title: Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults.
abstract: BACKGROUND
  Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae.
  
  
  OBJECTIVE
  This study examined the safety and immunogenicity in adults of three doses of a pneumococcal single-antigen protein vaccine candidate formulated with aluminum hydroxide adjuvant and recombinantly derived, highly detoxified, genetically mutated pneumolysin protein (PlyD1).
  
  
  METHODS
  This phase I, randomized, placebo-controlled, observer-blinded, dose-escalating study enrolled adults (18-50 years). In a pilot safety study, participants received a single injection of 10 μg PlyD1 and were observed for 24 h. Following review of the pilot safety data, participants were randomized (2:1) to receive two injections of PlyD1 at one of three doses or placebo 30 days apart. Assignment of second injection and successive dose cohorts was made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site reactions, solicited systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included geometric mean concentrations of anti-PlyD1 IgG as determined by ELISA and functional assessment in an in vitro toxin neutralization assay.
  
  
  RESULTS
  The study included a total of 100 participants, including 10 in the pilot study and 90 in the randomized study. None of the participants in the pilot study had SAEs, allergic reactions, or other safety concerns. Ninety participants received two doses of or placebo (n=30) or active vaccine candidate at 10 (n=20), 25 (n=20), or 50 μg (n=20). No vaccine-related SAE or discontinuation due to an AE occurred. Most solicited reactions were mild and transient. The most frequently reported solicited reactions were pain at the injection site and myalgia. Antigen-specific IgG levels and functional activity showed dose-related increases. When comparing the three dose levels, a plateau effect was observed at the 25 μg dose.
  
  
  CONCLUSIONS
  All dose levels were safe and immunogenic. Repeat vaccination significantly increased the level of anti-PlyD1 antibodies. Functional antibody activity was demonstrated in sera from vaccinated individuals (ClinicalTrials.gov no. NCT01444352).
authors.affiliation: Covance Clinical Research Unit AG, SPC 327-10, Lettenweg 118, CH-4123 Allschwil, Switzerland. thierry.kamtchoua@covance.com
authors.forename: Thierry
authors.initials: T
authors.lastname: Kamtchoua
authors.forename: Monica
authors.initials: M
authors.lastname: Bologa
authors.forename: Robert
authors.initials: R
authors.lastname: Hopfer
authors.forename: David
authors.initials: D
authors.lastname: Neveu
authors.forename: Branda
authors.initials: B
authors.lastname: Hu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Sheng
authors.forename: Nicolas
authors.initials: N
authors.lastname: Corde
authors.forename: Catherine
authors.initials: C
authors.lastname: Pouzet
authors.forename: Gloria
authors.initials: G
authors.lastname: Zimmermann
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gurunathan
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000536:Aluminum Hydroxide / Q000276:immunology; D000917:Antibody Formation; D001426:Bacterial Proteins / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests / Q000379:methods; D010865:Pilot Projects; D022242:Pneumococcal Vaccines / Q000009:adverse effects* / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D013301:Streptolysins / Q000276:immunology*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D000536:Aluminum Hydroxide