Angelique Kany Kany Luabeya1, Benjamin M N Kagina2, Michele D Tameris3, Hennie Geldenhuys3, Soren T Hoff4, Zhongkai Shi5, Ingrid Kromann4, Mark Hatherill3, Hassan Mahomed6, Willem A Hanekom3, Peter Andersen4, Thomas J Scriba3, Elisma Schoeman3, Colleen Krohn3, Cheryl L Day7, Hadn Africa3, Lebohang Makhethe3, Erica Smit3, Yolande Brown3, Sara Suliman3, E Jane Hughes3, Peter Bang4, Margaret A Snowden5, Bruce McClain5, Gregory D Hussey2. 1. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa. Electronic address: angelique.luabeya@uct.ac.za. 2. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa. 3. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa. 4. Statens Serum Institut (SSI), Copenhagen, Denmark. 5. Aeras, Rockville, MD, USA. 6. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Western Cape Government and Stellenbosch University, Cape Town, South Africa. 7. South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Department of Global Health, Rollins School of Public Health, Atlanta, GA, USA; Emory Vaccine Center, Emory University, Atlanta, GA, USA.
Abstract
BACKGROUND: H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis (M.tb) infection. METHODS: Low dose (15 μg H56 protein in 500 nmol IC31) or high dose (50 μg H56, 500 nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA. RESULTS: One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4(+) T cells. M.tb-infected vaccinees had higher frequencies of H56-induced CD4(+) T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ(+)TNF-α(+)IL-2(+)) and higher frequencies of H56-specific CD4(+) T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4(+) T cells, displaying a CD45RA(-)CCR7(-) effector memory phenotype, emerged after the second high-dose vaccination in M.tb-infected vaccinees. TNF-α(+)IL-2(+) H56-specific memory CD4(+) T cells were detected mostly after low-dose H56 vaccination in M.tb-infected vaccinees, and predominantly expressed a CD45RA(-)CCR7(+) central memory phenotype. Our results support further clinical testing of H56:IC31.
BACKGROUND: H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis (M.tb) infection. METHODS: Low dose (15 μg H56 protein in 500 nmol IC31) or high dose (50 μg H56, 500 nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA. RESULTS: One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4(+) T cells. M.tb-infected vaccinees had higher frequencies of H56-induced CD4(+) T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ(+)TNF-α(+)IL-2(+)) and higher frequencies of H56-specific CD4(+) T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4(+) T cells, displaying a CD45RA(-)CCR7(-) effector memory phenotype, emerged after the second high-dose vaccination in M.tb-infected vaccinees. TNF-α(+)IL-2(+) H56-specific memory CD4(+) T cells were detected mostly after low-dose H56 vaccination in M.tb-infected vaccinees, and predominantly expressed a CD45RA(-)CCR7(+) central memory phenotype. Our results support further clinical testing of H56:IC31.
Authors: Klaus Eyer; Carlos Castrillon; Guilhem Chenon; Jérôme Bibette; Pierre Bruhns; Andrew D Griffiths; Jean Baudry Journal: J Immunol Date: 2020-07-15 Impact factor: 5.422
Authors: Shabaana A Khader; Maziar Divangahi; Willem Hanekom; Philip C Hill; Markus Maeurer; Karen W Makar; Katrin D Mayer-Barber; Musa M Mhlanga; Elisa Nemes; Larry S Schlesinger; Reinout van Crevel; Raman (Krishna) Vankayalapati; Ramnik J Xavier; Mihai G Netea Journal: J Clin Invest Date: 2019-09-03 Impact factor: 14.808