High Antibody Titer Against Apical Membrane antigen-1 Is Required to Protect Against Malaria in the Aotus Model

PLoS One. 2009 Dec 3;4(12):e8138. doi: 10.1371/journal.pone.0008138.

Abstract

A Plasmodium falciparum 3D7 strain Apical Membrane Antigen-1 (AMA1) vaccine, formulated with AS02(A) adjuvant, slowed parasite growth in a recent Phase 1/2a trial, however sterile protection was not observed. We tested this AS02(A), and a Montanide ISA720 (ISA) formulation of 3D7 AMA1 in Aotus monkeys. The 3D7 parasite does not invade Aotus erythrocytes, hence two heterologous strains, FCH/4 and FVO, were used for challenge, FCH/4 AMA1 being more homologous to 3D7 than FVO AMA1. Following three vaccinations, the monkeys were challenged with 50,000 FCH/4 or 10,000 FVO parasites. Three of the six animals in the AMA+ISA group were protected against FCH/4 challenge. One monkey did not become parasitemic, another showed only a short period of low level parasitemia that self-cured, and a third animal showed a delay before exhibiting its parasitemic phase. This is the first protection shown in primates with a recombinant P. falciparum AMA1 without formulation in Freund's complete adjuvant. No animals in the AMA+AS02(A) group were protected, but this group exhibited a trend towards reduced growth rate. A second group of monkeys vaccinated with AMA+ISA vaccine was not protected against FVO challenge, suggesting strain-specificity of AMA1-based protection. Protection against FCH/4 strain correlated with the quantity of induced antibodies, as the protected animals were the only ones to have in vitro parasite growth inhibitory activity of >70% at 1:10 serum dilution; immuno-fluorescence titers >8,000; ELISA titers against full-length AMA1 >300,000 and ELISA titer against AMA1 domains1+2 >100,000. A negative correlation between log ELISA titer and day 11 cumulative parasitemia (Spearman rank r = -0.780, p value = 0.0001), further confirmed the relationship between antibody titer and protection. High titers of cross-strain inhibitory antibodies against AMA1 are therefore critical to confer solid protection, and the Aotus model can be used to down-select future AMA1 formulations, prior to advanced human trials.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Protozoan / immunology*
  • Antibody Formation / immunology
  • Antibody Specificity / immunology
  • Aotus trivirgatus
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Immunoassay
  • Malaria Vaccines / chemistry
  • Malaria Vaccines / immunology
  • Malaria, Falciparum / complications
  • Malaria, Falciparum / immunology*
  • Malaria, Falciparum / prevention & control*
  • Molecular Sequence Data
  • Parasitemia / complications
  • Parasitemia / immunology
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / immunology
  • Protein Folding
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / immunology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / immunology
  • Sequence Analysis, Protein
  • Titrimetry
  • Vaccination

Substances

  • Antibodies, Protozoan
  • Malaria Vaccines
  • Protozoan Proteins
  • Recombinant Proteins