Elsevier

Vaccine

Volume 35, Issue 1, 3 January 2017, Pages 132-141
Vaccine

H1:IC31 vaccination is safe and induces long-lived TNF-α+IL-2+CD4 T cell responses in M. tuberculosis infected and uninfected adolescents: A randomized trial

https://doi.org/10.1016/j.vaccine.2016.11.023Get rights and content

Highlights

  • H1:IC31 vaccination was well tolerated and had an acceptable safety profile.

  • Two vaccinations of 15 μg H1:IC31 induced the most durable immune response.

  • H1:IC31 induced long-lived memory CD4 T cells that co-express TNFα and IL-2.

Abstract

Background

Control of the tuberculosis epidemic requires a novel vaccine that is effective in preventing tuberculosis in adolescents, a key target population for vaccination against TB.

Methods

Healthy adolescents, stratified by M. tuberculosis-infection status, were enrolled into this observer-blinded phase II clinical trial of the protein-subunit vaccine candidate, H1:IC31, comprising a fusion protein (H1) of Ag85B and ESAT-6, formulated with the IC31 adjuvant. Local and systemic adverse events and induced T cell responses were measured after one or two administrations of either 15 μg or 50 μg of the H1 protein.

Results

Two hundred and forty participants were recruited and followed up for 224 days. No notable safety events were observed regardless of H1 dose or vaccination schedule. H1:IC31 vaccination induced antigen-specific CD4 T cells, co-expressing IFN-γ, TNF-α and/or IL-2. H1:IC31 vaccination of M.tb-uninfected individuals preferentially drove the emergence of Ag85B and ESAT-6 specific TNF-α+IL-2+CD4 T cells, while H1:IC31 vaccination of M.tb-infected individuals resulted in the expansion of Ag85B-specific but not ESAT-6–specific TNF-α+IL-2+CD4 T cells.

Conclusions

H1:IC31 was safe and immunogenic in uninfected and M.tb-infected adolescents. Two administrations of the 15 μg H1:IC31 dose induced the greatest magnitude immune response, and was considered optimal (South African National Clinical Trials Register, DoH-27-0612-3947; Pan African Clinical Trial Registry, PACTR201403000464306).

Section snippets

Background

A core component of the global strategy to control tuberculosis (TB) is the development of efficacious vaccines that prevent infection and disease in adolescents and adults [1], [2], [3], [4]. Bacille Calmette Guerin (BCG), the only licenced TB vaccine, has been widely administered for decades, but has been ineffective in controlling the worldwide epidemic [2]. Strategies involving a number of candidates are being assessed with heterologous vaccination of adolescents or adults to boost the

Trial design and participants

This was a phase II, single centre, randomized, observer-blinded (blinded to the subjects and those recording adverse events/drawing, processing blood samples and performing primary analyses), placebo-controlled clinical trial to evaluate safety and immunogenicity of H1:IC31 in healthy adolescents, who had received routine BCG at birth (Protocol available in supplementary material). We aimed to enrol 240 adolescents for randomization into one of four study groups. Group 1 received 2

Participants

Of the 452 participants who signed consent and were screened, 212 were excluded and 240 were included in the trial (Fig. 1). The median age of participants was 15 years, 64% were female, and the majority (85%) were of mixed race (known as Coloured in South Africa) (Table 1). The first participant was enrolled on 5 September 2012 and the final study visit was on 19 December 2013. Most exclusions were due to mismatched QFT status (for safety reasons QFT− participants were enrolled before QFT+

Discussion

We report results from a large phase II trial of the H1:IC31 vaccine candidate in BCG vaccinated, healthy M.tb-infected or uninfected adolescents from a TB endemic setting. The vaccine was well tolerated and had an acceptable safety profile. No differences in local or systemic adverse events were noted between M.tb-infected and uninfected adolescents and neither vaccine dose nor vaccination schedule had a marked effect. H1:IC31 was immunogenic and predominantly induced long-lived CD4 T cells

Conflict of interest

The authors declare no conflict of interest. The authors do not have a commercial or other association that might pose a conflict of interest.

Meetings where this information has been presented

Keystone Symposia: Host Response in Tuberculosis, January 22–27, 2015. Santa Fe, New Mexico, USA. Poster Presentation.

Keystone Symposia: Cell Biology and Immunology of Persistent Infection, January 31-February 4, 2016, Banff, Alberta, Canada. Poster Presentation.

5th Conference of the South African Immunology Society, March 6–9, 2016. Johannesburg, South Africa. Oral Presentation.

Contributions

HM and HG contributed equally to this work.

SSI was the sponsor of the study

Funding

This work was supported by the European Developing Countries Clinical Trials Partnership (EDCTP) [IP.2007.32080.001] (http://www.edctp.org/) and the Statens Serum Institut. HM was supported by the Carnegie Corporation. SSI, the sponsor of the trial, had no role in data collection however did contribute to study design, data management and storage, analysis, decision to publish and preparation of the manuscript. EDCTP had no role in data collection, study design, analysis, decision to publish or

Author’s contributions

HDG, HMo, WAH, STH, IK, PB, MH, PA and TJS designed the study, HDG, FR conducted the clinical work, ES, YB, AK, ME, LM, DAA, EM, VR, BMK, HMe, MM and TJS performed the immunology assays and analyses, KM, FL, HMe and HDG performed statistical analyses, and HMe drafted the article and revised it, HDG, STH, MR, IK, PB and TJS critically revised the manuscript. All authors reviewed and approved the final manuscript.

Acknowledgments

The authors thank the adolescents who participated in this study and acknowledge the contributions of the SATVI clinicians, nurses, and technicians to this study, as well as the local safety medical monitor, Prof. Andreas Diacon. Also, we thank Valneva GMBH, Austria for generously supplying ODN1a and KLK for the H1:IC31 vaccine. Erica Smit is an ISAC Shared Resources Laboratories Emerging Leader.

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    1

    These authors contributed equally to this work.

    2

    Current Affiliation: Vaccines for Africa Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

    3

    Current Affiliation: Division of Community Health, Department of Interdisciplinary Science, Faculty of Medicine and Health Sciences, Stellenbosch University and Metro District Health Services, Western Cape Government: Health.

    4

    See complete list of the THYB04 study group co-authors in the online version.

    5

    Current Affiliation: Cape Town HVTN Immunology Laboratory, Hutchinson Center Research Institute of South Africa, Cape Town, South Africa.

    6

    Current Affiliation: Bayer Healthcare Pty (Ltd), Pharmaceutical Division, Speciality Medicine, Isando, South Africa.

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