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

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Journal PLoS One
Date 2009 Dec 10
PMID 19997632
Citations 58
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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.

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References
1.
Hall N, Pain A, Berriman M, Churcher C, Harris B, Harris D . Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13. Nature. 2002; 419(6906):527-31. DOI: 10.1038/nature01095. View

2.
Spring M, Cummings J, Ockenhouse C, Dutta S, Reidler R, Angov E . 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. PMC: 2669163. DOI: 10.1371/journal.pone.0005254. View

3.
Lehtoranta L, Villberg A, Santanen R, Ziegler T . A novel, colorimetric neutralization assay for measuring antibodies to influenza viruses. J Virol Methods. 2009; 159(2):271-6. DOI: 10.1016/j.jviromet.2009.04.015. View

4.
Haynes J, Moch J, Smoot D . Erythrocytic malaria growth or invasion inhibition assays with emphasis on suspension culture GIA. Methods Mol Med. 2002; 72:535-54. DOI: 10.1385/1-59259-271-6:535. View

5.
Chen R, Markowitz L, Albrecht P, Stewart J, Mofenson L, Preblud S . Measles antibody: reevaluation of protective titers. J Infect Dis. 1990; 162(5):1036-42. DOI: 10.1093/infdis/162.5.1036. View