title: Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.
abstract: OBJECTIVE
  The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.
  
  
  METHODS
  A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations.
  
  
  RESULTS
  374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7).
  
  
  CONCLUSIONS
  FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00223990.
authors.affiliation: US Army Medical Research Unit-Kenya and the Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya. bogutu@wrp-ksm.org
authors.forename: Bernhards R
authors.initials: BR
authors.lastname: Ogutu
authors.forename: Odika J
authors.initials: OJ
authors.lastname: Apollo
authors.forename: Denise
authors.initials: D
authors.lastname: McKinney
authors.forename: Willis
authors.initials: W
authors.lastname: Okoth
authors.forename: Joram
authors.initials: J
authors.lastname: Siangla
authors.forename: Filip
authors.initials: F
authors.lastname: Dubovsky
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tucker
authors.forename: John N
authors.initials: JN
authors.lastname: Waitumbi
authors.forename: Carter
authors.initials: C
authors.lastname: Diggs
authors.forename: Janet
authors.initials: J
authors.lastname: Wittes
authors.forename: Elissa
authors.initials: E
authors.lastname: Malkin
authors.forename: Amanda
authors.initials: A
authors.lastname: Leach
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Soisson
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Milman
authors.forename: Lucas
authors.initials: L
authors.lastname: Otieno
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Holland
authors.forename: Mark
authors.initials: M
authors.lastname: Polhemus
authors.forename: Shon A
authors.initials: SA
authors.lastname: Remich
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Martin
authors.forename: Evelina
authors.initials: E
authors.lastname: Angov
authors.forename: V Ann
authors.initials: VA
authors.lastname: Stewart
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lyon
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.forename: Mark R
authors.initials: MR
authors.lastname: Withers
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D006801:Humans; D007223:Infant; D007630:Kenya; D017780:Malaria Vaccines / Q000008:administration & dosage*; D016778:Malaria, Falciparum / Q000517:prevention & control; D020066:Merozoite Surface Protein 1 / Q000276:immunology / Q000627:therapeutic use*; D010963:Plasmodium falciparum / Q000276:immunology; D011819:Rabies Vaccines; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000936:Antigen-Antibody Complex; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1; D011819:Rabies Vaccines