title: Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model.
abstract: BACKGROUND
  The complexity of immunity to malaria is well known, and clear correlates of protection 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. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination.
  
  
  METHODS
  We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model.
  
  
  RESULTS
  Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects.
  
  
  CONCLUSIONS
  These results represent novel insights into the immune repertoires involved in malaria vaccination.
authors.affiliation: The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; Mahidol-Oxford Tropical Medicine Research Unit, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Ratchawithi Road, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK. Electronic address: susie.dunachie@ndm.ox.ac.uk.
authors.forename: Susanna
authors.initials: S
authors.lastname: Dunachie
authors.affiliation: The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Tamara
authors.initials: T
authors.lastname: Berthoud
authors.affiliation: The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.affiliation: London School of Hygiene & Tropical Medicine, London W1CE 7HT, UK; The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Fletcher
mesh_terms: D000276:Adjuvants, Immunologic; D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008288:Malaria / Q000276:immunology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology; D014158:Transcription, Genetic; D014611:Vaccination; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma
keywords: Biomarkers; Malaria; Microarray; Plasmodium falciparum; Vaccine