Novel approaches to preclinical research and TB vaccine development

Abstract

The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Low-Dose NHP Challenge Models, Novel Approaches to Animal Models for TB Vaccine R&D, Novel Antigen Delivery Strategies, and Next Generation TB Vaccines and Vaccine Concepts. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30].

Tuberculosis vaccines: Opportunities and challenges

“…Viral vectors can deliver antigen‐encoding genes into host cells efficiently, trigger intracellular production of the antigen in vivo and induce both CD4 + and CD8 + T cell‐mediated immunity. Virus‐vectored subunit vaccines have the potential to activate innate immunity and do not need additional adjuvants . MVA85A, a modified vaccinia Ankara (MVA) virus delivering Ag85A, has been a leading vectored vaccine entering clinical trials .…”

“…Other viruses such as adenovirus type 35, adenovirus type 5, Sendai virus, lentivirus, parainfluenza virus type 2, parainfluenza virus 5, influenza virus, vesicular stomatitis virus (VSV), chimpanzee adenovirus and murine cytomegalovirus have also been exploited to construct TB subunit vaccines. Most of the early generation vaccines used M. tuberculosis antigens Ag85A, Ag85B, ESAT6 and Mtb10.4 . New virus‐vectored vaccines also contain antigens from replicating bacteria and dormant bacteria, as discussed above (see section Protein antigen screening and subunit vaccines ), to induce broader and multistage antigen‐specific immunity.…”

“…For example, recombinant VSV‐846 presents the antigens Rv3615c, Mtb10.4 and Rv2660c . Another advantage of virus‐vectored vaccines is that some viral vectors, including influenza A virus, parainfluenza, Sendai virus and MVA, can be administrated by the intranasal route and induce mucosal antigen‐specific Th1‐type immune responses in the lung tissue . Clinical trials showed that MVA85A and AERAS‐402, an adenovirus type 35‐vectored TB vaccine containing DNA coding for Ag85A, Ag85B and TB10.4 were safe in BCG‐vaccinated healthy adults, further documenting safety and acceptability of virus‐vectored subunit vaccine application in human beings.…”

Development of tuberculosis vaccines in clinical trials: Current status

“…These clinical TB vaccine candidates include subunit vaccines which can be adjuvanted fusion proteins M72 and H56, attenuated viral vectors such as MVA, or influenza virus expressing M. tb ‐specific antigens . In this regard, the main advantages of virus‐vectored vaccines are that several viral vectors can be administrated through intranasal route, inducing mucosal antigen‐specific immunity in the lung tissue, and also contain antigens from dormant mycobacteria and replicating mycobacteria to induce broader and multistage immune responses . In particular, the cytomegalovirus vector is able to express multiple M. tb antigens leading to long‐term immunity .…”

What We Have Learned and What We Have Missed in Tuberculosis Pathophysiology for a New Vaccine Design: Searching for the “Pink Swan”

“…In fact, all vaccines currently in clinical trials were selected on the basis of their capacity to induce Th1 biased CD4 T cells and, to a lesser extent, on CD8 T cell responses (12). Nevertheless, it soon became evident that M. tuberculosis infection could, in itself, induce a protective Th1 immune response, at least as effective as the one induced by BCG vaccination.…”