Phase 3 Safety and Immunogenicity Study of a Three-dose Series of Twenty-valent Pneumococcal Conjugate Vaccine in Healthy Infants and Toddlers

Abstract

Background: Global pediatric immunization programs with pneumococcal conjugate vaccines (PCVs) have reduced vaccine-type pneumococcal disease, but a substantial disease burden of non-PCV serotypes remains.

Methods: This phase 3, randomized (1:1), double-blind study evaluated safety and immunogenicity of 20-valent PCV (PCV20) relative to 13-valent PCV (PCV13) in healthy infants. Participants received 2 infant doses and a toddler dose of PCV20 or PCV13, with diphtheria-tetanus-acellular pertussis combination vaccine at all doses and measles, mumps, rubella and varicella vaccines at the toddler dose. Primary pneumococcal immunogenicity objectives were to demonstrate noninferiority (NI) of PCV20 to PCV13 for immunoglobulin G geometric mean concentrations after infant and toddler doses and percentages of participants with predefined serotype-specific immunoglobulin G concentrations after infant doses. Safety endpoints included local reactions, systemic events and adverse events.

Results: Overall, 1204 participants were vaccinated (PCV20, n = 601; PCV13, n = 603). One month after the toddler dose, 19/20 serotypes met NI for immunoglobulin G geometric mean concentrations; serotype 6B narrowly missed NI [PCV20/PCV13 geometric mean ratio: 0.57 (2-sided 95% confidence interval: 0.48-0.67); NI criterion: lower 2-sided 95% confidence interval >0.5]. Sixteen/twenty serotypes met NI for ≥1 primary objective after 2 infant doses. PCV20 induced robust opsonophagocytic activity, and boosting responses were observed for all vaccine serotypes, including those missing statistical NI. The safety/tolerability profile of PCV20 was like that of PCV13.

Conclusions: PCV20 3-dose series in infants was safe and elicited robust immune responses. Based on these results and PCV13 experience, PCV20 3-dose series is expected to be protective for all 20 vaccine serotypes. NCT04546425.

FIGURE 1.

IgG GMRs (PCV20/PCV13) and 2-sided 95% CIs 1 month after dose 3 (A) and 1 month after dose 2 (B). Assay results below LLOQ were set to 0.5 × LLOQ. For the PCV13 serotypes (circles), the compared results are from the corresponding serotype in the PCV13 group. †For the 7 additional serotypes (triangles), in (A), the compared results are from serotype 5 (the PCV13 serotype with the lowest GMC, not including serotype 3) in the PCV13 group, and in (B), the compared results are from serotype 6B (the PCV13 serotype with the lowest GMC) in the PCV13 group. *In the tables, actual values are shown for the PCV13 group for the 7 additional serotypes. Results are for the dose 3 and dose 2 evaluable immunogenicity populations for (A) and (B), respectively. GMR indicates geometric mean ratio.

FIGURE 2.

Differences (PCV20 − PCV13) with 2-sided 95% CIs in percentages of participants with predefined pneumococcal IgG levels 1 month after dose 2. The predefined pneumococcal IgG level for all serotypes is ≥0.35 μg/mL, except for the following: 5 (≥0.23 μg/mL), 6B (≥0.10 μg/mL) and 19A (≥0.12 μg/mL). For the PCV13 serotypes (circles), the compared results are from the corresponding serotype in the PCV13 group. †For the 7 additional serotypes (triangles), the compared results are from serotype 6B (the PCV13 serotype with the lowest percentage) in the PCV13 group. *In the table, actual values are shown for the PCV13 group for the 7 additional serotypes. Results are for the dose 2 evaluable immunogenicity population.

FIGURE 3.

OPA GMTs (2-sided 95% CIs) 1 month after dose 2 and 1 month after dose 3. Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis. OPA titers were determined on serum from randomly selected subsets of participants assuring equal representation of both vaccine groups. The number of participants with valid OPA titers for specified serotypes ranged from 96–118 after dose 2 to 72–109 after dose 3. GMFRs are not presented for PCV13 for the 7 additional serotypes not included in PCV13. Results are for the dose 2 and dose 3 evaluable immunogenicity populations. GMFR indicates geometric mean fold rise.

FIGURE 4.

Percentages of participants with reported (A) local reactions and (B) systemic events after each dose. For redness and swelling, mild: >0.0–2.0 cm; moderate: >2.0–7.0 cm; severe: >7.0 cm. For pain at the injection site, mild: hurts if gently touched; moderate: hurts if gently touched with crying; severe: causes limitation of limb movement. For decreased appetite, mild: decreased interest in eating; moderate: decreased oral intake; severe: refusal to feed. For drowsiness, mild: increased or prolonged sleeping bouts; moderate: slightly subdued, interfering with daily activity; severe: disabling, not interested in usual daily activity. For irritability, mild: easily consolable; moderate: requiring increased attention; severe: inconsolable, crying cannot be comforted. The number of participants included in each group was 580–603 depending on the group and time point. Values above bars are the percentages of participants reporting an event of any severity rounded to whole numbers. Results are for the safety population. Fever >40.0 °C was reported in 2 participants (0.3%) in the PCV20 group after dose 3. D indicates dose.