title: Safety and immunogenicity of a trivalent recombinant PcpA, PhtD, and PlyD1 pneumococcal protein vaccine in adults, toddlers, and infants: A phase I randomized controlled study.
abstract: BACKGROUND
  Pneumococcal protein vaccines (PPrVs) may provide improved protection over currently available polysaccharide and conjugated polysaccharide vaccines. Here, we examined the safety and immunogenicity of a trivalent recombinant PPrV containing PcpA, PhtD, and PlyD1.
  
  
  METHODS
  This was a phase I, single-center, randomized, observer-blind study with safety review between cohorts. Adults (18-50 years; n=30) and then toddlers (12-13 months; n=30) were randomized 2:1 to receive aluminum-adjuvanted trivalent PPrV (PPrV + adj) containing 50 μg per antigen or placebo. Infants (42-49 days; n=220) were next randomized to be injected at 6, 10, and 14 weeks of age with 10 μg PPrV + adj or placebo (n=60; 2:1); 25 μg PPrV + adj, 25 μg unadjuvanted PPrV, or placebo (n=100; 2:2:1); and 50 μg PPrV + adj or placebo (n=60; 2:1). Solicited reactions were recorded for 7 days and unsolicited adverse events for 30 days after each vaccination. Concentrations of antibodies to the three vaccine antigens were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Tenderness/pain was the most frequent injection-site reaction. Abnormal crying and irritability (infants), loss of appetite (toddlers), and headache, malaise, and myalgia (adults) were the most frequent systemic reactions. Reactions were mostly mild or moderate, resolved within 3 days, were not adjuvant- or dose-dependent, and were not increased by repeated vaccination. No immediate adverse events, hypersensitivity reactions, or treatment-related serious adverse events were reported. In all PPrV + adj cohorts, at least 75% of subjects had a ≥2-fold increase in all three antibody concentrations. In infants, antibody concentrations were higher with PPrV + adj than with unadjuvanted PPrV, higher with three than two vaccinations, and similar at the different vaccine doses.
  
  
  CONCLUSIONS
  The candidate trivalent PPrV was safe and immunogenic in adults, toddlers, and infants. Addition of aluminum adjuvant improved immunogenicity in infants without changing the safety profile.
authors.affiliation: International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: W Abdullah
authors.initials: WA
authors.lastname: Brooks
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Lee-Jah
authors.initials: LJ
authors.lastname: Chang
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA. Electronic address: robert.hopfer@sanofipasteur.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Hopfer
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D000534:Alum Compounds / Q000008:administration & dosage; D000942:Antigens, Bacterial / Q000097:blood / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D016037:Single-Blind Method; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D010919:Placebos; D022242:Pneumococcal Vaccines; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C041524:aluminum sulfate
keywords: Infants; Phase I clinical trials; Pneumococcal vaccine; Streptococcus pneumoniae