title: Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response.
abstract: BACKGROUND
  Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population.
  
  
  METHODS
  We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis.
  
  
  RESULTS
  One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A.
  
  
  CONCLUSIONS
  The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies.
  
  
  BACKGROUND
  ClinicalTrials.gov number NCT00953927.
authors.affiliation: Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, UK. magali.matsumiya@ndm.ox.ac.uk.
authors.forename: Magali
authors.initials: M
authors.lastname: Matsumiya
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Harris
authors.forename: Iman
authors.initials: I
authors.lastname: Satti
authors.forename: Lisa
authors.initials: L
authors.lastname: Stockdale
authors.forename: Rachel
authors.initials: R
authors.lastname: Tanner
authors.forename: Matthew K
authors.initials: MK
authors.lastname: O'Shea
authors.forename: Michelle
authors.initials: M
authors.lastname: Tameris
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.forename: Mark
authors.initials: M
authors.lastname: Hatherill
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
authors.forename: Helen A
authors.initials: HA
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D058501:Enzyme-Linked Immunospot Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000235:genetics*; D022423:Myeloid Cells / Q000276:immunology / Q000502:physiology*; D013019:South Africa; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000627:therapeutic use*; D006113:United Kingdom; D014611:Vaccination; D019444:Vaccines, DNA
chemical_list: C549320:MVA 85A; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA