Phase III Randomized Observer-Blind Placebo-Controlled Study of Live Attenuated RSV ΔNS2/Δ1313/I1314L Vaccine in Infants and Toddlers for RSV LRTD Prevention

The primary objective of this study is to demonstrate the clinical efficacy of the **RSVt vaccine** in preventing reverse transcription polymerase chain reaction (RT-PCR) confirmed **Respiratory Syncytial Virus (RSV)** lower respiratory tract disease (LRTD) after two doses during RSV Season 1. This objective is clinically relevant as it addresses the prevention of a significant viral disease that can lead to severe respiratory illness in infants and toddlers, potentially reducing the incidence of hospitalizations and severe health outcomes associated with RSV infections.

Secondary objectives include:

• Demonstrating the clinical efficacy of the RSVt vaccine for the prevention of RT-PCR confirmed RSV upper respiratory tract disease (URTD) and RSV-associated lower respiratory tract disease (LRTD) leading to hospitalization after two doses over RSV Season 1.
• Describing the clinical efficacy of the RSVt vaccine for the prevention of RT-PCR confirmed severe LRTD, LRTD necessitating urgent care, and acute respiratory disease (ARD) after two doses over RSV Season 1.
• Evaluating the clinical efficacy of the RSVt vaccine for the prevention of RT-PCR confirmed RSV LRTD, URTD, and ARD by RSV strain and baseline serostatus after two doses over RSV Seasons 1 and 2.
• Describing the safety profile of the RSVt vaccine and the RSV A and B serum neutralizing and RSV serum anti-F IgA and IgG antibody responses to the study intervention.

The clinical trial involves a total of **5960 participants** who are being studied to evaluate the efficacy of the RSVt vaccine in preventing **RSV lower respiratory tract disease**. The study population consists of both male and female subjects aged between **6 months to less than 22 months**. Participants are required to be healthy, as determined by a medical evaluation, and must have been born at full term, defined as **37 weeks or more** of gestation. The trial includes a vulnerable population, given the young age of the participants. The selection process ensures that only those meeting these criteria are included, with no specific lifestyle considerations such as diet or physical activity being highlighted as relevant to the study.

The clinical trial is a **Phase III**, randomized, observer-blind, placebo-controlled, multi-center, multinational study designed to evaluate the efficacy, immunogenicity, and safety of a **Respiratory Syncytial Virus (RSV)** vaccine in infants and toddlers. The primary objective is to demonstrate the clinical efficacy of the vaccine in preventing reverse transcription polymerase chain reaction (RT-PCR) confirmed RSV lower respiratory tract disease (LRTD) after two doses, over the first RSV season. The trial is expected to commence recruitment on May 15, 2024, and conclude by September 30, 2026, with an estimated duration of approximately 28 months.

Participants will be randomly assigned to receive either the live attenuated RSV vaccine or a placebo, administered as a nasal spray. The study will include several key visits: an initial screening visit to confirm eligibility, two vaccination visits, and multiple follow-up visits to monitor safety and efficacy outcomes. The inclusion criteria specify that participants must be aged between 6 months and less than 22 months, healthy as determined by medical evaluation, and born at full term (≥ 37 weeks of gestation).

The primary endpoint is the occurrence of LRTD associated with any RT-PCR confirmed RSV strain more than 21 days post-dose 2. Secondary endpoints include the occurrence of upper respiratory tract disease (URTD), severe LRTD, and acute respiratory disease (ARD) associated with RT-PCR confirmed RSV strains, as well as the presence of solicited and unsolicited adverse events. Participants will be involved in the study for the duration of the RSV season, with follow-up visits scheduled to assess the presence of adverse events and measure serum neutralizing antibody titers.

Conditions that may lead to early termination from the study include the occurrence of serious adverse events or the participant's withdrawal of consent. The study is not classified as low intervention, and the trial phase is categorized as Phase III. The trial is conducted under the sponsorship of Sanofi Pasteur Inc., with the investigational product being a pediatric formulation of the RSV vaccine. The study aims to provide critical data on the vaccine's ability to prevent RSV infections in a vulnerable pediatric population.

The clinical trial involves the administration of the **Live Attenuated Respiratory Syncytial Virus (RSV) ΔNS2/Δ1313/I1314L vaccine**. This experimental medication is formulated as a **nasal spray, suspension** and is intended for **nasal use**. The vaccine is designed as a **pediatric formulation** and is manufactured by Sanofi Pasteur Inc. The dosing regimen specifies a maximum daily dose of **6.4 log10 PFU/dose** and a maximum total dose of **6.7 log10 PFU/dose** over a treatment period of up to **3 months**. The vaccine is delivered using a nasal spray system, which does not possess a CE mark. The active substance is categorized as a structurally diverse substance, specifically a vaccine.

In addition to the experimental vaccine, the study employs a **placebo** as a comparator treatment. The placebo is referred to as "Matched" in the trial documentation. However, specific details regarding its pharmaceutical form, active substance, and route of administration are not provided. The placebo serves as a control to evaluate the efficacy, immunogenicity, and safety of the RSV vaccine in the study population, which includes infants and toddlers. The trial is designed as a Phase III, randomized, observer-blind, placebo-controlled, multi-center, multinational study.

The efficacy of the **Respiratory Syncytial Virus (RSV) vaccine** will be assessed in a Phase III, randomized, observer-blind, placebo-controlled, multi-center, multinational clinical trial. The primary endpoint for evaluating efficacy is the occurrence of lower respiratory tract disease (LRTD) during RSV Season 1, associated with any reverse transcription polymerase chain reaction (RT PCR) confirmed RSV strain, occurring more than 21 days post-dose 2. Secondary endpoints include the occurrence of upper respiratory tract disease (URTD) and acute respiratory disease (ARD) during RSV Season 1, associated with any RT PCR confirmed RSV strain, as well as the occurrence of hospitalizations and urgent care visits related to these conditions.

Additional secondary endpoints involve the measurement of RSV A and B serum neutralizing antibody titers and RSV serum anti-F Immunoglobulin A (IgA) and Immunoglobulin G (IgG) Electrochemiluminescence (ECL) antibody titers at baseline (D01) and 28 days post-dose 2. The presence of solicited administration site reactions, systemic reactions, and adverse events (AEs) will also be monitored within specified timeframes post-vaccination. The trial aims to demonstrate the clinical efficacy of the RSV vaccine in preventing RT PCR confirmed RSV lower respiratory tract disease in infants and toddlers over the course of RSV Season 1.