title: Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine.
abstract: BACKGROUND
  Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae.
  
  
  OBJECTIVE
  To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations.
  
  
  METHODS
  This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 μg) or PhtD-PcpA (10 μg each), participants in the main study received AH-adjuvanted PcpA (25 μg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 μg each), unadjuvanted PhtD-PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA).
  
  
  RESULTS
  Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 μg dose was observed as measured by geometric mean concentrations and by fold increases.
  
  
  CONCLUSIONS
  Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339).
authors.affiliation: Sanofi Pasteur, Toronto, ONT M2R 3T4, Canada. monica@mbpharma.ca
authors.forename: Monica
authors.initials: M
authors.lastname: Bologa
authors.forename: Thierry
authors.initials: T
authors.lastname: Kamtchoua
authors.forename: Robert
authors.initials: R
authors.lastname: Hopfer
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Sheng
authors.forename: Bryony
authors.initials: B
authors.lastname: Hicks
authors.forename: Garvin
authors.initials: G
authors.lastname: Bixler
authors.forename: Victor
authors.initials: V
authors.lastname: Hou
authors.forename: Vildana
authors.initials: V
authors.lastname: Pehlic
authors.forename: Tao
authors.initials: T
authors.lastname: Yuan
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gurunathan
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; 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: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; C113653:PcpA protein, Streptococcus; D010919:Placebos; D022242:Pneumococcal Vaccines; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C097552:histidine triad protein; D006867:Hydrolases