Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis

Abstract

Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-γ recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-γ, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis.

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

“…This protein family seems to be particularly interesting for vaccine purposes, as EsxV (Rv3619c) and EsxW (Rv3620c), or one of their paralogues, have been reported as T-cell targets in patients with TB (15), and both proteins have furthermore been included in a vaccine capable of boosting BCG (16). For five of the Esx gene pairs on the M.tb H37Rv chromosome, the flanking genes have been found to encode proteins involved in the secretion of the ESAT-6 family proteins.…”

Mtb32 is a promising tuberculosis antigen for DNA vaccination in pre- and post-exposure mouse models

“…The majority of TB antigens have been tested or screened in various prophylactic settings, whereas a relatively small number have been studied in therapeutic models. [4][5][6] Ag85A, 7 PstS3, 8 MPT64, 9 ACR, 10,11 Mtb39,12 Mtb72F (a fusion protein of Mtb32 and Mtb39) 13 and TB10.4 (ref. 14) were examined in this study.…”

Vaccine delivery system for tuberculosis based on nano-sized hepatitis B virus core protein particles

“…35,36 IFN-γ has been shown to be indispensable for resistance to mycobacterial and other intracellular infections and is often used as a single readout for Th1 responses. 22,37 The secretion of comparatively high amounts of IFN-γ in response to CFPsubmit your manuscript | www.dovepress.com…”

“…TNF on its own is another effector cytokine that can synergize with IFN-γ to eliminate intracellular pathogens. 22,43,44 The higher secretion of TNF in G5 upon stimulation with CFP-10 points to the fact that FVLP was able to induce a protective type of immune response. Compared to all other mice groups, the minimal production of IL-5 and IL-10 in G5 on stimulation with CFP-10 also emphasizes that a Th1 response is actually predominant when Mtb antigen is delivered as an FVLP.…”

“…[19][20][21] Recent research has shown that in comparison to native antigens, the fusion of two or more proteins when administered with adjuvants generated protective immunity in animal models. 22 However, purified proteins show low immune response without adjuvants and tend to have a protective efficacy that is lower than BCG. CFP-10 is a major secretory protein and is one of the most immunodominant and pathogen-specific antigens from Mtb.…”