title: Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.
abstract: Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant.
  
  
  
  BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150μg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+T cell responses.
  
  
  
  H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+T cell expansion, IFN-γ production and multifunctional CD4+Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50μg of H4 in combination with the 500nmol IC31 adjuvant dose.
  
  
  
  The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50μg of H4 and 500nmol of IC31.
  
  
  
  ClinicalTrials.gov, NCT02066428 and NCT02074956.
authors.affiliation: Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Norrby
authors.affiliation: Vaccine Research Center, University of Tampere, Tampere, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Vesikari
authors.affiliation: Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lindqvist
authors.affiliation: TIM, Department of Laboratory Medicine and CAST, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.affiliation: TIM, Department of Laboratory Medicine and CAST, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Raija
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: TIM, Department of Laboratory Medicine and CAST, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Mahdavifar
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Bennett
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: J Bruce
authors.initials: JB
authors.lastname: McClain
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Shepherd
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: Daner
authors.initials: D
authors.lastname: Li
authors.affiliation: Aeras, Rockville, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hokey
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: Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Adriëtte W
authors.initials: AW
authors.lastname: de Visser
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Joosten
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom H M
authors.initials: THM
authors.lastname: Ottenhoff
authors.affiliation: Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Center for Infectious Medicine (CIM), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Andersson
authors.affiliation: Center for Infectious Medicine (CIM), Karolinska Institutet, Stockholm, Sweden. Electronic address: susanna.brighenti@ki.se.
authors.forename: Susanna
authors.initials: S
authors.lastname: Brighenti
mesh_terms: D000217:Acyltransferases / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D000328:Adult; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004311:Double-Blind Method; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005387:Finland; D064368:Healthy Volunteers; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000009:adverse effects; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects; D010919:Placebos / Q000008:administration & dosage; D013548:Sweden; D016896:Treatment Outcome; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004338:Drug Combinations; C544002:IC31 adjuvant; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D010919:Placebos; C501710:TB10.4 antigen, Mycobacterium tuberculosis; D032581:Tuberculosis Vaccines; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis
keywords: Clinical trial; Human; Immunity; Safety; Tuberculosis; Vaccine