Benjamin M N Kagina1, Michele D Tameris2, Hennie Geldenhuys2, Mark Hatherill2, Brian Abel3, Gregory D Hussey1, Thomas J Scriba2, Hassan Mahomed4, Jerald C Sadoff5, Willem A Hanekom6, Nazma Mansoor, Jane Hughes, Marwou de Kock, Wendy Whatney, Hadn Africa, Colleen Krohn, Ashley Veldsman, Angelique Luabeya Kany Kany, Macaya Douoguih, Maria Grazia Pau, Jenny Hendriks, Bruce McClainc, Jacqueline Benko, Margaret A Snowden, David A Hokey. 1. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Division of Medical Microbiology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. 2. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa. 3. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore. 4. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Western Cape Government and Stellenbosch University, Cape Town, South Africa. 5. Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands. 6. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; Bill and Melinda Gates Foundation, Seattle, WA, USA. Electronic address: Willem.Hanekom@uct.ac.za.
Abstract
BACKGROUND: Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine. METHODS: In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6-9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo. The highest dose group received a second dose of vaccine or placebo 56 days after the first. The primary study outcome was safety. Whole blood intracellular cytokine staining assessed immunogenicity. RESULTS: Forty-two infants received AERAS-402 and 15 infants received placebo. During follow-up of 182 days, an acceptable safety profile was shown with no serious adverse events or discontinuations related to the vaccine. AERAS-402 induced a specific T cell response. A single dose of AERAS-402 induced CD4T cells predominantly expressing single IFN-γ whereas two doses induced CD4T cells predominantly expressing IFN-γ, TNF-α and IL-2 together. CD8T cells were induced and were more likely to be present after 2 doses of AERAS-402. CONCLUSIONS:AERAS-402 was safe and immunogenic in healthy infants previously vaccinated with BCG at birth. Administration of the highest dose twice may be the most optimal vaccination strategy, based on the induced immunity. Multiple differences in T cell responses when infants are compared with adults vaccinated with AERAS-402, in the same setting and using the same whole blood intracellular cytokine assay, suggest specific strategies may be important for vaccination for each population.
RCT Entities:
BACKGROUND: Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine. METHODS: In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6-9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo. The highest dose group received a second dose of vaccine or placebo 56 days after the first. The primary study outcome was safety. Whole blood intracellular cytokine staining assessed immunogenicity. RESULTS: Forty-two infants received AERAS-402 and 15 infants received placebo. During follow-up of 182 days, an acceptable safety profile was shown with no serious adverse events or discontinuations related to the vaccine. AERAS-402 induced a specific T cell response. A single dose of AERAS-402 induced CD4T cells predominantly expressing single IFN-γ whereas two doses induced CD4T cells predominantly expressing IFN-γ, TNF-α and IL-2 together. CD8T cells were induced and were more likely to be present after 2 doses of AERAS-402. CONCLUSIONS: AERAS-402 was safe and immunogenic in healthy infants previously vaccinated with BCG at birth. Administration of the highest dose twice may be the most optimal vaccination strategy, based on the induced immunity. Multiple differences in T cell responses when infants are compared with adults vaccinated with AERAS-402, in the same setting and using the same whole blood intracellular cytokine assay, suggest specific strategies may be important for vaccination for each population.
Authors: M Tameris; D A Hokey; V Nduba; J Sacarlal; F Laher; G Kiringa; K Gondo; E M Lazarus; G E Gray; S Nachman; H Mahomed; K Downing; B Abel; T J Scriba; J B McClain; M G Pau; J Hendriks; V Dheenadhayalan; S Ishmukhamedov; A K K Luabeya; H Geldenhuys; B Shepherd; G Blatner; V Cardenas; R Walker; W A Hanekom; J Sadoff; M Douoguih; L Barker; M Hatherill Journal: Vaccine Date: 2015-04-28 Impact factor: 3.641
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