title: The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8T cell responses.
abstract: BACKGROUND
  Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine.
  
  
  METHODS
  In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6-9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo. The highest dose group received a second dose of vaccine or placebo 56 days after the first. The primary study outcome was safety. Whole blood intracellular cytokine staining assessed immunogenicity.
  
  
  RESULTS
  Forty-two infants received AERAS-402 and 15 infants received placebo. During follow-up of 182 days, an acceptable safety profile was shown with no serious adverse events or discontinuations related to the vaccine. AERAS-402 induced a specific T cell response. A single dose of AERAS-402 induced CD4T cells predominantly expressing single IFN-γ whereas two doses induced CD4T cells predominantly expressing IFN-γ, TNF-α and IL-2 together. CD8T cells were induced and were more likely to be present after 2 doses of AERAS-402.
  
  
  CONCLUSIONS
  AERAS-402 was safe and immunogenic in healthy infants previously vaccinated with BCG at birth. Administration of the highest dose twice may be the most optimal vaccination strategy, based on the induced immunity. Multiple differences in T cell responses when infants are compared with adults vaccinated with AERAS-402, in the same setting and using the same whole blood intracellular cytokine assay, suggest specific strategies may be important for vaccination for each population.
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Division of Medical Microbiology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Benjamin M N
authors.initials: BM
authors.lastname: Kagina
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Tameris
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
authors.forename: Hennie
authors.initials: H
authors.lastname: Geldenhuys
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Hatherill
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
authors.forename: Brian
authors.initials: B
authors.lastname: Abel
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Division of Medical Microbiology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Hussey
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Western Cape Government and Stellenbosch University, Cape Town, South Africa.
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.affiliation: Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands.
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Sadoff
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Bill and Melinda Gates Foundation, Seattle, WA, USA. Electronic address: Willem.Hanekom@uct.ac.za.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.forename: Nazma
authors.initials: N
authors.lastname: Mansoor
authors.forename: Jane
authors.initials: J
authors.lastname: Hughes
authors.forename: Marwou
authors.initials: M
authors.lastname: de Kock
authors.forename: Wendy
authors.initials: W
authors.lastname: Whatney
authors.forename: Hadn
authors.initials: H
authors.lastname: Africa
authors.forename: Colleen
authors.initials: C
authors.lastname: Krohn
authors.forename: Ashley
authors.initials: A
authors.lastname: Veldsman
authors.forename: Angelique Luabeya Kany
authors.initials: AL
authors.lastname: Kany
authors.forename: Macaya
authors.initials: M
authors.lastname: Douoguih
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Pau
authors.forename: Jenny
authors.initials: J
authors.lastname: Hendriks
authors.forename: Bruce
authors.initials: B
authors.lastname: McClainc
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Benko
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Snowden
authors.forename: David A
authors.initials: DA
authors.lastname: Hokey
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007117:Immunization, Secondary; D007223:Infant; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D019444:Vaccines, DNA
chemical_list: C000592463:AERAS-402; D001500:BCG Vaccine; C573415:IFNG protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D032581:Tuberculosis Vaccines; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D007371:Interferon-gamma
keywords: AERAS-402; BCG; Infants; South Africa; Tuberculosis vaccines; Vaccine-induced T cell immunity