title: A randomized, controlled dose-finding Phase II study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults.
abstract: OBJECTIVE
  In this dose-finding Phase II study (NCT00621322), we evaluated the safety and immunogenicity of different formulations of the candidate tuberculosis vaccine containing the M72 antigen (10/20/40 μg doses) and the liposome-based AS01 Adjuvant System. We aimed to select the lowest-dose combination of M72 and AS01 that was clinically well tolerated with immunogenicity comparable to that of the previously tested M72/AS01B (40 μg) candidate vaccine.
  
  
  METHODS
  Healthy PPD-positive (induration 3-10 mm) adults (18-45 years) in The Philippines were randomized (4:4:4:4:1:1) to receive 2 injections, 1 month apart, of M72/AS01B (40 μg), M72/AS01E (10 μg), M72/AS01E (20 μg), M72/AS02D (10 μg), M72/Saline (40 μg) or AS01B alone, and were followed up for 6 months. AS01E and AS02D contain half the quantities of the immunostimulants present in AS01B. AS02D is an oil-in-water emulsion. Vaccine selection was based on the CD4(+) T-cell responses at 1 month post vaccination.
  
  
  RESULTS
  All formulations had a clinically acceptable safety profile with no vaccine-related serious adverse events reported. Two vaccinations of each adjuvanted M72 vaccine induced M72-specific CD4(+) T-cell and humoral responses persisting at 6 months post vaccination. No responses were observed with AS01B alone. One month post second vaccination, CD4(+) T-cell responses induced by each of the three M72/AS01 vaccine formulations were of comparable magnitudes, and all were significantly higher than those induced by M72/AS02D (10 μg) and M72/Saline.
  
  
  CONCLUSIONS
  The formulation with the lowest antigen and adjuvant dose, M72/AS01E (10 μg), fulfilled our pre-defined selection criteria and has been selected for further clinical development.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, University of the Philippines College of Medicine, 547 Pedro Gil Street, Ermita, Manila, 1000, Philippines.
authors.forename: Jaime
authors.initials: J
authors.lastname: Montoya
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Solon
authors.forename: Soledad Rosanna C
authors.initials: SR
authors.lastname: Cunanan
authors.forename: Luz
authors.initials: L
authors.lastname: Acosta
authors.forename: Anne
authors.initials: A
authors.lastname: Bollaerts
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Michel
authors.initials: M
authors.lastname: Janssens
authors.forename: Erik
authors.initials: E
authors.lastname: Jongert
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitié
authors.forename: Pascal
authors.initials: P
authors.lastname: Mettens
authors.forename: Salvacion
authors.initials: S
authors.lastname: Gatchalian
authors.forename: Carlota
authors.initials: C
authors.lastname: Vinals
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D004338:Drug Combinations; D032581:Tuberculosis Vaccines