DAR-901 vaccine for the prevention of infection with Mycobacterium tuberculosis among BCG-immunized adolescents in Tanzania: A randomized controlled,double-blind phase 2b trial |
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| Affiliation: | 1. Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania;2. Geisel School of Medicine at Dartmouth, Hanover, NH, USA;3. Boston University School of Public Health, Boston, MA, USA;4. Tokyo Medical and Dental University, Tokyo, Japan;5. Tufts University School of Medicine, Boston, MA, USA;1. Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;2. Fundacio Institut d’Investigacio en Ciencies de la Salut Germans Trias i Pujol, Universitat Autonoma de Barcelona, CIBERES, Barcelona, Spain;3. Centre for Infectious Diseases and International Health, Windeyer Institute of Medical Sciences, University College London, London, UK;4. Infectious Diseases Service, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;1. South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, South Africa;2. Department of Statistical Sciences, University of Cape Town, South Africa;1. South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, South Africa;2. Department of Statistical Sciences, University of Cape Town, South Africa;3. Statens Serum Institut, Copenhagen, Denmark;1. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa;2. Infectious Disease Research Institute, Seattle, WA, USA;3. Aeras, Rockville, MD, USA;1. South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa;2. KEMRI/CDC, Kisumu, Kenya;3. Centro de Investigação em Saúde de Manhiça (CISM), Manhiça, Mozambique;4. Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;5. Aeras, Rockville, MD, USA;6. Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands;7. State University of New York at Stony Brook, Stony Brook, NY, USA;8. Faculty of Medicine, Universidade Eduardo Mondlane, Maputo, Mozambique;1. Infectious Disease Research Institute, Seattle, WA, USA;2. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa;3. Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa;4. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;5. DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa;6. TASK Applied Sciences, Cape Town, South Africa;7. Center for Infectious Disease, Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA;8. Department of Global Health, University of Washington, Seattle, WA, USA;9. PAI Life Sciences, Seattle, WA, USA |
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| Abstract: | BackgroundSRL172 prevented disease due to Mycobacterium tuberculosis in a Phase 3 trial. DAR-901 represents a scalable manufacturing process for SRL172. We sought to determine if DAR-901 would prevent infection with M. tuberculosis among BCG-primed adolescents age 13–15 years in Tanzania.MethodsAdolescents with a negative T- SPOT.TBR interferon gamma release assay (IGRA) were randomized 1:1 to three intradermal injections of DAR-901 or saline placebo at 0, 2 and 4 months. Repeat IGRAs were performed at 2 months, and at 1, 2, and 3 years. The primary efficacy outcome was time to new TB infection (IGRA conversion to positive); the secondary outcome was time to persistent TB infection (IGRA conversion with repeat positive IGRA).ResultsAmong 936 participants screened 667 were eligible and randomized to their first dose of vaccine or placebo (safety cohort). At 2 months, 625 participants remained IGRA-negative and were scheduled for the additional two doses (efficacy cohort). DAR-901 was safe and well-tolerated. One DAR-901 recipient developed a vaccine site abscess. Neither the primary nor secondary endpoints differed between the two treatment arms (p = 0.90 and p = 0.20, respectively). DAR-901 IGRA converters had median responses to ESAT-6 of 50.1 spot-forming cells (SFCs) vs. 19.6 SFCs in placebo IGRA converters (p = 0.03).ConclusionsA three-dose series of 1 mg DAR-901 was safe and well-tolerated but did not prevent initial or persistent IGRA conversion. DAR-901 recipients with IGRA conversion demonstrated enhanced immune responses to ESAT-6. Since protection against disease may require different immunologic responses than protection against infection a trial of DAR-901 to prevent TB disease is warranted.Trial Registration. The trial is registered at ClinicalTrials.gov as NCT02712424. |
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| Keywords: | DAR-901 Tuberculosis Vaccine BCG Interferon gamma release assay Tanzania |
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