title: Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research.
abstract: BACKGROUND
  Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule against falciparum malaria would be compatible with the Expanded Programme on Immunization, or in combination with other prevention measures, interrupt epidemic malaria or protect individuals upon sudden travel to an endemic area.
  
  
  METHODS
  We conducted an open label, Phase 2a trial of two different full dose schedules of RTS,S/AS02 in 40 healthy malaria-naïve adults. Cohort 1 (n=20) was immunized on a 0, 1, and 3 month schedule and Cohort 2 (n=20) on a 0, 7, and 28 day schedule. Three weeks later, 38 vaccinees and 12 unimmunized infectivity controls underwent malaria challenge.
  
  
  RESULTS
  Both regimens had a good safety and tolerability profile. Peak GMCs of antibody to the circumsporozoite protein (CSP) were similar in Cohort 1 (78 microg/mL; 95% CI: 45-134) and Cohort 2 (65 microg/mL; 95% CI: 40-104). Vaccine efficacy for Cohort 1 was 45% (95% CI: 18-62%) and for Cohort 2, 39% (95% CI: 11-56%). Protected volunteers had a higher GMC of anti-CSP antibody (114 microg/mL) than did volunteers with a 2-day delay (70 microg/mL) or no delay (30 microg/mL) in the time to onset of parasitemia (Kruskal-Wallis, p=0.019). A trend was seen for higher CSP-specific IFN-gamma responses in PBMC from protected volunteers only in Cohort 1, but not in Cohort 2, for ex vivo and for cultured ELISPOT assays.
  
  
  CONCLUSIONS
  In malaria-naïve adults, the efficacy of three-dose RTS,S/AS02 regimens on either a 0, 1, and 3 month schedule or an abbreviated 0, 7, and 28 day schedule was not discernibly different from two previously reported trials of two-dose regimens given at 0, 1 month that conferred 47% (95% CI: -19 to 76%) protection and in another trial 42% (95% CI: 5-63%). A strong association of CSP-specific antibody with protection against malaria challenge is observed and confirms similar observations made in other studies. Subsequent trials of adjuvanted RTS,S in African children and infants on a 0, 1, and 2 month schedule have demonstrated a favorable safety and efficacy profile.
authors.affiliation: Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. kent.kester@us.army.mil
authors.forename: Kent E
authors.initials: KE
authors.lastname: Kester
authors.forename: James F
authors.initials: JF
authors.lastname: Cummings
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Robin
authors.initials: R
authors.lastname: Nielsen
authors.forename: B Ted
authors.initials: BT
authors.lastname: Hall
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gordon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwenk
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Holland
authors.forename: Gregory
authors.initials: G
authors.lastname: Richmond
authors.forename: Megan G
authors.initials: MG
authors.lastname: Dowler
authors.forename: Jackie
authors.initials: J
authors.lastname: Williams
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wirtz
authors.forename: Nadia
authors.initials: N
authors.lastname: Tornieporth
authors.forename: Laurence
authors.initials: L
authors.lastname: Vigneron
authors.forename: Martine
authors.initials: M
authors.lastname: Delchambre
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitie
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
mesh_terms: D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000517:prevention & control; D015800:Protozoan Proteins / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C493155:RTS,S-AS02A vaccine; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma