High antibody titer against apical membrane antigen-1 is required to protect against malaria in the Aotus model
| Autor: | Katharine K. Grady, JoAnn S. Sullivan, Sheetij Dutta, D. Gray Heppner, David E. Lanar, Jack Komisar, John W. Barnwell, William E. Collins, Carter L. Diggs, Adrian H. Batchelor, J. David Haynes, Lorraine Soisson |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Protein Folding
Molecular Sequence Data Plasmodium falciparum Protozoan Proteins Antibodies Protozoan lcsh:Medicine Enzyme-Linked Immunosorbent Assay Parasitemia Antigen Antibody Specificity Sequence Analysis Protein Malaria Vaccines parasitic diseases medicine Animals Amino Acid Sequence Apical membrane antigen 1 Malaria Falciparum lcsh:Science Virology/Vaccines Immunoassay Multidisciplinary biology Vaccination fungi lcsh:R Antibody titer Infectious Diseases/Protozoal Infections Titrimetry Apical membrane biology.organism_classification medicine.disease Virology Recombinant Proteins Titer Disease Models Animal Aotus trivirgatus Antibody Formation biology.protein lcsh:Q Antibody Research Article Infectious Diseases/Tropical and Travel-Associated Diseases |
| Zdroj: | PLoS ONE, Vol 4, Iss 12, p e8138 (2009) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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