Identification of antigens presented by MHC for vaccines against tuberculosis

Bettencourt, Paulo, Muller, Julius, Nicastri, Annalisa, Cantillon, Daire, Madhaven, Meera, Charles, Philip D, Fotso, Carine B, Wittenburg, Rachel, Bull, Naomi, Pinpathomrat, Nawamin, Waddell, Simon J, Stylianou, Elena, Hill, Adrain V S, Ternette, Nicola and McShane, Helen (2020) Identification of antigens presented by MHC for vaccines against tuberculosis. npj Vaccines, 5 (2). pp. 1-14. ISSN 2059-0105

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Abstract

Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry. We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated to membranes and involved in lipid biosynthesis and transport. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Brighton and Sussex Medical School > Global Health and Infection
Research Centres and Groups: Brighton and Sussex Centre for Global Health Research
Depositing User: Deborah Miller
Date Deposited: 28 Nov 2019 10:36
Last Modified: 03 Jan 2020 13:30
URI: http://sro.sussex.ac.uk/id/eprint/88310

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