title: Safety and immunogenicity of H1/IC31®, an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial.
abstract: BACKGROUND
  Novel tuberculosis vaccines should be safe, immunogenic, and effective in various population groups, including HIV-infected individuals. In this phase II multi-centre, double-blind, placebo-controlled trial, the safety and immunogenicity of the novel H1/IC31 vaccine, a fusion protein of Ag85B-ESAT-6 (H1) formulated with the adjuvant IC31, was evaluated in HIV-infected adults.
  
  
  METHODS
  HIV-infected adults with CD4+ T cell counts >350/mm3 and without evidence of active tuberculosis were enrolled and followed until day 182. H1/IC31 vaccine or placebo was randomly allocated in a 5:1 ratio. The vaccine was administered intramuscularly at day 0 and 56. Safety assessment was based on medical history, clinical examinations, and blood and urine testing. Immunogenicity was determined by a short-term whole blood intracellular cytokine staining assay.
  
  
  RESULTS
  47 of the 48 randomised participants completed both vaccinations. In total, 459 mild or moderate and 2 severe adverse events were reported. There were three serious adverse events in two vaccinees classified as not related to the investigational product. Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p = 0.015). Solicited systemic and unsolicited adverse events were similar by study arm. The baseline CD4+ T cell count and HIV viral load were similar by study arm and remained constant over time. The H1/IC31 vaccine induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells, as well as polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells.
  
  
  CONCLUSIONS
  H1/IC31 was well tolerated and safe in HIV-infected adults with a CD4+ Lymphocyte count greater than 350 cells/mm3. The vaccine did not have an effect on CD4+ T cell count or HIV-1 viral load. H1/IC31 induced a specific and durable Th1 immune response.
  
  
  BACKGROUND
  Pan African Clinical Trials Registry (PACTR) PACTR201105000289276.
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University Basel, Basel, Switzerland; Ifakara Health Institute, Bagamoyo, Tanzania.
authors.forename: Klaus
authors.initials: K
authors.lastname: Reither
authors.affiliation: Aurum Institute, Johannesburg, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Katsoulis
authors.affiliation: Aurum Institute, Johannesburg, South Africa.
authors.forename: Trevor
authors.initials: T
authors.lastname: Beattie
authors.affiliation: Aurum Institute, Johannesburg, South Africa.
authors.forename: Nicolene
authors.initials: N
authors.lastname: Gardiner
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University Basel, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lenz
authors.affiliation: Ifakara Health Institute, Bagamoyo, Tanzania.
authors.forename: Khadija
authors.initials: K
authors.lastname: Said
authors.affiliation: Ifakara Health Institute, Bagamoyo, Tanzania.
authors.forename: Elirehema
authors.initials: E
authors.lastname: Mfinanga
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University Basel, Basel, Switzerland; Ifakara Health Institute, Bagamoyo, Tanzania.
authors.forename: Christian
authors.initials: C
authors.lastname: Pohl
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Fielding
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Jeffery
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: Benjamin M
authors.initials: BM
authors.lastname: Kagina
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: Elisabeth J
authors.initials: EJ
authors.lastname: Hughes
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: 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: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.affiliation: Statens Serum Institute, Department of Infectious Disease Immunology, Copenhagen, Denmark.
authors.forename: Søren T
authors.initials: ST
authors.lastname: Hoff
authors.affiliation: Statens Serum Institute, Department of Vaccine Development, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Bang
authors.affiliation: Statens Serum Institute, Department of Vaccine Development, Copenhagen, Denmark.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kromann
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University Basel, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Daubenberger
authors.affiliation: Statens Serum Institute, Department of Infectious Disease Immunology, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Aurum Institute, Johannesburg, South Africa; London School of Hygiene and Tropical Medicine, London, United Kingdom; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Churchyard
mesh_terms: D000217:Acyltransferases / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000276:immunology; D006801:Humans; D008297:Male; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014376:Tuberculosis / Q000150:complications / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis