A Phase 3, Randomized, Double-blind, Active Comparator-controlled Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine-naïve Adults 18 to 64 years of Age With Increased Risk for Pneumococcal Disease

The primary objective of this Phase 3, randomized, double-blind, active comparator-controlled clinical study is to evaluate the **safety** and **tolerability** of the V116 vaccine in pneumococcal vaccine-naïve adults aged 18 to 64 years with increased risk for pneumococcal disease. This is assessed by the proportion of participants experiencing adverse events (AEs). Additionally, the study aims to evaluate the serotype-specific **opsonophagocytic activity** (OPA) geometric mean titers (GMTs) post-vaccination with V116 at 30 days and with PCV15 + PPSV23 at 12 weeks within each vaccination group separately. These objectives are clinically relevant as they provide critical data on the vaccine's safety profile and its ability to elicit an immune response, which is essential for preventing pneumococcal infections in at-risk populations.

Secondary objectives include: - Evaluating the serotype-specific **Immunoglobulin G** (IgG) geometric mean concentrations (GMCs) post-vaccination with V116 at Day 30 and with PCV15 + PPSV23 at Week 12 within each vaccination group separately. - Assessing the serotype-specific geometric mean fold rises (GMFRs) and the proportions of participants with a ≥4-fold rise from baseline (Day 1) to post-vaccination with V116 at Day 30 and from baseline to post-vaccination with PCV15 + PPSV23 at Week 12 for both OPA and IgG responses within each vaccination group separately.

The clinical trial involves a total of **400 participants** who are being evaluated for the safety and tolerability of the vaccine V116 in the context of **pneumococcal infection**. The study population includes individuals of any gender, aged between **18 and 64 years**. Participants were selected based on specific risk conditions for pneumococcal disease, such as diabetes mellitus, chronic liver disease, chronic obstructive pulmonary disease (COPD), asthma, chronic heart disease, and chronic kidney disease. All participants are required to be under stable medical management for these conditions for at least three months prior to the study, with no significant changes in treatment anticipated. The trial includes both male and female subjects, with females required to adhere to specific contraceptive guidelines if they are of childbearing potential. The study population is characterized by a diverse range of health conditions, and the trial does not exclude based on gender, thus ensuring a comprehensive evaluation of the vaccine's effects across different demographics.

The clinical trial is designed as a **randomized**, **double-blind**, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of a pneumococcal vaccine in adults aged 18 to 64 years who are at increased risk for pneumococcal disease. The trial will involve the administration of the investigational vaccine, V116, and a comparator regimen consisting of PCV15 and PPSV23. The study aims to assess the serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) and the incidence of adverse events (AEs) post-vaccination. The trial is expected to last until February 2024, with recruitment having commenced in April 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific risk conditions such as diabetes mellitus, chronic liver disease, chronic obstructive pulmonary disease (COPD), asthma, chronic heart disease, or chronic kidney disease. Following the screening, participants will receive the study vaccine or comparator at the baseline visit (Day 1). Subsequent follow-up visits will occur at Day 30 and Week 12 to monitor safety and immunogenicity outcomes, including the collection of blood samples for serotype-specific immunoglobulin G (IgG) and OPA responses. The end-of-study visit will mark the conclusion of participant involvement, which is anticipated to last approximately 12 weeks.

Participant involvement may be terminated early if they experience vaccine-related serious adverse events (SAEs) or if they no longer meet the study's inclusion criteria. The primary endpoints include the percentage of participants with solicited injection-site and systemic AEs from Day 1 through Day 5 post-vaccination, as well as vaccine-related SAEs throughout the study duration. Secondary endpoints focus on serotype-specific IgG geometric mean concentrations (GMCs) and geometric mean fold rises (GMFRs) from baseline to post-vaccination. The trial's methodology ensures rigorous assessment of the vaccine's safety and efficacy in the target population.

The clinical trial involves the administration of several treatments, including experimental and non-experimental medications. The **Pneumococcal 21-valent Conjugate Vaccine** is an experimental medication used in this study. It is formulated as a solution for injection and is administered intramuscularly. The vaccine contains multiple pneumococcal polysaccharide serotypes, each conjugated to CRM197, a non-toxic mutant of diphtheria toxin. The dosage is 0.5 ml per administration, with a maximum treatment period of one day. Participant compliance is monitored through scheduled visits and documentation of administration.

Another experimental treatment is the **Pneumococcus, Purified Polysaccharides Antigen Conjugated**. This product is also administered intramuscularly and is provided in a pharmaceutical form coded as PHF00243MIG. The dosage is consistent with the other treatments at 0.5 ml, with a single administration within the treatment period. The active substances include various pneumococcal polysaccharide serotypes conjugated to CRM197 and adsorbed on aluminum phosphate, enhancing the immunogenic response.

The study also includes a non-experimental treatment, **Sodium Chloride Intravenous Infusion BP 0.9% w/v**, which serves as a placebo. This solution for infusion is administered via intramuscular injection, with a dosage of 0.5 mg per administration. The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased results. Compliance is ensured through careful monitoring and documentation of each administration.

Additionally, the **Pneumococcus, Purified Polysaccharides Antigen** is used as a comparator in the study. It is administered intramuscularly in a pharmaceutical form coded as PHF00231MIG. The dosage is 0.5 ml, with a single administration allowed within the treatment period. This comparator helps evaluate the immunogenicity and safety of the experimental vaccines against a standard reference.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the evaluation of serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) postvaccination with V116 at 30 days postvaccination (Day 30) and with PCV15 + PPSV23 at 30 days postvaccination with the final dose in the regimen (Week 12). Additionally, the percentage of participants with solicited injection-site adverse events (AEs) from Day 1 through Day 5 postvaccination, solicited systemic AEs from Day 1 through Day 5 postvaccination, and vaccine-related serious adverse events (SAEs) from Day 1 through the duration of participation in the study will be monitored.

Secondary endpoints will focus on serotype-specific Immunoglobulin G (IgG) geometric mean concentrations (GMCs) postvaccination with V116 (Day 30) and PCV15 + PPSV23 (Week 12). The serotype-specific geometric mean fold rises (GMFRs) from baseline (Day 1) to postvaccination with V116 (Day 30) and from baseline (Day 1) to postvaccination with PCV15 + PPSV23 (Week 12) for both OPA and IgG responses will also be evaluated. Furthermore, the serotype-specific proportion of participants with a ≥4-fold rise from baseline (Day 1) to postvaccination with V116 (Day 30) and from baseline (Day 1) to postvaccination with PCV15 + PPSV23 (Week 12) for both OPA and IgG responses will be assessed.