Identification and Evaluation of Novel Protective Antigens for the Development of a Candidate Tuberculosis Subunit Vaccine.

Elena Stylianou,Deborah A Lewinsohn,Rachel Harrington-Kandt,Nawamin Pinpathomrat,David M Lewinsohn,Helen Mcshane,Gwendolyn M Swarbrick,Julia Beglov,Naomi Bull,Sabine Ehrt

doi:10.1128/iai.00014-18

Abstract

ABSTRACTThe development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, is urgently needed. The only currently available vaccine, M. bovis 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 M. tuberculosis 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 M. tuberculosis, 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.

Highlights

The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, is urgently needed
11 mycobacterial antigens have progressed to human clinical trials as part of subunit vaccines, with antigens from the antigen 85 (Ag85) complex being the most commonly used
Selecting protective antigens for inclusion in vaccines is a critical step in subunit vaccine development

Summary

Introduction

The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, is urgently needed. A recent study looking at the sequence variation of human T cell epitopes revealed that the majority of mycobacterial antigens and epitopes are hyperconserved, despite the presence of T-cell responses against the bacterium during the course of M. tuberculosis infection [9]. Whether this hyperconservation results in immune responses that favor the bacterium [9] or whether these antigens have an important function [10] remains to be clarified. Adjuvanted protein vaccine candidates use 11 mycobacterial antigens in different combinations (PepA, PPE18, Ag85A, Ag85B, TB10.4, PPE42, EsxV, EsxW, Rv1813, ESAT6, Rv2660c) [11,12,13,14,15], whereas only 3 antigens have been evaluated as recombinant viral vectors (Ag85A, Ag85B, TB10.4) [16,17,18]

Methods

Results

Conclusion