High-Level Highlights
1. Non-Inferior Flare Risk
The study successfully met its primary endpoint, demonstrating that the recombinant zoster vaccine (RZV) is non-inferior to placebo regarding the risk of disease flares in patients with autoimmune rheumatic diseases (AIRD). The flare rate was 14% in the vaccine group compared to 15% in the placebo group.
2. Attenuated Reactogenicity in Immunosuppressed Patients
Patients with AIRD reported fewer adverse events compared to healthy controls. This suggests that the baseline immunosuppressive therapy used to manage rheumatic conditions may dampen the immediate inflammatory response to the vaccine’s adjuvant system.
3. Robust Safety Profile
Serious adverse events were rare and balanced across the RZV and placebo groups, confirming that RZV is a safe option for this high-risk population who are often excluded from live-attenuated vaccine protocols.
Disease Burden and Clinical Context
Patients diagnosed with autoimmune rheumatic diseases (AIRD), such as rheumatoid arthritis, systemic lupus erythematosus, and vasculitis, face a significantly elevated risk of herpes zoster (HZ) compared to the general population. This vulnerability is multifactorial, stemming from intrinsic immune dysregulation associated with the underlying disease and the secondary effects of immunosuppressive medications. Traditional management involving glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and biological agents further compromises cell-mediated immunity, which is crucial for keeping the varicella-zoster virus in a latent state.
Historically, the prevention of shingles in this population was complicated by the nature of the available vaccines. The older live-attenuated zoster vaccine was generally contraindicated in patients on potent immunosuppression due to the risk of vaccine-derived viral replication. The advent of the recombinant zoster vaccine (RZV), which utilizes a viral surface glycoprotein (gE) combined with the AS01B adjuvant system, offered a non-live alternative. However, concerns remained among clinicians that the potent adjuvant system might trigger an immune-mediated flare of the underlying rheumatic condition. This phase 4 study addresses these concerns with high-level clinical evidence.
Study Design and Methodology
This single-center, double-blind, randomized, placebo-controlled, phase 4 study was conducted at a tertiary referral center in Brazil. The trial enrolled 1,192 patients aged 18 years or older with a confirmed diagnosis of an AIRD. A critical inclusion criterion was that patients had to be on a stable dose of glucocorticoids or DMARDs for at least 4 to 12 weeks prior to the initial study visit to ensure baseline disease stability.
Participants were randomly assigned in a 1:1 ratio to receive two doses of RZV or a saline placebo, administered 6 weeks apart. To provide a benchmark for safety and reactogenicity, a separate cohort of 393 healthy controls was enrolled and received two doses of RZV. Following the initial 84-day double-blind phase, patients in the placebo arm were transitioned to an open-label phase to receive the vaccine, ensuring all participants eventually had access to prophylaxis.
The primary outcome was the incidence of disease flares (worsening of disease activity) within 84 days of the first dose. Non-inferiority was predefined as the upper boundary of the one-sided 95% CI for the difference in flare rates between RZV and placebo being less than 5%.
Analysis of Key Findings
Efficacy and Flare Rates
The primary analysis included 559 patients in the RZV group and 557 in the placebo group. The results provided strong evidence of safety regarding disease stability. In the RZV group, 80 patients (14%) experienced a flare, while 84 patients (15%) in the placebo group experienced a flare. The between-group difference was calculated at -1.2% (95% CI -4.7 to 2.2). With a p-value for non-inferiority of 0.0018, the study clearly demonstrated that the vaccine does not exacerbate underlying autoimmune activity beyond the levels seen with a placebo injection.
Safety and Reactogenicity Comparisons
One of the most intriguing findings of the study was the comparison between AIRD patients and healthy controls regarding adverse events (AEs). Following the first dose, 77% of the AIRD-RZV group reported AEs, compared to 90% of the healthy control group. After the second dose, the rates were 72% and 81%, respectively. This indicates that while the vaccine is reactogenic, patients on immunosuppressive therapy actually report fewer symptoms—such as injection site pain, fatigue, or myalgia—than healthy individuals. This is likely due to the immunosuppressive agents blunting the cytokine response typically triggered by the AS01B adjuvant.
Serious Adverse Events
Safety monitoring showed that serious adverse events (SAEs) were infrequent. After the first dose, SAEs occurred in 1% of both the RZV and placebo groups. After the second dose, the incidence remained low (2% in RZV vs. 1% in placebo). No new safety signals were identified, and the profile was consistent with previous trials conducted in immunocompromised populations, such as those with hematologic malignancies or solid organ transplants.
Expert Commentary and Clinical Implications
The results of this phase 4 study are highly reassuring for the rheumatology community. For years, vaccine hesitancy in the context of autoimmune disease has been fueled by the theoretical risk of molecular mimicry or adjuvant-induced immune stimulation leading to disease flares. By utilizing a double-blind, placebo-controlled design—the gold standard of clinical evidence—this study provides definitive data that the RZV does not trigger significant short-term worsening of rheumatic diseases.
Clinicians should note the demographic diversity of the study population, which included nearly equal proportions of patients of African descent and White patients, enhancing the generalizability of the findings. The single-center nature of the study in Brazil is a limitation, but the large sample size and rigorous masking protocols lend significant weight to the conclusions. Furthermore, the observation that immunosuppressed patients experience fewer side effects than healthy controls can be used during patient counseling to manage expectations regarding post-vaccination discomfort.
While the study focused on safety and flares (short-term outcomes up to day 84), the long-term immunogenicity and efficacy of RZV in this specific cohort remain areas of ongoing interest. Given the high burden of HZ-related complications, such as post-herpetic neuralgia, these safety data support the proactive integration of RZV into the standard vaccination schedule for patients with AIRD.
Summary and Conclusions
The Brazilian phase 4 trial confirms that the recombinant zoster vaccine is safe and well-tolerated in patients with autoimmune rheumatic diseases. The study met its primary non-inferiority endpoint, showing no increased risk of disease flares compared to placebo. Furthermore, the vaccine exhibited a favorable reactogenicity profile in the AIRD population compared to healthy controls. These findings support current clinical guidelines recommending HZ vaccination for immunocompromised adults and should help reduce physician and patient concerns regarding vaccine-induced disease instability.
Funding and Trial Registration
This study was funded by GSK and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). The trial is registered with ClinicalTrials.gov under the identifier NCT05879419.
References
1. Aikawa NE, Medeiros-Ribeiro AC, Pasoto SG, et al. Recombinant herpes zoster vaccine in patients with autoimmune rheumatic diseases in Brazil: a double-blind, randomised, placebo-controlled, phase 4, non-inferiority study. Lancet Rheumatol. 2026 Feb 9:S2665-9913(25)00313-3. doi: 10.1016/S2665-9913(25)00313-3.
2. Stevens E, Waters M, Khanna S, et al. Safety and Immunogenicity of Recombinant Zoster Vaccine in Adults with Primary or Secondary Immunodeficiencies. Journal of Clinical Medicine. 2023; 12(14):4567.
3. Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020;79(1):39-52.