Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials
Maria Norrby, Timo Vesikari, Lars Lindqvist, Markus Maeurer, Raija Ahmed, Shahnaz Mahdavifar, Sean Bennett, J Bruce McClain, Barbara M Shepherd, Daner Li, David A Hokey, Ingrid Kromann, Søren T Hoff, Peter Andersen, Adriëtte W de Visser, Simone A Joosten, Tom H M Ottenhoff, Jan Andersson, Susanna Brighenti, Maria Norrby, Timo Vesikari, Lars Lindqvist, Markus Maeurer, Raija Ahmed, Shahnaz Mahdavifar, Sean Bennett, J Bruce McClain, Barbara M Shepherd, Daner Li, David A Hokey, Ingrid Kromann, Søren T Hoff, Peter Andersen, Adriëtte W de Visser, Simone A Joosten, Tom H M Ottenhoff, Jan Andersson, Susanna Brighenti
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Trial registration: ClinicalTrials.gov, NCT02066428 and NCT02074956.
Keywords: Clinical trial; Human; Immunity; Safety; Tuberculosis; Vaccine.
Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Source: PubMed