Dataset Information

Use of massively parallel pyrosequencing to evaluate the diversity of and selection on Plasmodium falciparum csp T-cell epitopes in Lilongwe, Malawi.

ABSTRACT: The development of an effective malaria vaccine has been hampered by the genetic diversity of commonly used target antigens. This diversity has led to concerns about allele-specific immunity limiting the effectiveness of vaccines. Despite extensive genetic diversity of circumsporozoite protein (CS), the most successful malaria vaccine is RTS/S, a monovalent CS vaccine. By use of massively parallel pyrosequencing, we evaluated the diversity of CS haplotypes across the T-cell epitopes in parasites from Lilongwe, Malawi. We identified 57 unique parasite haplotypes from 100 participants. By use of ecological and molecular indexes of diversity, we saw no difference in the diversity of CS haplotypes between adults and children. We saw evidence of weak variant-specific selection within this region of CS, suggesting naturally acquired immunity does induce variant-specific selection on CS. Therefore, the impact of CS vaccines on variant frequencies with widespread implementation of vaccination requires further study.

SUBMITTER: Bailey JA

PROVIDER: S-EPMC3491736 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Use of massively parallel pyrosequencing to evaluate the diversity of and selection on Plasmodium falciparum csp T-cell epitopes in Lilongwe, Malawi.

Bailey Jeffrey A JA Mvalo Tisungane T Aragam Nagesh N Weiser Matthew M Congdon Seth S Kamwendo Debbie D Martinson Francis F Hoffman Irving I Meshnick Steven R SR Juliano Jonathan J JJ

The Journal of infectious diseases 20120502 4

The development of an effective malaria vaccine has been hampered by the genetic diversity of commonly used target antigens. This diversity has led to concerns about allele-specific immunity limiting the effectiveness of vaccines. Despite extensive genetic diversity of circumsporozoite protein (CS), the most successful malaria vaccine is RTS/S, a monovalent CS vaccine. By use of massively parallel pyrosequencing, we evaluated the diversity of CS haplotypes across the T-cell epitopes in parasites ...[more]

PMID: 22551816

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Project description:BackgroundPlasmodium falciparum circumsporozoite protein (CSP) is a leading malaria vaccine candidate antigen, known to elicit protective antibody responses in humans (RTS,S vaccine). Recently, a DNA prime / adenovirus (Ad) vector boost vaccine encoding CSP and a second P. falciparum antigen, apical membrane antigen-1, also elicited sterile protection, but in this case associated with interferon gamma ELISpot and CD8+ T cell but not antibody responses. The finding that CSP delivered by an appropriate vaccine platform likely elicits protective cell-mediated immunity provided a rationale for identifying class I-restricted epitopes within this leading vaccine candidate antigen.MethodsLimited samples of peripheral blood mononuclear cells from clinical trials of the Ad vaccine were used to identify CD8+ T cell epitopes within pools of overlapping 15mer peptides spanning portions of CSP that stimulated recall responses. Computerized algorithms (NetMHC) predicted 17 minimal class I-restricted 9-10mer epitopes within fifteen 15mers positive in ELISpot assay using PBMC from 10 HLA-matched study subjects. Four additional epitopes were subsequently predicted using NetMHC, matched to other study subjects without initial 15mer ELISpot screening. Nine of the putative epitopes were synthesized and tested by ELISpot assay, and six of these nine were further tested for CD8+ T cell responses by ELISpot CD4+ and CD8+ T cell-depletion and flow cytometry assays for evidence of CD8+ T cell dependence.ResultsEach of the nine putative epitopes, all sequence-conserved, recalled responses from HLA-matched CSP-immunized research subjects. Four shorter sequences contained within these sequences were identified using NetMHC predictions and may have contributed to recall responses. Five (9-10mer) epitopes were confirmed to be targets of CD8+ T cell responses using ELISpot depletion and ICS assays. Two 9mers among these nine epitopes were each restricted by two HLA supertypes (A01/B07; A01A24/A24) and one 9mer was restricted by three HLA supertypes (A01A24/A24/B27) indicating that some CSP class I-restricted epitopes, like DR epitopes, may be HLA-promiscuous.ConclusionsThis study identified nine and confirmed five novel class I epitopes restricted by six HLA supertypes, suggesting that an adenovirus-vectored CSP vaccine would be immunogenic and potentially protective in genetically diverse populations.

Dataset Information

Use of massively parallel pyrosequencing to evaluate the diversity of and selection on Plasmodium falciparum csp T-cell epitopes in Lilongwe, Malawi.

Publications

Use of massively parallel pyrosequencing to evaluate the diversity of and selection on Plasmodium falciparum csp T-cell epitopes in Lilongwe, Malawi.

Similar Datasets

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