Abstract
BackgroundTwo conserved pneumococcal proteins, pneumolysin toxoid (dPly) and pneumococcal histidine triad protein D (PhtD), combined with 10 polysaccharide conjugates from the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) in two investigational pneumococcal vaccine (PHiD-CV/dPly/PhtD) formulations were immunogenic and well-tolerated when administered to Gambian children. Here, we report immunogenicity of the polysaccharide conjugates, and immunogenicity and reactogenicity of co-administered routine vaccines. MethodsIn this phase II, controlled, observer-blind, single-centre study, healthy infants aged 8–10 weeks were randomised (1:1:1:1:1:1) to six groups. Four groups received 3+0 schedule (2-3-4 months [M]) of PHiD-CV/dPly/PhtD (10 or 30 µg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine; and two groups received 2+1 schedule (2-4-9 M) of PHiD-CV/dPly/PhtD (30 µg of each protein) or PHiD-CV. All infants received diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HBV/Hib) and oral trivalent polio vaccines (OPV) at 2-3-4 M, and measles, yellow fever, and OPV vaccines at 9 M. We evaluated immune responses at 2-5-9-12 M; and reactogenicity 0–3 days post-vaccination. Results1200 infants were enrolled between June 2011 and May 2012; 1152 completed the study. 1 M post-primary vaccination, for each PHiD-CV serotype except 6B and 23F, ≥97.4% (3+0 schedule) and ≥96.4% (2+1 schedule) of infants had antibody concentrations ≥0.2 μg/mL. Immune responses were comparable between groups within the same vaccination schedules. Observed antibody geometric mean concentrations (GMCs) increased by 1 M post-primary vaccination compared to pre-vaccination. In the following months, GMCs and opsonophagocytic activity titres waned, with an increase post-booster for the 2+1 schedule. Immune responses to protein D and, DTPw-HBV/Hib, OPV, measles, and yellow fever vaccines were not altered by co-administration with pneumococcal proteins. Reactogenicity of co-administered vaccines was comparable between groups and did not raise concerns. ConclusionImmune responses to the 10 PHiD-CV polysaccharide conjugates and co-administered vaccines were not altered by addition of dPly and PhtD. ClinicalTrials.gov identifier NCT01262872.
Highlights
Pneumococcal disease mainly affects infants and young children and is responsible for approximately 500,000 deaths of children under 5 years of age every year [1]
While Streptococcus pneumoniae has more than 90 serotypes, only 6–11 of these serotypes were responsible for 70% of all invasive pneumococcal disease (IPD) globally before the introduction of pneumococcal conjugate vaccines (PCVs) [2,3]
New formulations containing highly conserved pneumococcal proteins such as pneumolysin toxoid and pneumococcal histidine triad protein D (PhtD) have been in development [7,8] and have the potential to offer protection against a wider spectrum of pneumococcal serotypes and prevent serotype emergence and replacement in nasopharyngeal colonisation [8,9,10]. These new protein antigens were combined with a PCV into one vaccine: the protein-based pneumococcal vaccine containing 10 serotype-specific PS conjugates of the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) combined with dPly and PhtD (PHiD-CV/dPly/PhtD) [11,12,13]
Summary
Pneumolysin toxoid (dPly) and pneumococcal histidine triad protein D (PhtD), combined with 10 polysaccharide conjugates from the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) in two investigational pneumococcal vaccine (PHiD-CV/dPly/PhtD) formulations were immunogenic and well-tolerated when administered to Gambian children. All infants received diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HBV/Hib) and oral trivalent polio vaccines (OPV) at 2-3-4 M, and measles, yellow fever, and OPV vaccines at 9 M. In the Abbreviations: ATP, according-to-protocol; CI, confidence interval; dPly, pneumolysin toxoid; DTPw-HBV/Hib, diphtheria-tetanus-whole cell pertussis-hepatitis BHaemophilus influenzae type b vaccine; ELISA, enzyme-linked immunosorbent assay; EPI, Expanded Programme on Immunisation; GMC, geometric mean concentration; GMT, geometric mean titre; IPD, invasive pneumococcal disease; IU, International Units; OPA, opsonophagocytic activity; OPV, oral trivalent polio vaccine; PCV, pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PHiD-CV, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine; PHiD-CV/ dPly/PhtD, pneumococcal vaccine that contains 10 PHiD-CV polysaccharide conjugates combined with conserved pneumococcal proteins - pneumolysin toxoid and pneumococcal histidine triad protein D; PhtD, pneumococcal histidine triad protein D; PS, polysaccharide; PRP, polyribosyl-ribitol-phosphate; TCID50, 50% tissue culture infectious dose; TVC, total vaccinated cohort; WHO, World Health Organization.
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