title: T-cell activation is an immune correlate of risk in BCG vaccinated infants.
abstract: Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case-control analysis to identify immune correlates of TB disease risk in Bacille Calmette-Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR(+) CD4(+) T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25-2.68, P=0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis-infected adolescents, activated HLA-DR(+) CD4(+) T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068-1.801, P=0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29-0.86, P=0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations.
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.|Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London W1CE7HT, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Fletcher
authors.affiliation: Aeras, Rockville, Maryland 20850, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Snowden
authors.affiliation: Aeras, Rockville, Maryland 20850, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Landry
authors.affiliation: Biostatistics Consultant, 1129 N. Illinois Street, Arlington, Virginia 22205, USA.
authors.forename: Wasima
authors.identifier: 0000-0001-7671-7305
authors.initials: W
authors.lastname: Rida
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Iman
authors.initials: I
authors.lastname: Satti
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Harris
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Magali
authors.initials: M
authors.lastname: Matsumiya
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Tanner
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: O'Shea
authors.affiliation: Aeras, Rockville, Maryland 20850, USA.
authors.forename: Veerabadran
authors.initials: V
authors.lastname: Dheenadhayalan
authors.affiliation: Aeras, Rockville, Maryland 20850, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Bogardus
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.|Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London W1CE7HT, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stockdale
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Marsay
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LF, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chomka
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Harrington-Kandt
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Zita-Rose
authors.initials: ZR
authors.lastname: Manjaly-Thomas
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX37BN, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Stylianou
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Fatoumatta
authors.initials: F
authors.lastname: Darboe
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Adam
authors.initials: A
authors.lastname: Penn-Nicholson
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nemes
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Hatherill
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hussey
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Michele
authors.initials: M
authors.lastname: Tameris
authors.affiliation: Aeras, Rockville, Maryland 20850, USA.
authors.forename: J Bruce
authors.initials: JB
authors.lastname: McClain
authors.affiliation: Aeras, Rockville, Maryland 20850, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Evans
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Paediatrics and Child Health, University of Cape Town, Cape Town 7935, South Africa.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
mesh_terms: D000293:Adolescent; D000917:Antibody Formation / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D015331:Cohort Studies; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007109:Immunity; D007074:Immunoglobulin G / Q000276:immunology; D007223:Infant; D016015:Logistic Models; D008213:Lymphocyte Activation / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010919:Placebos; D012307:Risk Factors; D013997:Time Factors; D014376:Tuberculosis / Q000097:blood / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA
chemical_list: D001500:BCG Vaccine; D006684:HLA-DR Antigens; D007074:Immunoglobulin G; C549320:MVA 85A; D010919:Placebos; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA