Long-term Evaluation of Efficacy, Safety, and Immune Response Persistence of Recombinant Varicella Zoster Virus Glycoprotein E Vaccine in Herpes Zoster Prevention in Older Adults

The primary objective of this study is to evaluate the **vaccine efficacy** (VE) of the Herpes Zoster subunit vaccine (HZ/su) in preventing Herpes Zoster (HZ). This is clinically relevant as Herpes Zoster, commonly known as shingles, can lead to significant morbidity, especially in older adults, and effective prevention can reduce the incidence and associated complications of the disease.

Secondary objectives include:

• Evaluating the VE of HZ/su in preventing HZ from one month post Dose 2 in the ZOSTER-006/022 studies until the end of the ZOSTER-101 study.
• Assessing the persistence of the humoral immune response to HZ/su.
• Assessing the persistence of the cell-mediated immune response to HZ/su.
• Evaluating the vaccine safety of HZ/su.

The clinical trial involves a total of **1414 participants** who are being studied to evaluate the vaccine efficacy of HZ/su in preventing **Herpes Zoster**. The study population includes both male and female subjects, with age categories 3 and 4, indicating an adult population. Participants were selected based on their ability to comply with the study protocol, as determined by the investigator, and must have completed the ZOSTER-049 study, having received at least one dose of HZ/su in previous studies ZOSTER-006/022. All participants are medically stable, as confirmed by medical history and clinical examination prior to study entry. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is a **Phase III** study designed to evaluate the long-term efficacy, safety, and persistence of immune response of a **Herpes Zoster** subunit vaccine in older adults. The trial follows a **randomized**, **open-label**, multi-country, multi-center design, with an estimated duration from October 2022 to August 2027. Participants who have completed the ZOSTER-049 study, having received at least one dose of the vaccine in previous studies (ZOSTER-006/022), are eligible for inclusion. The primary objective is to assess the vaccine's efficacy in preventing Herpes Zoster, with primary endpoints including confirmed cases during the study's total duration, from Day 1 through Month 48.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on medical history and clinical examination. Participants must provide written or witnessed informed consent before any study-specific procedures. Follow-up visits are scheduled at regular intervals, specifically at Day 1, and Months 12, 24, 36, and 48, to monitor anti-gE antibody concentrations and the frequency of gE-specific CD4+ T-cells. These visits also include assessments for serious adverse events (SAEs) and potential immune-mediated diseases (pIMDs) related to the study intervention. The end-of-study visit marks the conclusion of participant involvement, with a comprehensive evaluation of the vaccine's long-term effects.

Participant involvement is expected to last approximately 48 months, with conditions for early termination including non-compliance with protocol requirements or the occurrence of significant adverse events. The study is classified as low-intervention, as no new administration of the investigational medicinal product is planned. Instead, the focus is on monitoring through blood samples for immunogenicity assessment and lesion samples for vaccine efficacy evaluation. These procedures are considered to pose minimal additional risk compared to standard clinical practice.

The clinical trial involves the administration of **Shingrix**, a **Herpes zoster vaccine** (recombinant, adjuvanted), which is utilized to assess its prophylactic efficacy, safety, and persistence of immune response. The experimental medication is presented in the form of a **powder and suspension for suspension for injection**. The active substance in this vaccine is **recombinant varicella zoster virus glycoprotein E**, which is classified as a structurally diverse substance - vaccine. The vaccine is administered via the **intramuscular route**. The dosing schedule involves a maximum treatment period of one unit of time, with no specified maximum daily or total dose amount, indicating that the dosing is likely determined by the study protocol rather than a fixed daily regimen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of the Shingrix vaccine. Participant compliance with the dosing schedule is monitored as part of the study protocol to ensure accurate assessment of the vaccine's efficacy and safety. The trial is conducted under the sponsorship of GlaxoSmithKline Biologicals S.A., and the vaccine is not a pediatric formulation, indicating its use in an adult population. The study aims to evaluate the vaccine's effectiveness in preventing **Herpes zoster** and to assess the persistence of the immune response following one or two additional doses administered in the ZOSTER-049 study.

The efficacy of the Herpes Zoster subunit vaccine will be assessed in the ZOSTER-101 study through several primary and secondary endpoints. The primary endpoint is the number of confirmed Herpes Zoster (HZ) cases during the total duration of the study, from Day 1 through Month 48. Secondary endpoints include the number of confirmed HZ cases from one month post Dose 2 in the ZOSTER-006/022 studies until the end of the ZOSTER-101 study, as well as the measurement of **anti-gE antibody concentrations** at specified timepoints: Day 1, Months 12, 24, 36, and 48. Additionally, the frequency of gE-specific CD4+ T-cells secreting at least two activation markers (IFN-γ, IL-2, TNF-α, CD40L) will be evaluated at the same timepoints.

Data collection will involve blood samples for immunogenicity assessment and Herpes Zoster lesion samples for vaccine efficacy assessment. These samples will be collected through venepuncture and swab/needle sampling of lesions or crusts of suspected herpes zoster rash. The study will also monitor the number and percentage of participants with serious adverse events (SAEs) and potential immune-mediated diseases (pIMDs) that are causally related to the study intervention, as well as HZ-related complications of confirmed HZ cases, throughout the study duration. These assessments are designed to ensure a comprehensive evaluation of the vaccine's efficacy and safety over the long term.