A Phase Three Study of the Safety and Immunogenicity of a Four-dose Series of 20-Valent Pneumococcal Conjugate Vaccine in Healthy Infants

Abstract

Background: The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend pneumococcal disease protection beyond 13-valent PCV (PCV13).

Methods: This phase 3, double-blind study conducted in the United States/Puerto Rico evaluated PCV20 safety and immunogenicity. Healthy infants were randomized to receive a 4-dose series of PCV20 or PCV13 at 2, 4, 6 and 12-15 months old. Objectives included demonstrating noninferiority (NI) of PCV20 to PCV13 immunoglobulin G (IgG) geometric mean concentrations after doses 3 and 4 and percentages of participants with predefined IgG concentrations after dose 3, with 7 additional PCV20 serotypes compared with the lowest result among vaccine serotypes in the PCV13 group. Safety assessments included local reactions, systemic events, adverse events, serious adverse events and newly diagnosed chronic medical conditions.

Results: Overall, 1991 participants were vaccinated (PCV20, n = 1001; PCV13, n = 990). For IgG geometric mean concentrations 1 month after both doses 3 and 4, all 20 serotypes met NI criteria (geometric mean ratio lower 2-sided 95% confidence interval > 0.5). For percentages of participants with predefined IgG concentrations after dose 3, NI (percentage differences lower 2-sided 95% confidence interval > -10%) was met for 8/13 matched serotypes and 6/7 additional serotypes; 4 serotypes missed the statistical NI criterion by small margins. PCV20 also elicited functional and boosting responses to all 20 serotypes. The safety profile of PCV20 was similar to PCV13.

Conclusion: A 4-dose series of PVC20 was well tolerated and elicited robust serotype-specific immune responses expected to help protect infants and young children against pneumococcal disease due to the 20 vaccine serotypes. Clinical trial registration: NCT04382326.

FIGURE 1.

GMRs (PCV20/PCV13) and 2-sided 95% CIs 1 month after (A) dose 4 and (B) dose 3 and (C) differences (PCV20 − PCV13) and 2-sided 95% CIs in percentages of participants with predefined IgG concentrations 1 month after dose 3. 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 For the 7 additional serotypes (triangles), (A) the compared results are from serotype 1 (the PCV13 serotype with the lowest GMC, not including serotype 3) in the PCV13 group; (B) the compared results are from serotype 19A (the PCV13 serotype with the lowest GMC, not including serotype 3) in the PCV13 group and (C) the compared results are from serotype 23F (the PCV13 serotype with the lowest percentage, not including serotype 3) in the PCV13 group. Results are based on the evaluable immunogenicity population. *The IgG GMCs (A and B) and percentages with predefined IgG concentrations (C) shown in the tables for the 7 additional serotypes are the results from the corresponding serotypes. ^†The results used for the NI comparison for the 7 additional serotypes. GMC indicates geometric mean concentration; GMR, geometric mean ratio; IgG, immunoglobulin G; LLOQ, lower limit of quantitation; NI, noninferiority; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine.

FIGURE 2.

IgG GMCs (2-sided 95% CIs) 1 month after dose 3 and 1 month after dose 4 and GMFRs. GMCs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs (based on the Student t distribution). GMC indicates geometric mean concentrations; GMFR, geometric mean fold rise; IgG, immunoglobulin G; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine.

FIGURE 3.

OPA GMTs (2-sided 95% CIs) 1 month after dose 3 and 1 month after dose 4. 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. GMTs and 2-sided CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t distribution). GMFR indicates geometric mean fold rise; GMT, geometric mean titer; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine.

FIGURE 4.

Percentages of participants with reported (A) local reactions and (B) systemic events. Values above bars represent percentages of participants reporting events of any severity at each dose for each group. For redness and swelling, mild ≥ 0.0–2.0 cm, moderate ≥ 2.0–7.0 cm and 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. PCV20, n = 826–993. PCV13, n = 815–974. D indicates dose; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine.