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Structural basis of antigenic escape of a malaria vaccine candidate
Sheetij Dutta1, Seung Yeon Lee, Adrian H Batchelor
1Department of Epitope Mapping, Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. sheetij.dutta@na.amedd.army.mil
Abstract:
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 alpha-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.
Insights
Identifying antigenic escape residues (AER) in apical membrane antigen-1 (AMA-1) is key to malaria vaccine development. Understanding these polymorphic sites can improve vaccine efficacy against diverse parasite strains.
Area of Science:
- Immunology
- Vaccinology
- Parasitology
Background:
- Antibodies targeting apical membrane antigen-1 (AMA-1) show potential for malaria vaccines by inhibiting parasite invasion.
- Antigenic diversity in AMA-1 can limit vaccine effectiveness.
- Polymorphic sites within inhibitory epitopes are hypothesized to be antigenic escape residues (AER).
Purpose of the Study:
- To investigate the role of polymorphic sites in AMA-1 as antigenic escape residues (AER).
- To determine the inhibitory contribution of specific AMA-1 polymorphisms using an in vitro antigenic escape model.
- To explore the potential of chimeric AMA-1 proteins for broader vaccine efficacy.
Main Methods:
- Utilized an in vitro model to assess antigenic escape from anti-AMA-1 antibodies.
- Determined the inhibitory impact of 24 polymorphic sites in the 3D7 AMA-1 strain.
- Constructed and tested interstrain AER chimeric AMA-1 proteins (FVO and 3D7).
Main Results:
- A significant AER cluster with high inhibitory contribution was identified in domain 1 of AMA-1, primarily targeting residues on an alpha-helical loop.
- A second AER cluster was found in domain 2, with domain 3 polymorphisms enhancing its inhibitory effect.
- Chimeric AMA-1 proteins incorporating AER clusters from different strains elicited broad-spectrum inhibitory antibodies against multiple parasite strains.
Conclusions:
- Antigenic escape from anti-AMA-1 antibodies is influenced by specific polymorphic residues, particularly within domain 1.
- Interstrain AER chimeras offer a strategy to broaden vaccine-induced immune responses against diverse AMA-1 alleles.
- Genotyping high-impact AER may aid in classifying AMA-1 strains and evaluating vaccine allelic effects in field studies.
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