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TBVAC2020; Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development

Periodic Reporting for period 3 - TBVAC2020 (TBVAC2020; Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development)

Reporting period: 2018-01-01 to 2019-06-30

TBVAC2020 built on the highly successful, long-standing collaboration in previous EU FP5-, FP6- and FP7-funded Tuberculosis (TB) vaccine and biomarker R&D projects. Key partners and global leaders in the TB field from Europe, USA, Asia, Africa and Australia were part of the project.

TBVAC2020 innovated and diversified the TB vaccine pipeline by accelerating the development of ongoing and novel candidate vaccines and was highly successful in that. This was achieved by bottom-up approaches for vaccine discovery (WP1), developing new preclinical models addressing clinical challenges (WP2) and by identifying and validating correlates of protection (WP5), in combination with top-down portfolio management for vaccine candidate selection by comparative evaluation (WP6) and by head-to-head comparative preclinical, and early clinical, evaluation (WP3, WP4).
TBVAC2020 obtained the following substantial results:

WP1. WP1 identified 12 new approaches for novel vaccines (including 4 whole-cell and 6 subunit vaccines) with higher efficacy than BCG in TB challenge models. These were forwarded into advanced animal models and will deliver new vaccines for clinical trials. Considerable progress has also been achieved in the delivery of antigens using new vectors (e.g. HIV- and LCMV-derived), delivery systems (nanoparticles and liposomes), routes of delivery and adjuvants (cell-stimulating compounds, lipoproteins, glycolipids and polysaccharides) that strengthen the development of local immunity in the lung.

WP2. A number of novel preclinical models have been developed, each with a specific clinical objective. The preclinical toolbox has been diversified by models that recapitulate vaccine performance after post-exposure/therapeutic vaccination for prevention of relapse, vaccination in the context of TB risk factors, by refining existing models for enhanced readout through implementation of assays for the analysis of T lymphocyte function in guinea pigs, PET-CT imaging to monitor host inflammation and disease dynamics in non-human primates.
New leads for antigenic vaccine targets, signatures of functional T lymphocyte activation and exhaustion that correlate with risk of disease, and signatures of local polyfunctional Th17, IL10 and antigen-specific antibodies as correlates of protective immunity upon pulmonary mucosal vaccination have been identified.

WP3. In WP3 head-to-head testing of vaccines to date has provided safety, immunogenicity and efficacy data on 44 different vaccine concepts and formulations (including e.g. new routes of administration or new technologies) selected from a total of 64 applications for testing. These data enabled decisions on progression of vaccines from early discovery stages to pre-clinical development or iterative improvements in vaccine design. Altogether 13 vaccines were demonstrated to provide protection against M. tuberculosis (Mtb) challenge of which 7 were significantly better than BCG. Five vaccine candidates were selected for preclinical development.

WP4. A viral vector candidate has been selected for an experimental medicine study in humans to evaluate safety and local mucosal immunogenicity after administration via the aerosol route. The study after approval by regulatory authorities started in late 2018. Dose finding tests have been completed. No safety signals have been noticed in the vaccinated volunteers, and no vaccine related serious adverse event observed. Last patient follow-up visit is scheduled for early summer 2020.

WP5. WP5 identified, tested, evaluated and prioritized surrogate-endpoints of protection in human TB. Correlates were evaluated in carefully characterised, complementary and unique human cohorts from genetically and geographically diverse populations. Selected correlates were forwarded towards developing, harmonizing and standardizing correlate tests. Efforts are underway to develop these further into simple point-of-care tests for use in high burden and often lower resourced areas. WP5 also studied correlates of risk for TB disease in the above-mentioned cohorts. These will be extremely useful in stratifying individuals in observational and clinical intervention studies. To support data mining of genome wide host expression data a TB biomarker database has been developed containing 51 studies describing transcriptome signatures in patients with active TB disease. It contains not only published signatures but also all genes that are significantly differentially expressed between TB patients and appropriate control populations and will become public domain.

WP6. The PMC did review all candidates submitted to be evaluated in preclinical head-to-head models, and in clinical studies (overall 64 for head-to-head tests, and 4 for clinical testing). Its members participated in the continuous update of the stage gating criteria for progressing TB vaccine candidates along the development pipeline. Specific product and clinical development teams composed of experts in product and clinical development have supported further development of 8 candidate vaccines in preclinical or clinical development stages.

WP7. The annual TBVAC2020 meetings in 2018 and 2019 took place in Les Diablerets, Switzerland, and were preceded by public symposia covering progress issues in TB biomarker & vaccine R&D. The meetings were attended by up to 170 participants from 18 countries, representing research institutes, pharma, SMEs, funding and policy agencies, and partner organisations.
TB remains a major health threat to mankind. A estimated quarter of the world's population is currently infected by Mtb. The vast majority of TB cases occurs in developing countries. In addition, increasing incidence and prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB are increasingly threatening health security in all countries (15 of 22 MDR-TB high burden countries are European). BCG vaccination and all major global efforts to improve rapid and effective diagnosis and treatment regimens have limited effect in controlling the global spread of TB. Novel effective, safe TB vaccines hence are of utmost urgency and will have a huge impact on TB incidence.

TBVAC2020 supported i) 20 discovery approaches, ii) 4 preclinical stage vaccine candidates, and iii) 1 candidate at early clinical stage. The improved correlates of protection identified protective antigens, will accelerate development of vaccines and allow for an improved check of immunogenicity and efficacy at an early stage. Selection and prioritization of the most promising candidate vaccines for clinical testing together with improved robustness and diversity of newly identified biomarkers will contribute to shorten and accelerate clinical evaluation of novel vaccine candidates.

TBVI has been instrumental in the formation of the Global TB Vaccine Partnership between TBVI, BMGF, Aeras (now IAVI) and the Wellcome Trust. This partnership serves firstly to agree and recommend a series of Stage Gating criteria for vaccine selection, an approach that was initiated and led by the TBVI-TBVAC Product Development and Clinical Development Teams, and secondly to work together on advocacy and funding initiatives for larger scale Phase IIb/III efficacy trials. The TBVI-TBVAC2020 Consortium continues to provide leadership in this space and as it provides >50% of the pipeline of TB vaccine candidates, TBVI is a critical partner in the global TB vaccine field.