title: Individual-level factors associated with variation in mycobacterial-specific immune response: Gender and previous BCG vaccination status.
abstract: BACKGROUND
  A more effective tuberculosis (TB) vaccine is needed to eliminate TB disease. Many new vaccine candidates enhance the immunogenicity of the existing vaccine, Bacillus Calmette-Guérin (BCG). Understanding BCG induced immune variation is key to developing a new vaccine.
  
  
  OBJECTIVE
  We aimed to establish if individual-level covariates were associated with cell-mediated immune response (interferon gamma (IFN-γ)) at vaccine trial enrolment (baseline) in a long-term retrospective analysis (LTR) and after BCG vaccination in a short-term prospective analysis (STP).
  
  
  METHODS
  Four covariates were analysed: gender, country, BCG vaccination history and monocyte/lymphocyte cell count ratio. Univariable and multivariable linear regression were conducted on IFN-γ response at baseline for LTR, and area under the curve (AUC), 24 week and peak IFN-γ response for STP.
  
  
  RESULTS
  Previous BCG vaccination was strongly associated with higher IFN-γ response at baseline (LTR analysis) (p-values < 0.05). Being male showed a weak association with higher baseline response (p-value = 0.1). BCG revaccination was strongly associated with a larger response increase than primary-vaccination (AUC & peak p-values < 0.01), but did not differ at 24 weeks (STP analysis). All other covariates were non-significant (p-values > 0.1).
  
  
  CONCLUSIONS
  This analysis suggests that previous BCG vaccination and gender are associated with durable IFN-γ responses. Vaccine trials may need to stratify by BCG vaccination history and gender.
authors.affiliation: TB Modelling Group, CMMID, TB Centre, London School of Hygiene and Tropical Medicine, UK. Electronic address: sophie.rhodes@lshtm.ac.uk.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Rhodes
authors.affiliation: National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance, Imperial College London, UK.
authors.forename: Gwenan M
authors.initials: GM
authors.lastname: Knight
authors.affiliation: Infectious Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Fielding
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.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: College of Health and Life Sciences, Department of Life Sciences, Brunel University, UK.
authors.forename: Ansar A
authors.initials: AA
authors.lastname: Pathan
authors.affiliation: The Jenner Institute, UK University, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Fletcher
authors.affiliation: TB Modelling Group, CMMID, TB Centre, London School of Hygiene and Tropical Medicine, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: White
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D003430:Cross-Sectional Studies; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007115:Immunization Schedule; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D059425:Interferon-gamma Release Tests; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D012189:Retrospective Studies; D012737:Sex Factors; D013997:Time Factors; D014611:Vaccination; D055815:Young Adult
chemical_list: D001500:BCG Vaccine; D015415:Biomarkers; C573415:IFNG protein, human; D007371:Interferon-gamma
keywords: BCG; IFN-γ; Immune response; Tuberculosis