Evaluation of Safety and Immunogenicity of OVX033 Sarbecovirus Vaccine in Adults: A Phase 1/2a Randomized, Double-Blind, Multicenter Study

The primary objective of this study is to evaluate the **safety** and reactogenicity of two intramuscular (IM) administrations of the OVX033 sarbecovirus candidate vaccine, administered one month apart, at three dose levels (100µg, 250µg, and 500µg), in comparison to placebo. This evaluation is conducted in subjects aged 18 to 49 years during Phase 1, and in subjects aged 18 years and older during Phase 2a. The clinical relevance of this objective lies in determining the vaccine's safety profile and its potential adverse effects, which are critical for assessing its suitability for broader use.

Secondary objectives include:

• Phase 1: Evaluating the cell-mediated and humoral **immunogenicity** of the vaccine at the specified dose levels, compared to placebo, in subjects aged 18 to 49 years.
• Phase 2a: Assessing the humoral immunogenicity and additional cell-mediated immunogenicity parameters, such as the percentage of CD4+ and CD8+ T-cells expressing cytokines (IFNγ, IL2, and TNFα), in subjects aged 18 years and older. This evaluation may be conducted in a subset or all subjects, depending on ELISPOT results.

The clinical trial involves a study population comprising **healthy** male and female subjects, aged 18 to 49 years for Phase 1, and 18 years and older for Phase 2a. The sponsor has not provided the total number of participants. Participants were selected based on their health status, as determined by medical history and examination, and all subjects must have received at least two immunizations with a licensed SARS-CoV-2 (COVID-19) vaccine, with the last dose administered at least one month prior to the investigational vaccine. The trial does not include a vulnerable population. Participants are required to be reliable, willing to adhere to study procedures, and capable of using an eDiary on electronic devices. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the safety and immunogenicity of the OVX033 sarbecovirus candidate vaccine. The trial is structured in two phases: Phase 1, which follows a sequential dose-escalation design, and Phase 2a, which employs a parallel design across multiple centers. Participants will receive two intramuscular administrations of the vaccine at one-month intervals, with three different dose levels being tested (100 µg, 250 µg, and 500 µg). The trial will compare these doses against a placebo to assess both safety and immune response.

The trial is expected to commence recruitment on September 1, 2025, and conclude by February 28, 2027. Participants will be involved in the study for a duration that includes the initial administration phase and a subsequent observation period of five months following the second administration. The study visits are sequenced as follows: an initial inclusion (screening) visit to confirm eligibility, followed by the first administration visit, a second administration visit one month later, and several follow-up visits to monitor safety and immunogenicity. The end-of-study visit will mark the conclusion of the participant's involvement.

Inclusion criteria require participants to be healthy adults aged 18 years and older, with specific age-related criteria for Phase 1 and Phase 2a. Participants must have received at least two prior immunizations with a licensed SARS-CoV-2 vaccine, with the last dose administered at least one month before the investigational vaccine. Participants must also be able to comply with study procedures and use an electronic diary. Conditions for early termination from the study include non-compliance with study procedures or the occurrence of adverse events that warrant discontinuation as determined by the study investigators.

The clinical trial involves the administration of **OVX033**, a sarbecovirus candidate vaccine, which is formulated as a **solution for injection**. This experimental medication is administered via **intramuscular injection**. Participants receive two doses of OVX033, spaced one month apart, at varying dose levels of 100 µg, 250 µg, and 500 µg. The primary objective is to evaluate the safety, reactogenicity, and immunogenicity of OVX033 in comparison to a placebo. The vaccine is developed by OSIVAX and is classified as a structurally diverse substance, specifically a vaccine.

In addition to the experimental vaccine, the study utilizes a **placebo** control, which is a **solution for infusion** containing **sodium chloride** at a concentration of 0.9%. This placebo is provided under the product name "CHLORURE DE SODIUM 0,9 % B. BRAUN, solution pour perfusion" and is manufactured by B.BRAUN MEDICAL SAS. The placebo is administered via injection, serving as a comparator to assess the effects of the OVX033 vaccine. The use of sodium chloride as a placebo is standard in clinical trials to ensure blinding and to provide a baseline for evaluating the experimental treatment's efficacy and safety.

The efficacy of the OVX033 sarbecovirus candidate vaccine will be assessed through a series of primary and secondary endpoints in a Phase 1/2a clinical trial. The primary endpoints for Phase 1 include the evaluation of safety and reactogenicity, measured by the number and percentage of subjects reporting solicited local and systemic symptoms within 7 days post-administration, as well as unsolicited adverse events (AEs) within 29 days. Additionally, the incidence of COVID-19 symptoms and laboratory-confirmed SARS-CoV-2 and/or influenza cases, adverse events of special interest (AESI), medically attended adverse events (MAAEs), and serious adverse events (SAEs) will be monitored throughout the study duration.

In Phase 2a, the primary endpoint focuses on the **cell-mediated immune response** to OVX033, assessed by the change in NP-specific spot-forming units (SFUs) per million peripheral blood mononuclear cells (PBMCs), measured using the IFNγ ELISPOT assay at Day 8, Day 36, and Day 57, compared to pre-injection baselines. Secondary endpoints in both phases include the evaluation of NP-specific CD4+ and CD8+ T-cell frequencies using flow cytometry, geometric mean titers (GMTs) of anti-nucleocapsid (N) Immunoglobulin G (IgG) via ELISA, and the persistence of immune responses at Month 6 post-second administration. The study will also measure the anti-C4bp oligomerization domain IgG levels in subjects with significant increases in anti-OVX313 IgG.