Malaria Vaccines and Microarrays: Clinical and Laboratory Evaluation of Two Vaccine Regimens

Dunachie, Susanna Jane (2008). Malaria Vaccines and Microarrays: Clinical and Laboratory Evaluation of Two Vaccine Regimens. PhD thesis The Open University.



A vaccine for malaria is urgently required, but clear correlates of immunity against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. Two vaccine regimens were assessed in healthy malaria-naive subjects in Oxford, UK. Firstly a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the circumsporozoite (CS) antigen regimen induced high levels of anti-CS antibodies as well as moderate levels of antigen-specific IFN-ɣ secreting T cells. Secondly a DNA-prime, MVA-boost regimen expressing the multi-epitope string (ME) and thrombospondin related adhesion protein (TRAP) antigens induced high levels of antigen-specific IFN-ɣ secreting T cells. Complete or partial efficacy was seen for some individuals vaccinated with both regimens. Samples from these trials provided the opportunity to perform gene expression profiling.

Real-time RT-PCR and DNA microarrays were used to contrast gene expression changes in subjects before and after vaccination. To focus on antigen-specific changes, comparisons were made between cells stimulated with CS or TRAP peptide pools and unstimulated cells. Hundreds of genes were differentially expressed, many known to be induced by IFN-ɣ. Antigen-specific effects were seen on a number of pathways including antigen processing and presentation, the phosphatidylinositol signalling pathway and cell adhesion molecule interactions. The results were examined alongside information on protection against malaria in the sporozoite challenge for each subject. Parallel RT-PCR studies confirmed these findings and also revealed a potential key role for baseline TGF-β1 levels in antibody induction by RTS,S/AS02A. These results represent the first reported whole-genome expression studies following malaria vaccination and provide novel insights into the immune repertoires involved.

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