Structural basis of antigenic escape of a malaria vaccine candidate

Proceedings of the National Academy of Sciences of the United States of America - Tập 104 Số 30 - Trang 12488-12493 - 2007
Sandeep Dutta1, Seung Yeon Lee1, Adrian H. Batchelor2, David E. Lanar3
1*Department of Epitope Mapping,
2University of Maryland School of Pharmacy, Baltimore, MD 21201
3Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, MD 20910; and

Tóm tắt

Antibodies against the malaria vaccine candidate apical membrane antigen-1 (AMA-1) can inhibit invasion of merozoites into RBC, but antigenic diversity can compromise vaccine efficacy. We hypothesize that polymorphic sites located within inhibitory epitopes function as antigenic escape residues (AER). By using an in vitro model of antigenic escape, the inhibitory contribution of 24 polymorphic sites of the 3D7 AMA-1 vaccine was determined. An AER cluster of 13 polymorphisms, located within domain 1, had the highest inhibitory contribution. Within this AER cluster, antibodies primarily targeted five polymorphic residues situated on an α-helical loop. A second important AER cluster was localized to domain 2. Domain 3 polymorphisms enhanced the inhibitory contribution of the domain 2 AER cluster. Importantly, the AER clusters could be split, such that chimeras containing domain 1 of FVO and domain 2 + 3 of 3D7 generated antisera that showed similarly high level inhibition of the two vaccine strains. Antibodies to this chimeric protein also inhibited unrelated strains of the parasite. Interstrain AER chimeras can be a way to incorporate inhibitory epitopes of two AMA-1 strains into a single protein. The AER clusters map in close proximity to conserved structural elements: the hydrophobic trough and the C-terminal proteolytic processing site. This finding led us to hypothesize that a conserved structural basis of antigenic escape from anti-AMA-1 exists. Genotyping high-impact AER may be useful for classifying AMA-1 strains into inhibition groups and to detect allelic effects of an AMA-1 vaccine in the field.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 104 Số 30

12488-12493

Thông tin tác giả