure 3. Disease activity in the vaccinated population that received a third mRNA vaccine.

Changes in disease activity as measured by the (A–C) Physician Global Assessment (PGA) and (D–F) Patient Global Assessment (PtGA) at baseline and week 4 after booster in participants in the (A and D) mycophenolate mofetil/mycophenolic acid (MMF/MPA), (B and E) methotrexate (MTX), or (C and F) B cell–depleting therapy (BCDT) cohorts. Box-and-whisker plots display the interquartile range (IQR), with the line within the box indicating median values. Geometric mean values are represented by triangles and connected across study visits. Whiskers extend to 1.5 × IQR, with circles indicating outliers. The dashed line represents the positivity cutoff, and numbers indicate the number of participants analyzed at each time point. Change in score from baseline to week 4 did not significantly differ, as determined by the Wilcoxon signed-rank test.