Identification of antigens presented by MHC for vaccines against tuberculosis

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 with 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.

Potential T-cell and B-cell Epitopes of 2019-nCoV

“…Our pipeline provides a framework to identify strong epitope-based vaccine candidates-beyond 2019-nCoV-and might be applied against any unknown pathogens. Previous animal studies do show antigens with high MHC presentation scores are more likely to elicit strong T-cell responses, but the correlation between vaccine efficacy and T-cell responses is relatively weak [14,46,7]. When combined with future clinical data, our work can help the field untangle the relationship between antigen presentation scores and vaccine efficacy.…”

A Direct Role for the CD1b Endogenous Spacer in the Recognition of a Mycobacterium tuberculosis Antigen by T-Cell Receptors

“…Human leukocyte antigens (HLA), which are highly polymorphic (more than 26,000 alleles) ( 4 , 5 ), present a variety of Mtb peptides to T-cells, which is considered a key element in the immune response against Mtb ( 6 – 8 ). On the other hand, lipids, glycolipids, and lipopeptides, are presented to T cells by the non-polymorphic CD1 molecules ( 9 ).…”

Immunogenic SARS-CoV-2 Epitopes: In Silico Study Towards Better Understanding of COVID-19 Disease—Paving the Way for Vaccine Development

“…The epitopes derived from the S and E proteins respectively map to transmembrane helical segments 1214 WYIWLGFIAGLIAIVMVTIMLCC 1236 and 12 LIVNSVLLFLAFVVFLLVTLAIL 34 that, based on analysis using the TMHMM2.0 web server [ 31 ], are bitopic in nature, i.e., the predicted transmembrane helices span the lipid bilayer only once. In fact, our predicted epitopes share features, such as being membrane associated, with the well-studied and clinically important epitopes in HIV [ 49 ] and tuberculosis [ 50 ]. This supports the idea that the transmembrane helical epitopes of SARS-CoV-2 could potentially stimulate cytotoxic T-cell-mediated immune responses.…”