title: A recombinant adenovirus expressing immunodominant TB antigens can significantly enhance BCG-induced human immunity.
abstract: BACKGROUND
  Despite the availability of Bacille Calmette Guérin (BCG) vaccines, Mycobacterium tuberculosis currently infects billions of people and millions die annually from tuberculosis (TB) disease. New TB vaccines are urgently needed.
  
  
  METHODS
  We studied the ability of AERAS-402, a recombinant, replication-deficient adenovirus type 35 expressing the protective M. tuberculosis antigens Ag85A, Ag85B, and TB10.4, to boost BCG immunity in an area of low TB endemicity.
  
  
  RESULTS
  In volunteers primed with BCG 3 or 6 months prior to AERAS-402 boosting, significant CD4(+) and CD8(+) T cell responses were induced. Ag85-specific responses were more strongly boosted than TB10.4-specific responses. Frequencies of TB-specific CD8(+) T cells reached>50 fold higher than pre-AERAS boosting levels, remarkably higher than reported in any previous human TB vaccine trial. Multiparameter flow cytometric assays demonstrated that AERAS-402-boosted CD4(+) and CD8(+) T cells were multifunctional, producing multiple cytokines and other immune effector molecules. Furthermore, boosted T cells displayed lymphoproliferative capacity, and tetramer analyses confirmed that antigen-specific CD8(+) T cells were induced. BCG and AERAS-402 vaccinations given 3 and 6 months apart appeared equivalent.
  
  
  CONCLUSIONS
  Our results indicate that AERAS-402 is a promising TB vaccine candidate that can significantly enhance both CD4(+) and CD8(+) TB-specific T cell responses after BCG priming. ClinicalTrials.gov Identifier: NCT01378312.
authors.affiliation: Division of Infectious Diseases, Allergy & Immunology, Departments of Internal Medicine & Molecular Microbiology, Saint Louis University Medical Center & Center for Vaccine Development, Saint Louis, MO 63104, USA. hoftdf@slu.edu
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.forename: Azra
authors.initials: A
authors.lastname: Blazevic
authors.forename: Jaime
authors.initials: J
authors.lastname: Stanley
authors.forename: Bernard
authors.initials: B
authors.lastname: Landry
authors.forename: Donata
authors.initials: D
authors.lastname: Sizemore
authors.forename: Eloi
authors.initials: E
authors.lastname: Kpamegan
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gearhart
authors.forename: Alison
authors.initials: A
authors.lastname: Scott
authors.forename: Sandra
authors.initials: S
authors.lastname: Kik
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pau
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: J Bruce
authors.initials: JB
authors.lastname: McClain
authors.forename: Jerald
authors.initials: J
authors.lastname: Sadoff
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics*; D000328:Adult; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D005822:Genetic Vectors; D006805:Human Experimentation; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; C501710:TB10.4 antigen, Mycobacterium tuberculosis; D032581:Tuberculosis Vaccines; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; C121433:antigen 85B, Mycobacterium tuberculosis