Identification of the protective characteristics of a promising TB vaccine candidate

Project Overview

M.tb remains the deadliest infectious disease with 1.6 million deaths in 2017{Organisation, 2018 #1} (1).  Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only available vaccine against TB but its efficacy is highly variable (2). For this reason an effective vaccine is urgently needed. We have developed a promising vaccine candidate composed of a viral vector expressing the mycobacterial antigen PPE15 (3). This antigen belongs to the PE/PPE family of mycobacterial proteins that has been receiving a lot of attention due to the high degree of similarity, and yet high conservation amongst its members (4).

This project aims to further characterize this promising antigen as well as identify ways to further improve its efficacy. To achieve the first, protective regions of this antigen will need to be discovered. This will improve our understanding of which antigen characteristics are responsible for protective immune responses and potentially allow the selection of more promising antigens for vaccine development. To improve the efficacy, different vectors and routes of administration will be evaluated.

 

Training Opportunities

This project will involve the use of a large number of techniques that include:  Molecular biology, Immunisations, Flow cytometry, ELISpot, ELISA, Protein expression and purification, M.tb challenge experiments

Theme

Immunology & Infectious Disease and Physiology, Cellular & Molecular Biology

Admissions

Project reference number: 745

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Helen McShane Jenner Institute Oxford University, Old Road Campus Research Building GBR helen.mcshane@ndm.ox.ac.uk
Dr Elena Stylianou NDM UOXF GBR elena.stylianou@ndm.ox.ac.uk

Brennan MJ. 2017. The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination. Infect. Immun., 85 (6), Read abstract | Read more

The genome of , the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex. Hide abstract

Stylianou E, Harrington-Kandt R, Beglov J, Bull N, Pinpathomrat N, Swarbrick GM, Lewinsohn DA, Lewinsohn DM, McShane H. 2018. Identification and Evaluation of Novel Protective Antigens for the Development of a Candidate Tuberculosis Subunit Vaccine. Infect. Immun., 86 (7), Read abstract | Read more

The development of a vaccine against tuberculosis (TB), a disease caused by , is urgently needed. The only currently available vaccine, BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognized during the course of human infection. A replication-deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually, and these vectors were evaluated for protective efficacy in murine challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4 and CD8 CXCR3 KLRG1 T cells, previously associated with protection against , were enriched in the vaccinated groups compared to the control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models, together with the identification of further novel protective antigens using this selection strategy, is now merited. Hide abstract