Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

PLoS One. 2009;4(4):e5254. doi: 10.1371/journal.pone.0005254. Epub 2009 Apr 23.

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.

Methodology/principal findings: 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.

Significance: 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.

Trial registration: www.clinicaltrials.gov NCT00385047.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Adjuvants, Immunologic / pharmacology
  • Adolescent
  • Adult
  • Alleles
  • Animals
  • Antigens, Protozoan / administration & dosage
  • Antigens, Protozoan / genetics
  • Antigens, Protozoan / immunology*
  • Double-Blind Method
  • Drug Combinations
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Lipid A / administration & dosage
  • Lipid A / analogs & derivatives*
  • Lipid A / pharmacology
  • Malaria Vaccines / administration & dosage*
  • Malaria Vaccines / adverse effects
  • Malaria Vaccines / immunology
  • Malaria, Falciparum / prevention & control*
  • Membrane Proteins / administration & dosage
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Middle Aged
  • Plasmodium falciparum / immunology
  • Plasmodium falciparum / metabolism
  • Protozoan Proteins / administration & dosage
  • Protozoan Proteins / genetics
  • Protozoan Proteins / immunology*
  • Saponins / administration & dosage*
  • Saponins / pharmacology

Substances

  • ASO2A adjuvant
  • Adjuvants, Immunologic
  • Antigens, Protozoan
  • Drug Combinations
  • Lipid A
  • Malaria Vaccines
  • Membrane Proteins
  • Protozoan Proteins
  • Saponins
  • apical membrane antigen I, Plasmodium

Associated data

  • ClinicalTrials.gov/NCT00385047