title: Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection.
abstract: BACKGROUND
  To further increase the efficacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals).
  
  
  METHODS
  In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later.
  
  
  RESULTS
  RTS,S/AS01B and RTS,S/AS02A were well tolerated and were safe. The efficacy of RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidence interval [CI], 32.9%-67.1%) and 32% (95% CI, 17.6%-47.6%), respectively. At the time of initial challenge, the RTS,S/AS01B group had greater circumsporozoite protein (CSP)-specific immune responses, including higher immunoglobulin (Ig) G titers, higher numbers of CSP-specific CD4(+) T cells expressing 2 activation markers (interleukin-2, interferon [IFN]-gamma, tumor necrosis factor-alpha, or CD40L), and more ex vivo IFN-gamma enzyme-linked immunospots (ELISPOTs) than did the RTS,S/AS02A group. Protected vaccine recipients had a higher CSP-specific IgG titer (geometric mean titer, 188 vs 73 mug/mL; P < .001), higher numbers of CSP-specific CD4(+) T cells per 10(6) CD4(+) T cells (median, 963 vs 308 CSP-specific CD4(+) T cells/10(6) CD4(+) T cells; P < .001), and higher numbers of ex vivo IFN-gamma ELISPOTs (mean, 212 vs 96 spots/million cells; P < .001). At rechallenge, 4 of 9 vaccine recipients in each group were still completely protected.
  
  
  CONCLUSIONS
  The RTS,S/AS01B malaria vaccine warrants comparative field trials with RTS,S/AS02A to determine the best formulation for the protection of children and infants. The association between complete protection and immune responses is a potential tool for further optimization of protection. Trial registration. ClinicalTrials.gov identifier NCT00075049.
authors: Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910, USA. kent.kester@us.army.mil
authors: Kent E
authors: KE
authors: Kester
authors: James F
authors: JF
authors: Cummings
authors: Opokua
authors: O
authors: Ofori-Anyinam
authors: Christian F
authors: CF
authors: Ockenhouse
authors: Urszula
authors: U
authors: Krzych
authors: Philippe
authors: P
authors: Moris
authors: Robert
authors: R
authors: Schwenk
authors: Robin A
authors: RA
authors: Nielsen
authors: Zufan
authors: Z
authors: Debebe
authors: Evgeny
authors: E
authors: Pinelis
authors: Laure
authors: L
authors: Juompan
authors: Jack
authors: J
authors: Williams
authors: Megan
authors: M
authors: Dowler
authors: V Ann
authors: VA
authors: Stewart
authors: Robert A
authors: RA
authors: Wirtz
authors: Marie-Claude
authors: MC
authors: Dubois
authors: Marc
authors: M
authors: Lievens
authors: Joe
authors: J
authors: Cohen
authors: W Ripley
authors: WR
authors: Ballou
authors: D Gray
authors: DG
authors: Heppner
mesh_terms: D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology / Q000592:standards; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D009073:Mozambique / Q000453:epidemiology; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000276:immunology*; D013997:Time Factors
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines