title: The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial.
abstract: BACKGROUND
  New, more effective vaccines to prevent tuberculosis (TB) disease are needed urgently. H4:IC31 is an investigational vaccine that contains a fusion protein of the immunodominant antigens TB10.4 and Ag85B, formulated in IC31 adjuvant. We assessed the safety and immunogenicity of H4:IC31 in South African adults from a TB endemic setting.
  
  
  METHODS
  In this double blind, placebo controlled, phase I trial, Mycobacterium tuberculosis-uninfected, HIV-uninfected, healthy adults with a history of childhood BCG vaccination were randomly allocated to two intramuscular vaccinations with 5, 15, 50 or 150 μg H4 formulated in 500nmol IC31, two months apart. Vaccinees were followed for six months to assess safety; immunogenicity was measured by ELISpot and intracellular cytokine staining assays.
  
  
  RESULTS
  Thirty-two participants received H4:IC31 and 8 received placebo. Injection site adverse events were common but mild; mild fatigue was the most common systemic adverse event. Frequencies of adverse events did not differ between dosage groups. Detectable antigen-specific CD4 T cell responses were induced by all doses of H4:IC31, but doses below 50 μg induced the highest frequencies of CD4 T cells, comprised predominantly of IFN-γ(+)TNF-α(+)IL-2(+) or TNF-α(+)IL-2(+) cells. These memory responses persisted up to the end of follow up, on study day 182.
  
  
  CONCLUSIONS
  H4:IC31 demonstrated an acceptable safety profile and was immunogenic in South African adults. In this trial, the 15 μg dose appeared to induce the most optimal immune response.
authors.affiliation: South African Tuberculosis Vaccine Initiative, 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, Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: Mearns
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
authors.forename: David J C
authors.initials: DJ
authors.lastname: Miles
authors.affiliation: South African Tuberculosis Vaccine Initiative, 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
authors.initials: M
authors.lastname: Tameris
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hokey
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Zhongkai
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Clinical Research-HIV Therapeutics Group, Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Bennett
authors.affiliation: Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kromann
authors.affiliation: Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Søren T
authors.initials: ST
authors.lastname: Hoff
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, 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 and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, 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 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, Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa. Electronic address: Thomas.scriba@uct.ac.za.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: South African Tuberculosis Vaccine Initiative, 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
authors.initials: M
authors.lastname: van Rooyen
authors.affiliation: Clinical Research-HIV Therapeutics Group, Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bruce McClain
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ryall
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: de Bruyn
mesh_terms: D000293:Adolescent; D000328:Adult; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000032:analysis; D004311:Double-Blind Method; D004338:Drug Combinations; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos / Q000008:administration & dosage; D013019:South Africa; D013194:Staining and Labeling; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines; D004338:Drug Combinations; C544002:IC31 adjuvant; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D010919:Placebos; D032581:Tuberculosis Vaccines
keywords: Adults; Clinical trial; H4:IC31; Mycobacterium tuberculosis; The trial was registered with the South African National Clinical Trials Register (number DoH 27-1108-2525) and ClinicalTrials.gov (NCT02109874); Vaccine