Evaluation of Epicutaneous Versus Intramuscular Administration of Live Attenuated Measles, Mumps, and Rubella Vaccine in Inducing Mucosal Immune Response in Adults

The primary objective of this study is to evaluate whether **epicutaneous vaccination** (EV) with the live attenuated Measles, Mumps, and Rubella (MMR) vaccine induces an appropriate mucosal measles IgA response three months post-intervention in human volunteers. This is clinically relevant as it explores an alternative route of administration that could potentially enhance mucosal immunity, which is crucial for protection against respiratory pathogens.

Secondary objectives include assessing whether EV with the MMR vaccine generates appropriate systemic and respiratory (mucosal) immune responses at various time points: 14 days, 1.5 months, 3 months, and 6 months, and again after a cross-over intervention at the same intervals. These objectives aim to provide a comprehensive understanding of the immune response dynamics following EV, which could inform future vaccination strategies.

The clinical trial involves **human volunteers** aged 18 to 34 years, who are **MMR-naive** and in good health. Both male and female participants are included, with a requirement for safe contraception for female participants. The study does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, ensuring participants are within the specified age range and health status. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the induction of respiratory immune responses through epicutaneous vaccination with the **measles, mumps, and rubella (MMR)** vaccine. This study employs a randomized cross-over design involving human volunteers to assess whether epicutaneous vaccination (EV) with the live attenuated MMR vaccine generates an appropriate mucosal measles IgA response three months post-intervention. The trial is conducted in a double-blind manner to ensure unbiased results, with a control group receiving the standard MMR vaccine administration via subcutaneous or intramuscular injection. The primary endpoint is the level of measles-specific mucosal IgA immune response, measured by ELISA methods, three months after EV compared to the standard administration. Secondary endpoints include the measurement of measles neutralizing antibodies, IgG, IgM, and IgA levels, as well as CD4+ and CD8+ T-cell responses in various biological samples.

The trial is expected to last until December 30, 2024, with recruitment starting on June 15, 2023. Participants will be involved in the study for a maximum treatment period of one month. The study includes several visits: an initial screening visit to confirm eligibility based on criteria such as age (18 to 34 years), MMR-naive status, and overall health, followed by vaccination visits and subsequent follow-up visits to monitor immune responses and any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. Participants may be terminated early from the study if they experience significant adverse events or if they no longer meet the inclusion criteria. The trial is categorized as a Phase 4 study, emphasizing the need to publish primary results in scientific journals. The study aims to provide valuable insights into the efficacy of epicutaneous vaccination compared to traditional methods, potentially influencing future vaccination strategies.

The clinical trial involves the administration of **M-M-RvaxPro**, a powder and solvent for suspension for injection, which is a live attenuated vaccine targeting measles, mumps, and rubella. The vaccine contains three active substances: **Rubella virus Wistar RA 27/3 strain** (live, attenuated) produced in WI-38 human diploid lung fibroblasts, **Mumps virus Jeryl Lynn (Level B) strain** (live, attenuated) produced in chick embryo cells, and **Measles virus Edmonston-Enders strain** (live, attenuated) produced in chick embryo cells. The pharmaceutical form is a suspension for injection, and the vaccine is administered via injection. The maximum daily dose is 0.5 ml, with a total maximum dose of 1 ml over a treatment period of one day.

In this study, the **M-M-RvaxPro** vaccine is also administered via intraepidermal use as part of a randomized cross-over design to evaluate the induction of respiratory immune responses. The objective is to assess whether epicutaneous vaccination with the live attenuated MMR vaccine generates an appropriate mucosal measles IgA response three months post-intervention. The vaccine is provided by Merck Sharp & Dohme BV and is not a pediatric formulation. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed by evaluating the **measles-specific mucosal IgA immune response** three months after epicutaneous vaccination (EV) with the live attenuated Measles, Mumps, and Rubella (MMR) vaccine. The primary endpoint involves comparing these IgA levels with those obtained from the standard MMR vaccine administration via subcutaneous or intramuscular injection. The measurement of IgA levels will be conducted using ELISA methods, a well-established laboratory technique for quantifying antibodies.

Secondary endpoints include the assessment of nasal secretion and serum for measles neutralizing antibodies using the gold standard PRNT, as well as the measurement of Measles, Mumps, and Rubella IgG, IgM, and IgA levels by ELISA. Additionally, full blood samples will be analyzed for measles-specific CD4+ and CD8+ T-cell responses, and tonsil brushings will be used to evaluate similar T-cell responses. The frequency of side effects or adverse events will also be monitored and compared 30 days post-vaccination.