Shingles Vaccine Generates Strong Immune Response in Patients With RA Receiving Upadacitinib

Most patients with rheumatoid arthritis (RA) treated with upadacitinib and methotrexate had robust antibody and T-cell responses to the recombinant zoster vaccine (Shingrix; GSK), according to 60-week clinical trial results.1

Adults with RA face nearly double the risk of infection compared with the general population, in part due to immune dysfunction and long-term use of immunosuppressive therapies.2 Janus kinase (JAK) inhibitors like upadacitinib are associated with an elevated risk of herpes zoster or shingles, making prevention through vaccination a priority.3 However, data on the immunogenicity of the recombinant zoster vaccine in this setting have been limited.

Protection Over 60 Weeks

Published in RMD Open, the randomized controlled trial substudy included 95 patients in the ongoing SELECT-COMPARE trial (NCT02629159), of whom 93 received both doses of the vaccine at baseline and week 12.1 By week 16, researchers found 87.8% of patients achieved a satisfactory humoral response, defined as a 4-fold rise in antibody titers against varicella-zoster glycoprotein E (gE). At 60 weeks, 71.4% of patients maintained this response.

An exploratory analysis in 38 patients also assessed T-cell activity. More than 60% achieved a cell-mediated immune (CMI) response at all measured time points, underscoring the vaccine’s durability of protection. At week 60, more than half of patients (52.9%) achieved both humoral and CMI responses, while another 35% showed either an antibody or T-cell response.

Cell-mediated immunity is particularly important for long-term herpes zoster protection, as susceptibility to shingles in older adults is linked more closely to waning T-cell activity than antibody levels.4 “Given our patients’ underlying disease and use of immunosuppressive therapy, we anticipated a diminished magnitude in humoral and cellular response compared with that of a healthy population,” the authors noted.1

More than half of patients achieved both humoral and CMI responses at week 60. | Image credit: Halfpoint – stock.adobe.com

Consistent Safety Profile

The safety profile was consistent with prior research, according to the authors. Nearly 39% of patients reported an adverse event within 30 days of vaccination, most of which were mild or moderate. Injection site pain was the most common, affecting 4.2% of participants. One moderate case of shingles occurred during follow-up, translating to 0.9 events per 100 patient-years, compared with 2.8 events per 100 patient-years observed among unvaccinated patients receiving upadacitinib in the main SELECT-COMPARE trial. No serious adverse events related to vaccination were reported.

Neither patient age nor corticosteroid use seemed to influence antibody response. Rates were similar between those aged 50 to 64 years and those 65 years and older, as well as between corticosteroid users and nonusers.

More Diverse Studies Needed

The authors noted several limitations, including that this substudy’s sample was relatively small and predominantly White, which may limit generalizability to more diverse patient populations. It was also a single-arm, open-label design without a placebo control, and the data were descriptive only, as no inferential statistical testing was performed. Nearly half of patients were also receiving concomitant corticosteroids at baseline, a slightly higher proportion than in real-world RA cohorts, according to the authors, which could affect immune responses. Variability in baseline disease characteristics and treatment exposures may have also influenced results.

“These findings can be confirmed in future randomised controlled trials that enrol relatively larger cohorts that can directly control for potential confounders, such as differences in baseline disease severity, immune status and treatment duration,” the authors said. “Future studies should also investigate whether temporary suspension of upadacitinib or methotrexate use before vaccination could improve the immune response to [recombinant zoster vaccine], especially in older adults who are more likely to have less vigorous immune response to vaccination.”

References

1. Winthrop KL, Klaff J, Penn SK, et al. Immunogenicity of adjuvanted recombinant zoster vaccine in patients with rheumatoid arthritis treated with upadacitinib: 60-week results from a randomised controlled trial substudy. RMD Open. 2025;11(3):e005521. doi:10.1136/rmdopen-2025-005521
2. Sandler DS, Ruderman EM, Brown T, et al. Understanding vaccination rates and attitudes among patients with rheumatoid arthritis. Am J Manag Care. 2016;22(3):161-167.
3. Din S, Selinger CP, Black CJ, Ford AC. Systematic review with network meta-analysis: risk of Herpes zoster with biological therapies and small molecules in inflammatory bowel disease. Aliment Pharmacol Ther. 2023;57(6):666-675. doi:10.1111/apt.17379
4. Bhattacharya A, Jan L, Burlak O, et al. Potent and long-lasting humoral and cellular immunity against varicella zoster virus induced by mRNA-LNP vaccine. NPJ Vaccines. 2024;9(1):72. doi:10.1038/s41541-024-00865-5