title: Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS,S/AS02A.
abstract: BACKGROUND
  RTS,S/AS02A, a pre-erythrocytic Plasmodium falciparum vaccine based upon the circumsporozoite protein, is the only vaccine demonstrated in field trials to confer partial protection against a range of malaria disease manifestations. Pre-clinical studies are on-going to identify new RTS,S formulations with improved magnitude and duration of specific immunity.
  
  
  METHODS
  Rhesus macaques were immunized with saline or one of four "RTS,S/adjuvant" formulations at 0, 4, and 12 weeks: RTS,S/AS01B, RTS,S/AS02A-standard (current formulation), RTS,S/AS05 or RTS,S/AS06. An RTS,S/AS02A-accelerated group was immunized at 0, 1, and 4 weeks. Outcomes were safety, RTS,S-specific antibody, and IFN-gamma and IL-5 ELISpots (weeks 14 and 34).
  
  
  RESULTS
  All regimens were safe and, except for RTS,S/AS06, generated equivalent high titer antibody levels. For IFN-gamma ELISpots, RTS,S/AS01B had the highest geometric mean (GM) values at weeks 14 and 34, and was the only group with an overall GM mean (weeks 14+34) higher than RTS,S/AS02A-standard (p<0.015). For IFN-gamma to IL-5 ELISpot response ratios, RTS,S/AS01B had the highest values at weeks 14 and 34, and was the only group higher than RTS,S/AS02A-standard at each individual time point and overall (weeks 14+34) (p<0.015).
  
  
  CONCLUSIONS
  RTS,S/AS01B is a safe and immunogenically superior formulation for cellular responses, in comparison with the RTS,S/AS02A-standard. Phase 1, 2a, and 2b clinical trials are underway to determine if RTS,S/AS01B demonstrates improved immunogenicity and protective efficacy against experimental challenge and natural mosquito-borne malaria.
authors.affiliation: Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA. ann.stewart@na.amedd.army.mil
authors.forename: V Ann
authors.initials: VA
authors.lastname: Stewart
authors.forename: Shannon M
authors.initials: SM
authors.lastname: McGrath
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Walsh
authors.forename: Stacey
authors.initials: S
authors.lastname: Davis
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Hess
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ware
authors.forename: Kent E
authors.initials: KE
authors.lastname: Kester
authors.forename: James F
authors.initials: JF
authors.lastname: Cummings
authors.forename: J Robert
authors.initials: JR
authors.lastname: Burge
authors.forename: Gerald
authors.initials: G
authors.lastname: Voss
authors.forename: Martine
authors.initials: M
authors.lastname: Delchambre
authors.forename: Nathalie
authors.initials: N
authors.lastname: Garçon
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Tang
authors.forename: Joe D
authors.initials: JD
authors.lastname: Cohen
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000032:analysis / Q000096:biosynthesis; D000918:Antibody Specificity; D001774:Blood Chemical Analysis; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000096:biosynthesis; D003627:Data Interpretation, Statistical; D004906:Erythrocyte Count; D007111:Immunity, Cellular / Q000502:physiology; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D007958:Leukocyte Count; D008253:Macaca mulatta; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D011786:Quality Control
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D016207:Cytokines; D015848:Interleukin-5; D017780:Malaria Vaccines; D007371:Interferon-gamma