A phase I, open-label trial on the safety and immunogenicity of the adjuvanted tuberculosis subunit vaccine H1/IC31® in people living in a TB-endemic area

Jemal Hussein, Martha Zewdie, Lawrence Yamuah, Ahmed Bedru, Markos Abebe, Alemnew F Dagnew, Menberework Chanyalew, Asfawesen G Yohannes, Jemal Ahmed, Howard Engers, T Mark Doherty, Peter Bang, Ingrid Kromann, Søren T Hoff, Abraham Aseffa, Jemal Hussein, Martha Zewdie, Lawrence Yamuah, Ahmed Bedru, Markos Abebe, Alemnew F Dagnew, Menberework Chanyalew, Asfawesen G Yohannes, Jemal Ahmed, Howard Engers, T Mark Doherty, Peter Bang, Ingrid Kromann, Søren T Hoff, Abraham Aseffa

Abstract

Background: H1/IC31® is a tuberculosis (TB) subunit vaccine candidate consisting of the fusion protein of Ag85B and ESAT-6 (H1) formulated with the IC31® adjuvant. Previous trials have reported on the H1/IC31® vaccine in M. tuberculosis (Mtb)-naïve, BCG-vaccinated and previously Mtb-infected individuals. In this trial, conducted between December 2008 and April 2010, the safety and immunogenicity of H1/IC31® was assessed in participants living in Ethiopia - a highly TB-endemic area.

Methods: Healthy male participants aged 18-25 years were recruited into four groups. Participants in group 1 (N = 12) and group 2 (N = 12) were Tuberculin Skin Test (TST) negative and QuantiFERON-TB Gold in-tube test (QFT) negative (Mtb-naïve groups), participants in group 3 (N = 3) were TST positive and QFT negative (BCG group), and participants in group 4 (N = 12) were both TST and QFT positive (Mtb-infected group). H1 vaccine alone (group 1) or H1 formulated with the adjuvant IC31® (groups 2, 3 and 4) was administered intramuscularly on day 0 and day 56. Safety and immunogenicity parameters were evaluated for up to 32 weeks after day 0.

Results: The H1/IC31®vaccine was safe and generally well tolerated. There was little difference among the four groups, with a tendency towards a higher incidence of adverse events in Mtb-infected compared to Mtb-naïve participants. Two serious adverse events were reported in the Mtb-infected group where a relationship to the vaccine could not be excluded. In both cases the participants recovered without sequelae within 72 h. Immunogenicity assays, evaluated in the 29 participants who received both vaccinations, showed a stronger response to TB antigens in the Mtb-naïve group vaccinated with the adjuvant.

Conclusion: The trial confirmed the need for an adjuvant for the vaccine to be immunogenic and highlighted the importance of early phase testing of a novel TB vaccine candidate in TB-endemic areas.

Trial registration: ClinicalTrials.gov, ID: NCT01049282. Retrospectively registered on 14 January 2010.

Keywords: Immunogenicity; Tuberculosis; Vaccines.

Conflict of interest statement

Ethics approval and consent to participate

The trial application was reviewed and approved by the Danish National Committee on Biomedical Research Ethics; the Institutional Review Board at the investigation site, Armauer Hansen Research Institute (AHRI), All Africa Leprosy Rehabilitation and Training Centre (ALERT) Ethical Review Committee; and the National Research Ethics Review Committee of Ethiopia. Written informed consent was obtained from all participants.

Consent for publication

Not applicable

Competing interests

PB and IK are employed at Staten Serum Institut which owns the H1/IC31® vaccine rights. MD and AFD are currently employed at Glaxo-Smith Kline (GSK); SH is employed at Novo Nordisk, but none of the described work is funded by GSK or Novo Nordisk and the views described here are solely those of the authors. No other conflicts of interest were identified.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow diagram of participant screening, enrollment and vaccination
Fig. 2
Fig. 2
QuantifERON-TB Gold-in-tube assay conversion after H1/IC31® vaccinations. Blood samples for the Quantiferon-TB Gold-in-tube assay were taken prior to administration of the first H1/IC31® vaccination (study day 0) and at final visit (study day 224). Each dot indicates the IFN-γ concentration (IU/ml) for each study participant prior to, and after, study vaccinations in groups 1, 2, 3 and 4. A horizontal dotted line represents the cutoff value for Quantiferon positivity. The p values between day 0 and 224 were calculated by the Wilcoxon matched-pairs signed rank test
Fig. 3
Fig. 3
Longitudinal kinetics of H1-specific T cells measured by IFN-γ ELISA. Lines represent the median secreted IFN-γ levels in response to stimulation with Ag85B or ESAT-6 peptide pool for groups 1, 2 and 4. Error bars indicates interquartile range. Black arrows indicate vaccination time points. For each stimulation, area under the curve (AUC) values were compared using Kruskal-Wallis (overall effect) and if p < 0.05, Mann-Whitney tests were performed for comparison between individual groups
Fig. 4
Fig. 4
H1-specific IgG antibody titers. H1-specific IgG levels were measured before first vaccination (study day 0) and at five subsequent study days. Shown are the medians for groups 1, 2 and 4. Error bars represent the interquartile range. Black arrows indicate vaccination time points. A dotted line indicates IgG measured at baseline. For each group, vaccination time points were compared using Kruskal-Wallis (overall effect) and, if p < 0.05, Mann-Whitney tests compared each post-vaccination time point to baseline (day 0). Asterisks indicate a significantly increased titer in group 4 at study days 98 and 224 compared to baseline (p = 0.0002 and 0.024)

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Source: PubMed

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