title: First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults.
abstract: BACKGROUND
  H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis (M.tb) infection.
  
  
  METHODS
  Low dose (15 μg H56 protein in 500 nmol IC31) or high dose (50 μg H56, 500 nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA.
  
  
  RESULTS
  One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4(+) T cells. M.tb-infected vaccinees had higher frequencies of H56-induced CD4(+) T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ(+)TNF-α(+)IL-2(+)) and higher frequencies of H56-specific CD4(+) T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4(+) T cells, displaying a CD45RA(-)CCR7(-) effector memory phenotype, emerged after the second high-dose vaccination in M.tb-infected vaccinees. TNF-α(+)IL-2(+) H56-specific memory CD4(+) T cells were detected mostly after low-dose H56 vaccination in M.tb-infected vaccinees, and predominantly expressed a CD45RA(-)CCR7(+) central memory phenotype. Our results support further clinical testing of H56:IC31.
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa. Electronic address: angelique.luabeya@uct.ac.za.
authors.forename: Angelique Kany Kany
authors.initials: AK
authors.lastname: Luabeya
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Institute of Infectious Disease and Molecular Medicine (IDM), 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 (IDM), School of Child and Adolescent Health, University of Cape Town, 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 (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Hennie
authors.initials: H
authors.lastname: Geldenhuys
authors.affiliation: Statens Serum Institut (SSI), Copenhagen, Denmark.
authors.forename: Soren T
authors.initials: ST
authors.lastname: Hoff
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Zhongkai
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Statens Serum Institut (SSI), Copenhagen, Denmark.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kromann
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, 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 (IDM), School of Child and Adolescent Health, University of Cape Town, 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: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.affiliation: Statens Serum Institut (SSI), Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, 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 (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Elisma
authors.initials: E
authors.lastname: Schoeman
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Colleen
authors.initials: C
authors.lastname: Krohn
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Department of Global Health, Rollins School of Public Health, Atlanta, GA, USA; Emory Vaccine Center, Emory University, Atlanta, GA, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Hadn
authors.initials: H
authors.lastname: Africa
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Lebohang
authors.initials: L
authors.lastname: Makhethe
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Erica
authors.initials: E
authors.lastname: Smit
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Yolande
authors.initials: Y
authors.lastname: Brown
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: Sara
authors.initials: S
authors.lastname: Suliman
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa.
authors.forename: E Jane
authors.initials: EJ
authors.lastname: Hughes
authors.affiliation: Statens Serum Institut (SSI), Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Bang
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Snowden
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: McClain
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Hussey
mesh_terms: D000217:Acyltransferases / Q000008:administration & dosage / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood*; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D009842:Oligopeptides / Q000008:administration & dosage; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D004338:Drug Combinations; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C544002:IC31 adjuvant; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D032581:Tuberculosis Vaccines; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis
keywords: Clinical trial; H56; Latent; Tuberculosis; Vaccine