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Eliciting Mucosal Immunity to Tuberculosis

Periodic Reporting for period 2 - EMI-TB (Eliciting Mucosal Immunity to Tuberculosis)

Reporting period: 2016-07-01 to 2017-12-31

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
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 made significant progress. 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 performed. 20 independent animal studies have been performed so far, which yielded three new mucosal vaccine candidates for TB (Nano-FP1, Spore-FP1 and Lipo-AE; all have been published). These 3 candidates are now being tested in additional animal models (modified mouse model, guinea pigs and NHP) before selection of a single, best performing vaccine candidate for the NHP TB challenge study. In WP3, the cohorts of TB patients and controls have been recruited in Spain, Mozambique and Italy, and protocols for analysis of clinical samples have been established. Significant studies have been already performed on these samples and immunological, transcriptomic and proteomic biomarkers of infection and host response to it (both innate and adapted) have been identified. Though very much 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 unfortunately 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, alternative approaches have been undertaken to identify and harness the potential of CD8 T cell mediated immunity in TB, with encouraging initial results. WPs 5 and 6 have enabled all the key activities to progress by provision of reagents, research tools and clinical samples. The progress of the project has been reviewed at the second annual meeting and several decisions have been made about priorities and future directions. Overall, the project is very much on course to deliver its key objective, i.e. a new mucosal vaccine candidate for TB although some delays (up to 6 months) have occurred due to factors outside our control.
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. 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 candidates, Spore-FP1, nano-FP1 and Lipo-AE, have so far consistently conferred statistically significant reduction in the lung bacterial burden, corroborating immunological evidence of Th1 cytokine production, cellular responses and serum and mucosal antibodies. In further studies, we have identified Spore-FP1 as our lead candidate and have already generated very encouraging results in terms of its suitability for aerosolized delivery, which is the most realistic mode of respiratory delivery of a new TB vaccine. In the other studies, we have performed transcriptomic and proteomic analysis of mucosal clinical samples (i.e. saliva and sputum) and have uncovered 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 sample 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.
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