Phase 3 Randomized Study on Safety and Immunogenicity of 21-Valent Pneumococcal Conjugate Vaccine in Healthy Infants and Toddlers

The primary objective of this study is to evaluate the **non-inferiority** of the antibody response, specifically immunoglobulin type G (IgG), induced by the 21-valent pneumococcal conjugate vaccine (PCV21) compared to the 15-valent pneumococcal conjugate vaccine (15vPCV) for shared serotypes at 30 days post-toddler dose (PTD). This is assessed by the seroresponse rate and the geometric mean concentration (GMC). Additionally, the study aims to demonstrate the **superiority** of the IgG antibody response and serotype-specific IgG levels induced by PCV21 for the six serotypes unique to PCV21 at 30 days PTD. These objectives are clinically relevant as they assess the potential of PCV21 to provide broader protection against pneumococcal infections in infants and toddlers.

Secondary objectives include: - Demonstrating the non-inferiority of the immune response of routine pediatric vaccines administered concomitantly with PCV21 versus 15vPCV at 30 days PTD. - Demonstrating the non-inferiority of the serotype-specific IgG Ab level induced by PCV21 versus 15vPCV for shared serotypes at 30 days post-primary series (PPS). - Demonstrating the superiority of the serotype-specific IgG Ab level induced by PCV21 for the six serotypes unique to PCV21 at 30 days PPS. - Describing the antibody response (IgG) induced for all serotypes included in PCV21 at 30 days PPS. - Describing the serotype-specific IgG Ab level for all serotypes included in PCV21 at 30 days PTD relative to pre-toddler dose. - Describing the immune response of routine pediatric vaccines administered concomitantly with PCV21 versus 15vPCV at 30 days PPS. - Describing the serotype-specific opsonophagocytic activity (OPA) titer for all serotypes included in PCV21 at 30 days PPS and PTD. - Describing the serotype-specific OPA titer for all serotypes included in PCV21 at 30 days PTD relative to pre-toddler dose. - Characterizing the safety profile of PCV21 after each and any dose.

The clinical trial focuses on evaluating the efficacy of pneumococcal immunization in a pediatric population. The study includes both **male** and **female** participants, aged between 42 to 112 days at the time of inclusion. Participants are required to be healthy, as determined by a comprehensive medical evaluation, including medical history and physical examination. The trial population comprises infants born at full term (≥ 37 weeks) with a birth weight of ≥ 2.5 kg, or those born after a gestation period of more than 28 weeks through 36 weeks with a birth weight of ≥ 1.5 kg, provided they are medically stable. The trial involves a vulnerable population, given the young age of the participants. However, the total number of participants and specific lifestyle considerations such as diet or physical activity are not disclosed by the sponsor.

The clinical trial is designed as a **randomized**, modified **double-blind**, active-controlled, parallel-group, 2-arm study to evaluate the safety and immunogenicity of a 21-valent **pneumococcal conjugate vaccine** in healthy infants and toddlers. The trial aims to demonstrate the non-inferiority and superiority of the antibody response induced by the 21-valent vaccine compared to a 15-valent vaccine for shared and unique serotypes, respectively. The primary endpoints include the seroresponse rate and IgG concentration for both vaccines. Secondary endpoints involve various antibody concentrations and titers, as well as the presence of adverse events throughout the study.

The trial will commence with a screening visit to assess eligibility based on criteria such as age (42 to 112 days), health status, and birth conditions. Participants will be randomly assigned to receive either the 21-valent or 15-valent vaccine via **intramuscular injection**. The study will include multiple follow-up visits to monitor the immune response and safety, with specific attention to any immediate adverse events, solicited injection site reactions, and serious adverse events. The end-of-study visit will occur six months post the last vaccine injection to evaluate long-term safety and immunogenicity outcomes.

The expected duration of participant involvement is approximately 13 months, with the trial estimated to conclude by May 2028. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or any medical condition that, in the investigator's opinion, would compromise the participant's safety or the integrity of the study data. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of two pneumococcal conjugate vaccines. The first experimental medication is the **Pneumococcal Conjugate Vaccine (PCV)**, produced by Sanofi Pasteur Inc. This vaccine is formulated as a **suspension for injection** and is administered via **intramuscular injection**. The dosage for this vaccine is 0.5 ml per administration, with a maximum total dose of 2 ml over the treatment period. The treatment period is set to a maximum of 13 weeks. The vaccine contains a combination of pneumococcal polysaccharide serotypes, including serotypes 6A, 4, 6B, 9V, 14, 18C, 19F, 23F, 33F, 8, 22F, 19A, 15B, 12F, 11A, 9N, 7F, 5, 3, 1, and 10A. These serotypes are structurally diverse substances, classified as vaccines. The vaccine is specifically designed for pediatric use.

The second treatment in the study is the **Vaxneuvance suspension for injection in pre-filled syringe**, a pneumococcal polysaccharide conjugate vaccine (15-valent, adsorbed) manufactured by Merck Sharp & Dohme B.V. This vaccine is also a **suspension for injection** and is administered via **intramuscular injection**. The dosage is similarly 0.5 ml per administration, with a maximum total dose of 2 ml over the treatment period, which is also set to a maximum of 13 weeks. The active substances in this vaccine include pneumococcal polysaccharide serotypes 33F, 22F, 4, 19F, 18C, 14, 9V, 6B, 23F, 1, 3, 5, 6A, 7F, and 19A, each conjugated to CRM197. These substances are also structurally diverse and classified as vaccines. This formulation is intended for pediatric use as well.

Both vaccines are administered as part of a randomized, modified double-blind, active-controlled, parallel-group study. The primary objective is to evaluate the safety and immunogenicity of the 21-valent pneumococcal conjugate vaccine in comparison to the 15-valent vaccine. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the 21-valent pneumococcal conjugate vaccine (PCV21) will be assessed in a Phase 3 clinical trial involving healthy infants and toddlers. The primary endpoints for evaluating efficacy include the **seroresponse rate** and **IgG concentration** for both PCV21 and 15-valent pneumococcal conjugate vaccine (15vPCV) serotypes. These endpoints will be measured at 30 days post-toddler dose (PTD), which corresponds to post dose 3 for full-term infants and post dose 4 for preterm infants. The trial aims to demonstrate the non-inferiority of the antibody response induced by PCV21 compared to 15vPCV for shared serotypes, as well as the superiority of PCV21 for the six serotypes unique to it.

Secondary endpoints include a range of antibody concentrations and titers against other antigens, such as anti-hepatitis B surface antigen (HBsAg), anti-polyribosylribitol phosphate (PRP), anti-poliovirus types (1, 2, and 3), anti-diphtheria, anti-tetanus, anti-pertussis, anti-measles, anti-mumps, anti-rubella, and anti-varicella. Additionally, serotype-specific opsonophagocytic activity (OPA) titers for all serotypes included in PCV21 will be assessed. The presence of immediate adverse events, solicited and unsolicited injection site and systemic reactions, serious adverse events (SAEs), and adverse events of special interest (AESIs) will also be monitored throughout the study, extending to six months post-last vaccine injection.