title: High antibody titer against apical membrane antigen-1 is required to protect against malaria in the Aotus model.
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.
authors.affiliation: Department of Epitope Mapping, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America. sheetij.dutta@us.army.mil
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.forename: JoAnn S
authors.initials: JS
authors.lastname: Sullivan
authors.forename: Katharine K
authors.initials: KK
authors.lastname: Grady
authors.forename: J David
authors.initials: JD
authors.lastname: Haynes
authors.forename: Jack
authors.initials: J
authors.lastname: Komisar
authors.forename: Adrian H
authors.initials: AH
authors.lastname: Batchelor
authors.forename: Lorraine
authors.initials: L
authors.lastname: Soisson
authors.forename: Carter L
authors.initials: CL
authors.lastname: Diggs
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
authors.forename: William E
authors.initials: WE
authors.lastname: Collins
authors.forename: John W
authors.initials: JW
authors.lastname: Barnwell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D001029:Aotus trivirgatus; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007118:Immunoassay; D017780:Malaria Vaccines / Q000737:chemistry / Q000276:immunology; D016778:Malaria, Falciparum / Q000150:complications / Q000276:immunology* / Q000517:prevention & control*; D008969:Molecular Sequence Data; D018512:Parasitemia / Q000150:complications / Q000276:immunology; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology; D017510:Protein Folding; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology; D020539:Sequence Analysis, Protein; D017186:Titrimetry; D014611:Vaccination
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins