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Background  Malaria is responsible for up to a 600,000 deaths per year; conveying an urgent need for the development of a malaria vaccine. Studies with whole sporozoite vaccines in mice and non-human primates have shown that sporozoite-induced CD8 +  T cells targeting liver stage antigens can mediate sterile protection. There is a need for a direct method to identify and phenotype malaria vaccine-induced CD8 +  T cells in humans.    Methods  Fluorochrome-labelled tetramers consisting of appropriate MHC class I molecules in complex with predicted binding peptides derived from  Plasmodium falciparum  AMA-1 were used to label  ex vivo  AMA-1 epitope specific CD8 +  T cells from research subjects responding strongly to immunization with the NMRC-M3V-Ad-PfCA (adenovirus-vectored) malaria vaccine. The identification of these CD8 +  T cells on the basis of their expression of early activation markers was also investigated.    Results  Analyses by flow cytometry demonstrated that two of the six tetramers tested: TLDEMRHFY: HLA-A*01:01 and NEVVVKEEY: HLA-B*18:01, labelled tetramer-specific CD8 +  T cells from two HLA-A*01:01 volunteers and one HLA-B*18:01 volunteer, respectively. By contrast, post-immune CD8 +  T cells from all six of the immunized volunteers exhibited enhanced expression of the CD38 and HLA-DR hi  early activation markers. For the three volunteers with positive tetramer staining, the early activation phenotype positive cells included essentially all of the tetramer positive, malaria epitope- specific CD8 +  T cells suggesting that the early activation phenotype could identify all malaria vaccine-induced CD8 +  T cells without prior knowledge of their exact epitope specificity.    Conclusions  The results demonstrated that class I tetramers can identify  ex vivo  malaria vaccine antigen-specific CD8 +  T cells and could therefore be used to determine their frequency, cell surface phenotype and transcription factor usage. The results also demonstrated that vaccine antigen-specific CD8 +  T cells could be identified by activation markers without prior knowledge of their antigen-specificity, using a subunit vaccine for proof-of-concept. Whether, whole parasite or adjuvanted protein vaccines will also induce {CD38 and HLA-DR hi } +  CD8 +  T cell populations reflective of the antigen-specific response will the subject of future investigations.

malaria journal

Ex vivo tetramer staining and cell surface phenotyping for early activation markers CD38 and HLA-DR to enumerate and characterize malaria antigen-specific CD8+ T-cells induced in human volunteers immunized with a Plasmodium falciparum adenovirus-vectored malaria vaccine expressing AMA1