Community Research and Development Information Service - CORDIS

H2020

EMI-TB Report Summary

Project ID: 643558
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - EMI-TB (Eliciting Mucosal Immunity to Tuberculosis)

Reporting period: 2015-01-01 to 2016-06-30

Summary of the context and overall objectives of the project

Tuberculosis (TB) is a global health problem, killing 1.5 million of people every year. The only currently available vaccine, Mycobacterium bovis BCG, is effective against severe childhood forms, but it demonstrates a variable efficacy against the pulmonary form of TB in adults. Many of these adult TB cases result from the reactivation of an initially controlled, latent Mycobacterium tuberculosis (MTB) infection. Effective prophylactic vaccination remains the key long-term strategy for combating TB. Continued belief in reaching this goal requires unrelenting innovation in the formulation and delivery of candidate vaccines. It is also based on the assumption, that the failure of recent human vaccine trials could have been due to a sub-optimal vaccine design and delivery, and therefore should not erode the key principle that a TB vaccine is an attainable target. This proposal focuses on mucosal vaccination, which has been considered in the past, but not implemented efficiently. The innovation of the proposal is focused on several important aspects of vaccine development and testing, including the use of novel technologies for vaccine delivery, novel ways of specific targeting of mucosal immune cells and tissues, the use of polypeptides incorporating early and latent MTB antigens and putative CD8+ T cell epitopes, and application of novel tools for identifying early predictors and correlates of vaccine-induced protection. The overall objective is to design a vaccine that will induce a broad-ranging immune response to MTB both systemically and in the mucosa of the lungs, and provide the currently missing links in protective immunity to this pathogen.
The primary outcome of EMI-TB will be a novel vaccine candidate for TB that will either boost or supplement systemic BCG and thus confer a superior level of protection against primary and reactivation TB infection.

The secondary objectives will be:
i) Development of several generic vaccine delivery platforms that could be used against other infectious diseases
ii) An improved understanding of protective immune mechanisms in TB, especially those operating in the mucosa
iii) Better predictors of vaccine efficacy and correlates of protection
iv) Improved animal models of MTB infection for vaccine testing

To achieve these objectives, the work is divided in 6 workpackages (WPs), all of which have been initiated and the work advanced. Thus in WP1, 10 independent animal studies have been performed so far, comparing a number of TB vaccine formulations and delivery systems, as described in the proposal. These studies have so far yielded at least 1 definitive vaccine candidate, with additional candidates currently being assessed. In WP3, the initial cohorts of TB patients and controls have been recruited in Spain, Mozambique and Italy, and protocols for analysis of clinical samples have been established. Initial studies have been already performed on these samples. In WP4, several novel CD8 T cell peptides have been tested for immunogenicity in HLA-A.2 transgenic mice, which so far have not yielded a desirable cytotoxic T cell response. However, other peptides will be tested and alternative approaches undertaken to identify and harness the potential of CD8 T cell mediated immunity in TB. Work has also commenced and progressed as planned in all the other WPs, as is detailed in the Technical report.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Good progress has been made in all Workpackages (WPs) and most deliverables have been achieved despite the initial delay. To achieve the Project's objectives, the work is divided in 6 workpackages (WPs), all of which have been initiated and the work advanced. Thus in WP1, The aerosol MTB challenge model has been set up by Participant 1 and comparative screening of a number of vaccine candidates and delivery systems is underway. 10 independent animal studies have been performed so far, which yielded at least 1 definitive vaccine candidate (FP1+YcNaMA+PolyIC), with additional candidates currently being assessed for selection in the next 6 months. The 3 best-performing vaccine candidates will then be tested in additional animal models before selection of a single, best performing vaccine candidate for the NHP study. In WP3, the initial cohorts of TB patients and controls have been recruited in Spain, Mozambique and Italy, and protocols for analysis of clinical samples have been established. Initial studies have been already performed on these samples and several investigations are currently underway to uncover the immunological, transcriptomic and proteomic markers of a protective host response to the infection. Though exploratory in their nature, these studies are likely to yield some important insights into the mechanisms of the protective immunity in TB. In WP4, several novel CD8 T cell peptides have been tested for immunogenicity in HLA-A.2 transgenic mice, which so far have not yielded a desirable cytotoxic T cell response. Part of the difficulty is the limitation of the in vivo models of testing, relying on HLA-A2 transgenic animals. However, other peptides will be tested and alternative approaches undertaken to identify and harness the potential of CD8 T cell mediated immunity in TB. WPs 5 and 6 have enabled the timely start of all scientific activities by provision of reagents, research tools and clinical samples. The progress of the project has been reviewed at the first annual meeting and several decisions have been made about priorities and future directions.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

There is evidence to suggest that, compared to other sites, mucosal vaccination via the respiratory tract is more efficient in inducing protection against mucosal infections, although the presence of an adjuvant is mandatory for induction of immunity and avoidance of tolerance. However, there are currently very few mucosal adjuvants that are non-toxic and capable of inducing robust cellular immune responses. Hence, there is a need to improve mucosal vaccine delivery systems and enhance vaccine uptake in vivo, which will minimise over-reliance on exogenous immune-modulating substances. Ideally, a safe, mucosal vaccine, when applied as a boost to BCG, will stimulate and perpetuate mucosal immunity and will not only impede the initial infection at the airways but also confer a better protection against reactivation TB. The research conducted so far within this project has produced strong evidence that vaccine formulations designed to partly mimic MTB itself are capable of inducing mucosal and systemic immunity and confer protection in mice against aerosol MTB challenge. Our lead vaccine candidate, based on Yc-NaMA nanoparticles and FP1 fusion protein comprising Ag85B, Acr and HBHA antigens has so far consistently conferred statistically significant reduction in the lung bacterial burden, corroborating immunological evidence of Th1 cytokine production, cellular responses and serum antibodies. The latter antigen (HBHA) has not previously been used in this context, i.e. as a lung epithelium targeting vehicle, for enhanced vaccine interaction with the mucosal tissues. Further progress has been made in testing a wide range of delivery systems designed for mucosal applications and we anticipate additional vaccine candidates in the next 6 months. In the other aspects of this reserach project, we have developed protocols for transcriptomic and proteomic analysis of mucosal clinical samples (i.e. saliva and sputum) and are currently employing them to uncover unique molecular signatures associated with infection and/or protection. Such approaches had been employed in the past for blood but are largely unexplored for mucosal samples, largely due to complexity of processing without perturbing the original molecular signatures. We anticipate that these exploratory studies will provide us with a unique insight into the dynamic changes that occur during a protective immune response and guide our future vaccine design and testing. Finally, we have developed a reliable ultra-low dose model of MTB infection in NHP, which will allow us to test the best performing vaccine candidate in a setting that highly resembles human infection. Though the project has not generated outputs with immediate socio-economical impacts as yet, we do expect that a new vaccine candidate will eventually achieve such an impact in the longer term future. With that in mind, we have already conducted the IP analysis within the EMI-TB consortium, which will aid our future IP development and management, and ultimately facilitate the translation of our research into a product that will have a significant impact on health and society in general.

Related information

Record Number: 190409 / Last updated on: 2016-11-15
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