Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases

Summary

Introduction: Patients with autoimmune rheumatic diseases (ARDs), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PAs), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) , systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM) and primary vasculitides, have a high risk of herpes zoster (HZ) infection. This increased susceptibility is caused by a deficient cell-mediated immune response due to the underlying disease and glucocorticoid and immunosuppressive treatments that impair the T-cell response, including conventional and unconventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and biological agents. In this context, the recent availability of a recombinant vaccine against HZ (RZV or Shingrix®), composed of recombinant VZV glycoprotein E (gE) and the AS01B adjuvant system (HZ/su), is a major progress regarding safety for immunosuppressed patients. Its effectiveness, however, has been clearly demonstrated for non-immunosuppressed patients and in selected populations of immunocompromised individuals. There are no prospective controlled studies evaluating the immunogenicity of RZV and its impact on the activity of the underlying disease, as well as its safety in patients with ARDs at high-risk for HZ.

Hypothesis: RZV has a good safety profile, including with respect to underlying rheumatic disease activity, in patients with ARDs at high risk of HZ.

Objectives: Primary: To assess the short-term safety profile in relation to underlying disease activity in patients with ARDs at high risk of HZ immunized with RZV compared to unvaccinated patients. Secondary: To evaluate the general safety of the vaccine in patients with ARDs at high risk of HZ immunized with RZV and non-immunosuppressed control subjects (CG); the humoral and cellular immunogenicity of RZV in patients with ARDs at high risk of HZ compared to CG; the influence of disease treatment on vaccine response; the 12-month persistence of humoral immunogenicity and incident cases of HZ. Specific studies will also be carried out to evaluate the effect of drug withdrawal (methotrexate-MTX and mycophenolate mofetil-MMF) after vaccination in increasing the immune response in patients with ARDs with controlled underlying disease.

On November 19, 2025, the institutional Ethics Committee approved an amendment to extend the project's timeframe to evaluate the following hypothesis:

\- Immunosuppression may hamper 5-year long-term sustainability of humoral and cellular immune responses to RZV in ARD patients.

No new patients will be recruited, nor will any new intervations be performed. ARD patients previously included in the study and non-immunosuppressed control subjects who received both vaccine doses and collected samples for immunogenicity 6 weeks and one year after the second dose will be part of the proposed extension. A total of 1,025 ARD patients enrolled and 365 healthy controls will be included in the long-term follow-up phase. Considering a conservative 10% dropout, the final patient sample will be approximately 1,000.

Ethical statement: The extension protocol was approved by the institutional Ethics Committee (report 7.988.896), and written consent will be obtained from all participants prior to inclusion. Humoral immunogenicity will be evaluated by analyzing the serum concentrations of anti-gE antibodies (ELISA) of blood samples collected from participants at 5-year after complete VZR vaccination, as previously described (Cunningham et al., 2018). Cellular immunogenicity will be evaluated in a convenience sample (20% of the total research participants) of patients with ARDs and healthy controls at 5-year after complete VZR vaccination. Vaccine efficacy will be evaluated by incident cases of HZ in the period of 5 years after RZV vaccination. Participants will be followed for 5 years after the second RZV dose through monthly contacts and routine clinical visits every 3-6 months.

Conditions

• Rheumatoid Arthritis
• Spondylitis, Ankylosing
• Spondyloarthritis
• Systemic Lupus Erythematosus
• Sjogren's Syndrome
• Systemic Sclerosis
• Idiopathic Inflammatory Myopathies
• Vasculitis, Systemic
• Juvenile Idiopathic Arthritis
• Dermatomyositis, Juvenile
• Behçet Disease

Interventions

BIOLOGICAL

Recombinant Herpes Zoster Vaccine (RZV)

RZV comprise 50 μg of recombinant VZV glycoprotein E and the liposome-based AS01B adjuvant system (which contains 50 μg of 3-O-desacyl-4'-monophosphoryl lipid A \[MPL\] and 50 μg of Quillaja saponaria Molina, fraction 21 (QS21, licensed by GSK from Antigenics, a subsidiary of Agenus)). Vaccine will be administered (0.5 ml) into the deltoid muscle at inclusion and 6 weeks (two doses).

OTHER

MTX Discontinuation

Evaluation of discontinuation of the use of methotrexate (MTX) for 2 weeks after each vaccine dose in ARD patients: patients using MTX at a stable dose for at least 12 weeks, prednisone maximum dose of 5 mg/day, in association or not with other drugs except rituximab will be consecutively evaluated at outpatient clinics regarding disease activity. Those considered to be at stable disease (at remission or low disease activity according to specific standardized disease activity indexes) will be randomized (1:1) into two arms: one that will withhold MTX for 2 weeks after each vaccine dose (MTX-withhold) and other that will maintain stable therapy (MTX-maintain).

OTHER

MMF Discontinuation

Evaluation of discontinuation of the use of mycophenolate mofetil (MMF) for one week after each vaccine dose in ARD patients: patients using MMF at a stable dose for at least 12 weeks, prednisone maximum dose of 7.5 mg/day, not associated with other immunosuppressive therapy, will be consecutively evaluated at outpatient clinics regarding disease activity. Those considered to be at stable disease (at remission or low disease activity according to specific standardized disease activity indexes) will be randomized (1:1) into two arms: one that will withhold MMF for 2 weeks after each vaccine dose (MMF-withhold) and other that will maintain stable therapy (MMF-maintain).

OTHER

Placebo

Patients with ARDs who received the placebo at study entry (P2). ARD patients will be randomly assigned in a 1:1 ratio, with the use of an automated Web and telephone system, to one of two subgroups: P1, patients allocated to receive vaccine right after randomization (at D0 and D42), and P2, patients allocated to receive placebo at D0 and D42. Subsequently, blindness will be broken at D84 and P2 patients will receive vaccine doses at the D84 and D126.

OTHER

MTX maintain

MTX dose will be held stable after the two vaccine doses for comparison of vaccine immunogenicity and disease activity with the MTX-withhold group.

OTHER

MMF maintain

MMF dose will be held stable after the two vaccine doses for comparison of vaccine immunogenicity and disease activity with the MMF-withhold group.

Sponsors & Collaborators

• GlaxoSmithKline

  collaborator INDUSTRY

• University of Sao Paulo General Hospital

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2023-05-23

Primary Completion

2025-12-01

Completion

2032-06-30

Countries

• Brazil

Study Locations