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
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.
References (28)
- et al.
Innovative clinical trial designs to rationalize TB vaccine development
Tuberculosis
(2015) - et al.
Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting
Vaccine
(2015) - et al.
First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults
Vaccine
(2015) - et al.
Protective immunity to tuberculosis with Ag85B-ESAT-6 in a synthetic cationic adjuvant system IC31
Vaccine
(2006) - et al.
Ag85B-ESAT-6 adjuvanted with IC31(R) promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection
Vaccine
(2011) - et al.
Ag85B-ESAT-6 adjuvanted with IC31 promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in naive human volunteers
Vaccine
(2010) - et al.
Qualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry
J Immunol Methods
(2015) - et al.
Novel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studies
J Immunol Methods
(2004) - et al.
The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: a randomized controlled trial
Vaccine
(2015) - et al.
TB vaccine development: where are we and why is it so difficult?
Thorax
(2015)
Global tuberculosis report
Vaccines for TB: lessons from the Past Translating into Future Potentials
J Immunol Res
Tuberculosis in children
N Engl J Med
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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.