title: Serum indoleamine 2,3-dioxygenase activity is associated with reduced immunogenicity following vaccination with MVA85A.
abstract: BACKGROUND
  There is an urgent need for improved vaccines to protect against tuberculosis. The currently available vaccine Bacille Calmette-Guerin (BCG) has varying immunogenicity and efficacy across different populations for reasons not clearly understood. MVA85A is a modified vaccinia virus expressing antigen 85A from Mycobacterium tuberculosis which has been in clinical development since 2002 as a candidate vaccine to boost BCG-induced protection. A recent efficacy trial in South African infants failed to demonstrate enhancement of protection over BCG alone. The immunogenicity was lower than that seen in UK trials. The enzyme Indoleamine 2,3-dioxygenase (IDO) catalyses the first and rate-limiting step in the breakdown of the essential amino acid tryptophan. T cells are dependent on tryptophan and IDO activity suppresses T-cell proliferation and function.
  
  
  METHODS
  Using samples collected during phase I trials with MVA85A across the UK and South Africa we have investigated the relationship between vaccine immunogenicity and IDO using IFN-γ ELISPOT, qPCR and liquid chromatography mass spectrometry.
  
  
  RESULTS
  We demonstrate an IFN-γ dependent increase in IDO mRNA expression in peripheral blood mononuclear cells (PBMC) following MVA85A vaccination in UK subjects. IDO mRNA correlates positively with the IFN-γ ELISPOT response indicating that vaccine specific induction of IDO in PBMC is unlikely to limit the development of vaccine specific immunity. IDO activity in the serum of volunteers from the UK and South Africa was also assessed. There was no change in serum IDO activity following MVA85A vaccination. However, we observed higher baseline IDO activity in South African volunteers when compared to UK volunteers. In both UK and South African serum samples, baseline IDO activity negatively correlated with vaccine-specific IFN-γ responses, suggesting that IDO activity may impair the generation of a CD4+ T cell memory response.
  
  
  CONCLUSIONS
  Baseline IDO activity was higher in South African volunteers when compared to UK volunteers, which may represent a potential mechanism for the observed variation in vaccine immunogenicity in South African and UK populations and may have important implications for future vaccination strategies.
  
  
  BACKGROUND
  Trials are registered at ClinicalTrials.gov; UK cohort NCT00427830, UK LTBI cohort NCT00456183, South African cohort NCT00460590, South African LTBI cohort NCT00480558.
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. rachel.tanner@ndm.ox.ac.uk.
authors.forename: Rachel
authors.initials: R
authors.lastname: Tanner
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. kristina.kakalacheva@uzh.ch.|Present address: Department of Neuroinflammation, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. kristina.kakalacheva@uzh.ch.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kakalacheva
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. ellenmiller1988@gmail.com.|Present address: Royal Sussex County Hospital, Eastern road, Brighton, UK. ellenmiller1988@gmail.com.
authors.forename: Ellen
authors.initials: E
authors.lastname: Miller
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. Ansar.Pathan@brunel.ac.uk.|Present address: Centre for Infection, Immunity and Disease Mechanisms, Biosciences, School of Health Sciences and Social Care, Brunel University, Middlesex, UK. Ansar.Pathan@brunel.ac.uk.
authors.forename: Ansar A
authors.initials: AA
authors.lastname: Pathan
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK. rod.chalk@sgc.ox.ac.uk.
authors.forename: Rod
authors.initials: R
authors.lastname: Chalk
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. clarekingsley@gmail.com.|Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. clarekingsley@gmail.com.
authors.forename: Clare R
authors.initials: CR
authors.lastname: Sander
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Thomas.Scriba@uct.ac.za.
authors.forename: Tom
authors.initials: T
authors.lastname: Scriba
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Michele.Tameris@uct.ac.za.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tameris
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. thawkridge@aeras.org.|Vaccines for Africa Initiative, Cape Town, South Africa. thawkridge@aeras.org.
authors.forename: Tony
authors.initials: T
authors.lastname: Hawkridge
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Hassan.Mahomed@uct.ac.za.|Division of Community Health, Stellenbosch University, Stellenbosch, South Africa. Hassan.Mahomed@uct.ac.za.|Metropolitan District Health Services, Western Cape, Government: Health, Cape Town, South Africa. Hassan.Mahomed@uct.ac.za.
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. ghussey@uct.ac.za.|Vaccines for Africa Initiative, Cape Town, South Africa. ghussey@uct.ac.za.
authors.forename: Greg
authors.initials: G
authors.lastname: Hussey
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Willem.Hanekom@uct.ac.
authors.forename: Willem
authors.initials: W
authors.lastname: Hanekom
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. Anna.Checkley@lshtm.ac.uk.|Present address: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. Anna.Checkley@lshtm.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Checkley
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. helen.mcshane@ndm.ox.ac.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, UK. helen.fletcher@lshtm.ac.uk.|Present address: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. helen.fletcher@lshtm.ac.uk.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D001500:BCG Vaccine; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood / Q000187:drug effects* / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism*; D013019:South Africa; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000494:pharmacology*; D006113:United Kingdom; D014611:Vaccination; D019444:Vaccines, DNA; D055815:Young Adult
chemical_list: D001500:BCG Vaccine; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C549320:MVA 85A; D012333:RNA, Messenger; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma