Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases

NCT05879419 | Active Not Recruiting Phase 4 DMC

• 1 other identifier: 67374823.0.0000.0068
• Study Type: interventional
• Target: 2,005
• Locations: 1 country
• Sites: 1

Brief 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

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

Keywords

Recombinant herpes zoster vaccine; Herpes zoster; Autoimmune rheumatic diseases; Disease activity; Safety; Immunogenicity; Disease-modifying anti-rheumatic drugs; Biological disease-modifying anti-rheumatic drugs; Glucocorticoid

Outcome Measures

Primary Outcomes (3)

• Subproject A: Disease safety (flare) in ARD patients immunized with RZV in comparison to non-vaccinated ARD patients (placebo group)

  Flare will be defined as a new flare or worsening of previous disease activity according to established scores for each ARD or the change of therapy. Disease activity will be evaluated in ARD patients according to specific standardized disease activity indexes: RA (DAS28 - Disease Activity Score 28, RA-CDAI - Rheumatoid Arthritis Clinical Disease Activity Index), SLE (SLEDAI2K - Systemic Lupus Erythematosus Disease Activity Index 2000), pSS (ESSDAI- EULAR Sjögren's Syndrome Disease Activity Index), IIM (MMT - Manual Muscle Test), AxS (ASDAS - Ankylosing Spondylitis Disease Activity Score), and vasculitis (Birmingham Vasculitis Activity Score).

  Six months

• Subproject B: Effect of MTX discontinuation on immunogenicity in comparison to MTX maintenance

  Humoral immunogenicity will be assessed through serum anti-gE antibody concentrations analysis (ELISA) of blood samples collected from participants at pre-vaccination, 6 weeks, and one-year after the second dose of RZV. The frequencies of gE-specific CD4\[2+\] T cells (CD4+ T-cells expressing at least 2 activation markers of the 4 markers assessed: interferon-γ, interleukin 2, tumor necrosis factor-α, and CD40 ligand) will be measured after in vitro stimulation with a pool of peptides covering the gE ectodomain, by intracellular cytokine staining and detection by flow cytometry, in a convenience sample (20% of total research participants).

  One year

• Subproject B: Effect of MMF discontinuation on immunogenicity in comparison to MMF maintenance

  Humoral immunogenicity will be assessed through serum anti-gE antibody concentrations analysis (ELISA) of blood samples collected from participants at pre-vaccination, 6 weeks, and one-year after the second dose of RZV. The frequencies of gE-specific CD4\[2+\] T cells (CD4+ T-cells expressing at least 2 activation markers of the 4 markers assessed: interferon-γ, interleukin 2, tumor necrosis factor-α, and CD40 ligand) will be measured after in vitro stimulation with a pool of peptides covering the gE ectodomain, by intracellular cytokine staining and detection by flow cytometry, in a convenience sample (20% of total research participants).

  One year

Secondary Outcomes (2)

• Subproject A: Incidence of vaccine adverse events [safety and tolerability] in ARD patients immunized with RZV in comparison to non-vaccinated ARD patients (placebo group) and non-immunosupressed controls (control group)

  Eighteen months

• Subproject A: Humoral immunogenicity of the RZV in ARD patients in comparison to non-immunosupressed control group

  One year

Other Outcomes (1)

• Subproject A: Incident cases of HZ after RZV vaccination in ARD patients and in the non-immunosupressed control group

  Eighteen months

Study Arms (7)

Subproject A: Patients with ARDs who received the vaccine at study entry (P1)

ACTIVE COMPARATOR

Patients with ARDs who received the vaccine at study entry (P1) (n = 590). 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.

Biological: Recombinant Herpes Zoster Vaccine (RZV)

Subproject A: Patients with ARDs who received the placebo at study entry (P2)

PLACEBO COMPARATOR

Subproject A: Patients with ARDs who received the placebo at study entry (P2) (n = 590). 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.

Biological: Recombinant Herpes Zoster Vaccine (RZV); Other: Placebo

Subproject A: Control group of non-immunosuppressed individuals (CG)

ACTIVE COMPARATOR

Subproject A: Control group of non-immunosuppressed individuals (CG) (n = 393). The control group of non-immunosuppressed individuals (CG) (≥50 years old) will be invited to receive the vaccine at study entry (3 patients:1 control).

Biological: Recombinant Herpes Zoster Vaccine (RZV)

Subproject B: MTX-withhold

ACTIVE COMPARATOR

Subproject B: MTX-withhold (n = 101). 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, to be randomized 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).

Biological: Recombinant Herpes Zoster Vaccine (RZV); Other: MTX Discontinuation

Subproject B: MTX-maintain

ACTIVE COMPARATOR

Subproject B: MTX-maintain (n = 101). 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, to be randomized 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).

Biological: Recombinant Herpes Zoster Vaccine (RZV); Other: MTX maintain

Subproject B: MMF-withhold

ACTIVE COMPARATOR

Subproject B: MMF-withhold (n = 115). Patients with ARDs 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 one week after each vaccine dose (MMF-withhold) and other that will maintain stable therapy (MMF-maintain).

Biological: Recombinant Herpes Zoster Vaccine (RZV); Other: MMF Discontinuation

Subproject B: MMF-maintain

ACTIVE COMPARATOR

Subproject B: MMF-maintain (n = 115). Patients with ARDs 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 one week after each vaccine dose (MMF-withhold) and other that will maintain stable therapy (MMF-maintain).

Biological: Recombinant Herpes Zoster Vaccine (RZV); Other: MMF maintain

Interventions

MTX Discontinuation OTHER

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).

Subproject B: MTX-withhold

Recombinant Herpes Zoster Vaccine (RZV) BIOLOGICAL

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).

Also known as: Shingrix®

Subproject A: Control group of non-immunosuppressed individuals (CG); Subproject A: Patients with ARDs who received the placebo at study entry (P2); Subproject A: Patients with ARDs who received the vaccine at study entry (P1); Subproject B: MMF-maintain; Subproject B: MMF-withhold; Subproject B: MTX-maintain; Subproject B: MTX-withhold

MMF Discontinuation OTHER

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).

Subproject B: MMF-withhold

Placebo OTHER

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.

Subproject A: Patients with ARDs who received the placebo at study entry (P2)

MTX maintain OTHER

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

Subproject B: MTX-maintain

MMF maintain OTHER

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

Subproject B: MMF-maintain

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects will be adults (≥18 years-old).
• ARD patients will be selected from patients regularly followed up at the Outpatient Rheumatology Clinics of the Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil, according to the specific classification criteria: RA (Aletaha et al., 2010), SLE (Petri et al., 2012), pSS (Vitali et al., 2002), SSc (van den Hoogen et al., 2013), IIM (Lundberg et al., 2017), axial spondyloarthritis (axSpA) (Rudwaleit et al., 2009), PsA (Tillett et al., 2012) and granulomatosis with polyangiitis (Leavitt et al., 1990).

You may not qualify if:

• history of any reaction or hypersensitivity to any component of the vaccine;
• previous HZ vaccination;
• any occurrence of Guillain-Barré syndrome;
• hospitalization, acute infectious disease or fever at the time of vaccination;
• pregnancy or lactation at the time of vaccination;
• history of HZ within the 12 months preceding the first dose of study vaccine;
• people living with HIV/AIDS (PLWHA).

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Rheumatology Division of Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo

São Paulo, São Paulo, 05403-000, Brazil

Location

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MeSH Terms

Conditions

Arthritis, Rheumatoid; Spondylitis, Ankylosing; Spondylarthritis; Lupus Erythematosus, Systemic; Sjogren's Syndrome; Scleroderma, Systemic; Myositis; Systemic Vasculitis; Arthritis, Juvenile; Dermatomyositis; Behcet Syndrome; Herpes Zoster

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Axial Spondyloarthritis; Spondylarthropathies; Spondylitis; Spinal Diseases; Bone Diseases; Ankylosis; Xerostomia; Salivary Gland Diseases; Mouth Diseases; Stomatognathic Diseases; Dry Eye Syndromes; Lacrimal Apparatus Diseases; Eye Diseases; Skin Diseases; Muscular Diseases; Neuromuscular Diseases; Nervous System Diseases; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Polymyositis; Uveitis, Anterior; Panuveitis; Uveitis; Uveal Diseases; Hereditary Autoinflammatory Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Skin Diseases, Vascular; Varicella Zoster Virus Infection; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Subproject A: Randomized prospective study of adult patients with ARDs who will receive two intramuscular doses of RZV 6 weeks apart or placebo. Subproject B: Specific studies will to evaluate the effect of drug withdrawal (MTX and MMF) after vaccination in increasing the immune response in patients with ARDs with controlled baseline disease. Randomization of patients with ARDs with well-controlled disease selected for the MTX discontinuation protocol will divide them into two groups: MTX-suspension, in which MTX will be suspended for 2 weeks after each vaccine dose, and another group that will maintain stable therapy (MTX-maintenance). The same applies to patients undergoing the MMF discontinuation protocol (but the MMF suspension time will be one week after each vaccine dose).
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Subproject A: Randomized prospective study of adult patients with ARDs who will receive two intramuscular doses of RZV 6 weeks apart or placebo. Subproject B: Specific studies will evaluate the effect of drug withdrawal (MTX and MMF) after vaccination in increasing the immune response in patients with ARDs with controlled baseline disease. Randomization of patients with ARDs with well-controlled disease selected for the MTX discontinuation protocol will divide them into two groups: MTX-suspension, in which MTX will be suspended for 2 weeks after each vaccine dose, and another group that will maintain stable therapy (MTX-maintenance), with assessments of immunogenicity and disease activity. The same applies to patients undergoing the MMF discontinuation protocol (but the MMF suspension time will be one week after each vaccine dose).

Study Record Dates

• First Submitted: May 2, 2023
• First Posted: May 30, 2023
• Study Start: May 23, 2023
• Primary Completion: December 1, 2025
• Study Completion (Estimated): June 30, 2032
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)