Non-Inferiority Trial Assessing Immunogenicity and Safety of Intradermal vs. Intramuscular Rabies Virus (Inactivated) Strain Flury LEP in Adults

The primary objective of this study is to determine if a 4 x 0.1 mL intradermal (**ID**) or a 1 x 1.0 mL intramuscular (**IM**) priming dose of the rabies vaccine is clinically not inferior to the standard of care schedule. This is assessed by the boostability, defined as the percentage of subjects with rabies antibodies ≥ 0.5 IU/mL, 7 days after booster doses. This objective is clinically relevant as it evaluates the potential for alternative dosing regimens to provide effective immunogenicity, which could enhance vaccination strategies against **rabies**.

Secondary objectives include:

• Assessing serological response (titre ≥ 3.0 IU/ml and ≥ 10 IU/ml) 7 and 28 days after the booster vaccination in all arms.
• Evaluating seroconversion at day 28 after pre-exposure vaccination for the 3 regimens, with a titre ≥ 0.5 IU/ml considered successful.
• Assessing the serological response (≥ 0.5 IU/ml) at all other visits for the different arms.
• Determining which vaccination schedule results in the steepest slope of difference in antibody response between successive visits after the booster.
• Estimating the difference in antibody response for each arm between the day of the booster and days 7, 28, and 90 after the booster.
• Assessing the geometric mean titres at all visits for the 3 arms and comparing the GMTs between the respective intervention groups and the standard of care group.

The clinical trial involves a study population comprising both **male** and **female** participants, aged between 18 to 60 years. The trial is focused on individuals residing permanently in Belgium during the study period. Participants are required to be in general good health, with no specific health conditions mentioned as part of the inclusion criteria. The total number of participants is not provided by the sponsor. The selection process for the trial population includes individuals who are willing to provide written informed consent and adhere to the study schedule. Additionally, women of childbearing potential are required to use contraception for one month following each vaccination. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial is designed to assess the effectiveness of different dosing schedules for **rabies** vaccination, with a focus on the boostability of rabies antibodies. The trial includes a vulnerable population, although specific details about this group are not disclosed.

The clinical trial is designed to evaluate the **immunogenicity** and safety of a rabies vaccine using two different dosing regimens in adults. This is a two-centre, open-label, non-inferiority trial comparing an intradermal (ID) and an intramuscular (IM) single-visit dosing regimen. The trial aims to determine if a 4 x 0.1 mL ID or a 1 x 1.0 mL IM priming dose is clinically not inferior to the standard of care schedule, as assessed by the percentage of subjects with rabies antibodies ≥ 0.5 IU/mL seven days after booster doses. The trial is expected to commence recruitment on April 1, 2024, and conclude by August 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 60 years), willingness to provide informed consent, and permanent residency in Belgium. Following the initial visit, participants will receive their assigned vaccination regimen. Follow-up visits will occur to monitor antibody levels and safety, with primary endpoints measured on day 7 after the booster. Secondary endpoints include antibody levels on days 7 and 28 post-booster, and the geometric mean titers (GMTs) at all visits. The end-of-study visit will assess the final antibody response and overall safety.

The expected duration of participant involvement is approximately 17 months, from the initial screening to the end-of-study visit. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with the study protocol, or adverse events that compromise participant safety. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the results, contributing valuable data to the field of rabies prevention.

The clinical trial involves the administration of **Rabipur**, a vaccine formulated as a **solution for injection**. The active substance in this experimental medication is the **rabies virus (inactivated) strain Flury LEP**. The pharmaceutical form is a powder and solvent for solution for injection, provided in a pre-filled syringe. The vaccine is administered via **intramuscular injection**. The dosing regimen for the trial includes a maximum daily dose of 1 mL, with a total maximum dose of 4 mL over the treatment period. The maximum treatment period is 4 days. The vaccine is manufactured by Bavarian Nordic A/S and is not a pediatric formulation.

In this study, the experimental treatment is compared to a standard-of-care therapy. The trial aims to assess the immunogenicity and safety of the vaccine by determining if a 4 x 0.1 mL intradermal or a 1 x 1.0 mL intramuscular priming dose is clinically not inferior to the standard schedule. The primary endpoint is the boostability, defined as the percentage of subjects with rabies antibodies ≥ 0.5 IU/mL, measured 7 days after booster doses. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed by evaluating the **boostability** of rabies antibodies in participants. The primary endpoint is the difference in boostability on day 7 after the booster between the respective intervention groups and the standard of care group. Secondary endpoints include the percentage of subjects with rabies antibodies ≥3.0 IU/mL and ≥10.0 IU/mL on day 7 and day 28 after booster vaccination, as well as the percentage of subjects with rabies antibodies ≥0.5 IU/mL on day 28 after pre-exposure vaccination and at every visit for each regimen. Additionally, rabies serology slopes between successive visits after the booster, the mean difference in antibody response between the day of the booster and days 7, 28, and 90 after the booster, and the geometric mean titers (GMTs) at all visits in all arms will be analyzed. The ratio between the GMTs in the intervention arms and the standard of care arm will also be evaluated. These parameters will be measured at specified timepoints, including day 7, day 28, and day 90, using validated laboratory tests to ensure accurate and reliable data collection and analysis.