Assessment of Immunogenicity of Recombinant Zoster Vaccine in Immunosuppressed Rheumatic Disease Patients Treated with JAK Inhibitors and Methotrexate

The primary objective of this study is to assess the **immunogenicity** of the recombinant zoster vaccine (RZV) in patients with rheumatic disease (RD) who are treated with Janus kinase inhibitors (JAKi) either as monotherapy or in combination with Methotrexate, or with Methotrexate alone. This evaluation will focus on the gE-specific antibody and T cell responses one month after the second vaccine dose, which is clinically relevant for understanding the vaccine's effectiveness in this immunosuppressed population.

Secondary objectives include:

• Monitoring the reactogenicity profile by evaluating the frequency of local and systemic symptoms.
• Measuring inflammatory responses, including changes in serum cytokines and gene expression, one day after each dose of RZV.
• Assessing the persistence of gE-specific antibody and T cell responses one year post-vaccination.
• Correlating the inflammatory response at day one post-vaccination with immunogenicity and/or reactogenicity.
• Evaluating the function of immune cells at the time of vaccination and correlating with the vaccine response.
• Assessing the effect of the vaccine on the underlying rheumatologic disease during follow-up.
• Measuring the functionality of antibodies before and after vaccination.
• Assessing functional and epigenetic changes in specific innate cells one month and one year post-vaccination.
• Comparing the quality of the gE-specific T cell response post-vaccination.
• Evaluating the memory B cell response and changes in BCR repertoire following vaccination.
• Comparing the magnitude of immune and inflammatory responses post-vaccination with RZV and COVID-19 mRNA vaccines in a specific cohort.
• Assessing the level of serum JAKi in the blood to correlate with the vaccine response.

The clinical trial involves participants diagnosed with **rheumatic disease** who are undergoing treatment with JAK-inhibitors, either as monotherapy or in combination with Methotrexate, or with Methotrexate alone. The study population includes both male and female subjects aged 18 years and older, all of whom are in a stable clinical condition as assessed by the recruiting investigators. Participants are required to be able and willing to provide informed consent. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on individuals scheduled to receive the RZV vaccine, with no specific lifestyle considerations such as diet or physical activity mentioned.

The clinical trial is designed to evaluate the **immunogenicity** of the recombinant zoster vaccine (RZV) in patients with **rheumatic disease** who are undergoing treatment with JAK inhibitors, either as monotherapy or in combination with **methotrexate**, or with methotrexate alone. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thereby minimizing bias. The trial is authorized to commence on April 1, 2025, with an estimated completion date of April 1, 2027, spanning a total duration of approximately two years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), stable clinical condition, and willingness to provide informed consent. Following the initial screening, participants will receive the RZV vaccine, with subsequent follow-up visits scheduled to monitor the immune response and any adverse effects. The primary endpoint will be assessed at day 90, one month after the second vaccine dose, by measuring the geometric mean titer of gE-specific IgG and the mean of gE-specific CD4+ T cells. Secondary endpoints include the frequency of self-reported clinical symptoms, changes in pro-inflammatory markers, and the persistence of antibody and T cell responses over time.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including withdrawal of consent, adverse events, or any significant protocol deviations. The study aims to provide valuable insights into the immune response elicited by the RZV vaccine in this specific patient population, contributing to the understanding of vaccine efficacy and safety in individuals with rheumatic diseases. The trial will adhere to all regulatory requirements and ethical standards to ensure the safety and well-being of all participants throughout the study period.

The clinical trial involves the administration of several **experimental medications** and a non-experimental treatment. **Upadacitinib** is administered as a prolonged-release tablet with a maximum daily dose of 15 mg. The route of administration is oral, and the treatment period extends up to 12 months. **Upadacitinib** is a synthetic chemical substance used in this study.

**Methotrexate** is utilized in two forms: a solution for injection and a tablet. The maximum daily dose for both forms is 25 mg. The injectable form is administered via injection, while the tablet is taken orally. The treatment duration for **Methotrexate** is also up to 12 months. It is a synthetic chemical substance.

**Filgotinib** is provided as a film-coated tablet with a maximum daily dose of 200 mg, administered orally. The treatment period is up to 12 months. **Filgotinib** is a synthetic chemical substance.

**Baricitinib** is administered as a film-coated tablet with a maximum daily dose of 4 mg. The route of administration is oral, and the treatment period is up to 12 months. **Baricitinib** is a synthetic chemical substance.

**Tofacitinib** is provided in tablet form with a maximum daily dose of 11 mg, administered orally. The treatment duration is up to 12 months. **Tofacitinib** is a synthetic chemical substance.

The non-experimental treatment in this trial is the **Shingrix** vaccine, which is a recombinant, adjuvanted herpes zoster vaccine. It is administered as a suspension for injection, with a total dose of 1 ml given intramuscularly. The vaccine is administered in two doses, two months apart, with a maximum treatment period of 67 days. The active substance in the vaccine is **recombinant varicella zoster virus glycoprotein E**, a structurally diverse substance.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the **geometric mean titer (GMT)** of gE-specific IgG measured by ELISA and the mean of gE-specific CD4+ T cells expressing at least two markers (CD40L, IFN-gamma, IL-2, TNF-alpha) measured by flow cytometry. These measurements will be taken at day 90, which is one month after the second vaccine dose.

Secondary endpoints will evaluate various aspects of the immune response and clinical outcomes. These include the frequency of self-reported clinical symptoms occurring 7 days post-vaccination, changes in pro-inflammatory markers such as cytokines and CRP, and differential gene expression profiles assessed by RNA sequencing. The kinetics of GMT of gE-specific IgG and gE-specific CD4+ T cells will be monitored at multiple timepoints (day 0, 60, 90, and 360) to assess the persistence of antibody and T cell responses. Disease activity will be evaluated using validated scales such as the Rheumatoid Arthritis Disease Activity Index (RADAI) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), along with patient global assessments on a 0-10 scale.

Additional assessments include monitoring episodes of shingles, evaluating ADCC (antibody-dependent cellular cytotoxicity), and measuring levels of isotypes and avidity before and after vaccination. The study will also explore changes in memory phenotypes, activation and transcription marker levels, and TCR repertoire post-vaccination. Comparisons will be made between immune responses to the RZV vaccine and COVID-19 mRNA vaccines in a subset of participants. The level of JAK inhibitors will be quantified using mass spectrometry to correlate with vaccine response, including adaptive responses and reactogenicity.