title: Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1) administered in adjuvant system AS01B or AS02A.
abstract: BACKGROUND
  This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems.
  
  
  RESULTS
  After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL), full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL) and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-gamma) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements.
  
  
  CONCLUSIONS
  All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali.
  
  
  BACKGROUND
  www.clinicaltrials.gov NCT00385047.
authors.affiliation: United States Military Malaria Vaccine Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America. michele.spring@us.army.mil
authors.forename: Michele D
authors.initials: MD
authors.lastname: Spring
authors.forename: James F
authors.initials: JF
authors.lastname: Cummings
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.forename: Randall
authors.initials: R
authors.lastname: Reidler
authors.forename: Evelina
authors.initials: E
authors.lastname: Angov
authors.forename: Elke
authors.initials: E
authors.lastname: Bergmann-Leitner
authors.forename: V Ann
authors.initials: VA
authors.lastname: Stewart
authors.forename: Stacey
authors.initials: S
authors.lastname: Bittner
authors.forename: Laure
authors.initials: L
authors.lastname: Juompan
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kortepeter
authors.forename: Robin
authors.initials: R
authors.lastname: Nielsen
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.forename: Ev
authors.initials: E
authors.lastname: Tierney
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ware
authors.forename: Megan
authors.initials: M
authors.lastname: Dowler
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Sake J
authors.initials: SJ
authors.lastname: de Vlas
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
authors.forename: Jack L
authors.initials: JL
authors.lastname: Williams
authors.forename: Kent E
authors.initials: KE
authors.lastname: Kester
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tucker
authors.forename: Meng
authors.initials: M
authors.lastname: Shi
authors.forename: Elissa
authors.initials: E
authors.lastname: Malkin
authors.forename: Carole
authors.initials: C
authors.lastname: Long
authors.forename: Carter L
authors.initials: CL
authors.lastname: Diggs
authors.forename: Lorraine
authors.initials: L
authors.lastname: Soisson
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Dubois
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: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D004311:Double-Blind Method; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000276:immunology / Q000378:metabolism; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012503:Saponins / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C501939:ASO2A adjuvant; D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D004338:Drug Combinations; D008050:Lipid A; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D012503:Saponins; C090077:apical membrane antigen I, Plasmodium