A phase 3, multicenter, randomized, double-blind, active-comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of a 4-dose regimen of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants (PNEU-PED).

BACKGROUND: Pneumococcal disease (PD) remains a major health concern with considerable morbidity and mortality in children. Currently licensed pneumococcal conjugate vaccines (PCVs) confer protection against PD caused by most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and additional serotypes 22F and 33F. This pivotal phase 3 study compared safety and immunogenicity of V114 and PCV13. METHODS: 1720 healthy infants were randomized 1:1 to receive a 4-dose regimen of V114 or PCV13 concomitantly with other routine pediatric vaccines. Safety was evaluated after each dose as proportion of participants with adverse events (AEs). Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured at 1-month post-dose 3 (PD3), pre-dose 4, and 1-month post-dose 4 (PD4). IgG response rates, geometric mean concentrations (GMCs), and opsonophagocytic activity (OPA) were compared between vaccination groups. RESULTS: The proportion, maximum intensity, and duration of injection-site, systemic, and serious AEs were generally comparable between V114 and PCV13 groups. In comparison to PCV13, V114 met non-inferiority criteria for all 15 serotypes based on IgG response rates at PD3. V114 met non-inferiority criteria by IgG GMCs for all serotypes at PD3 and PD4, except for serotype 6A at PD3. V114-induced antibodies had bactericidal activity as assessed by OPA. Further, V114 met superiority criteria for shared serotype 3 and unique serotypes 22F and 33F compared to PCV13 by serotype-specific IgG GMCs at both PD3 and PD4. Immunogenicity of concomitantly administered routine pediatric vaccines was comparable in V114 and PCV13 groups. CONCLUSIONS: In healthy infants, V114 displays acceptable safety and tolerability profiles and generates comparable immune responses to PCV13. V114 also met superiority criteria for serotypes 3, 22F, and 33F. These results support use of V114 for prevention of PD as part of routine infant vaccination schedules. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03893448; EudraCT: 2018-004109-21.

A phase 3, multicenter, randomized, double-blind study to evaluate the interchangeability of V114, a 15-valent pneumococcal conjugate vaccine, and PCV13 with respect to safety, tolerability, and immunogenicity in healthy infants (PNEU-DIRECTION).

BACKGROUND: Pneumococcal disease (PD) remains a major health concern globally. In children, pneumococcal conjugate vaccines (PCVs) provide protection against PD from most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and public health important serotypes 22F and 33F. This phase 3 study evaluated safety and immunogenicity of mixed PCV13/V114 regimens using a 3 + 1 dosing schedule when changing from PCV13 to V114 at doses 2, 3, or 4. METHODS: 900 healthy infants were randomized equally to 5 intervention groups. PCVs were administered in a 3-dose infant series at 2, 4, and 6 months of age followed by a toddler dose at 12-15 months along with concomitant routine vaccines. Safety was evaluated as the proportion of participants with adverse events (AEs). Immunoglobulin G (IgG) responses to the 15 serotypes in V114 were measured at 30 days post-dose 3 and 30 days post-dose 4 (PD4). RESULTS: Frequencies of injection-site and systemic AEs were generally comparable across all intervention groups. At 30 days PD4 (primary endpoint), IgG geometric mean concentrations (GMCs) for the 13 shared serotypes were generally comparable between mixed V114/PCV13 and 4-dose regimens of PCV13 or V114. In mixed regimens at 30 days PD4, a toddler dose of V114 was sufficient to achieve IgG GMCs comparable to a 4-dose regimen of V114 for serotype 22F, while at least one infant dose was needed in addition to the toddler dose to achieve IgG GMCs comparable to a 4-dose regimen of V114 for serotype 33F. CONCLUSIONS: V114 was well tolerated with a generally comparable safety profile to PCV13. For 13 shared serotypes, both mixed regimens and the V114 4-dose regimen induced generally comparable antibody responses to 4-dose regimen with PCV13. Study results support interchangeability of V114 with PCV13 in infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03620162; EudraCT: 2018-001151-12.