Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, Placebo-controlled, Dose-Selection Trial

Am J Respir Crit Care Med. 2019 Jan 15;199(2):220-231. doi: 10.1164/rccm.201802-0366OC.


Rationale: Global tuberculosis (TB) control requires effective vaccines in TB-endemic countries, where most adults are infected with Mycobacterium tuberculosis (M.tb).

Objectives: We sought to define optimal dose and schedule of H56:IC31, an experimental TB vaccine comprising Ag85B, ESAT-6, and Rv2660c, for M.tb-infected and M.tb-uninfected adults.

Methods: We enrolled 98 healthy, HIV-uninfected, bacillus Calmette-Guérin-vaccinated, South African adults. M.tb infection was defined by QuantiFERON-TB (QFT) assay. QFT-negative participants received two vaccinations of different concentrations of H56 in 500 nmol of IC31 to enable dose selection for further vaccine development. Subsequently, QFT-positive and QFT-negative participants were randomized to receive two or three vaccinations to compare potential schedules. Participants were followed for safety and immunogenicity for 292 days.

Measurements and main results: H56:IC31 showed acceptable reactogenicity profiles irrespective of dose, number of vaccinations, or M.tb infection. No vaccine-related severe or serious adverse events were observed. The three H56 concentrations tested induced equivalent frequencies and functional profiles of antigen-specific CD4 T cells. ESAT-6 was only immunogenic in QFT-negative participants who received three vaccinations.

Conclusions: Two or three H56:IC31 vaccinations at the lowest dose induced durable antigen-specific CD4 T-cell responses with acceptable safety and tolerability profiles in M.tb-infected and M.tb-uninfected adults. Additional studies should validate applicability of vaccine doses and regimens to both QFT-positive and QFT-negative individuals. Clinical trial registered with (NCT01865487).

Keywords: H56; QuantiFERON-TB (QFT); clinical trial; subunit vaccine; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / immunology
  • Acyltransferases / therapeutic use
  • Adolescent
  • Adult
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / therapeutic use
  • Bacterial Proteins / immunology
  • Bacterial Proteins / therapeutic use
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Male
  • Middle Aged
  • Oligodeoxyribonucleotides / immunology
  • Oligodeoxyribonucleotides / therapeutic use
  • Oligopeptides / immunology
  • Oligopeptides / therapeutic use
  • South Africa
  • Treatment Outcome
  • Tuberculosis / immunology
  • Tuberculosis / prevention & control*
  • Tuberculosis Vaccines / immunology
  • Tuberculosis Vaccines / therapeutic use*
  • Young Adult


  • Antigens, Bacterial
  • Bacterial Proteins
  • Drug Combinations
  • ESAT-6 protein, Mycobacterium tuberculosis
  • IC31 adjuvant
  • Oligodeoxyribonucleotides
  • Oligopeptides
  • Rv2660c protein, Mycobacterium tuberculosis
  • Tuberculosis Vaccines
  • Acyltransferases
  • antigen 85B, Mycobacterium tuberculosis

Associated data