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Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development (TBVAC2020)
Project
Project code: FLI-Leitg-08-Ri-0462, 643381
Contract period: 01.12.2014
- 30.06.2019
Budget: 18,200,000 Euro
Purpose of research: Applied research
The TBVAC2020 proposal builds on the highly successful and long-standing collaborations in subsequent EC-FP5-, FP6- and FP7-funded TB vaccine and biomarker projects, but also brings in a large number of new key partners from excellent laboratories from Europe, USA, Asia, Africa and Australia, many of which are global leaders in the TB field. This was initiated by launching an open call for Expressions of Interest (EoI) prior to this application and to which interested parties could respond. In total, 115 EoIs were received and ranked by the TBVI Steering Committee using proposed H2020 evaluation criteria. This led to the prioritisation of 52 R&D approaches included in this proposal. TBVAC2020 aims to innovate and diversify the current TB vaccine and biomarker pipeline while at the same time applying portfolio management using gating and priority setting criteria to select as early as possible the most promising TB vaccine candidates, and accelerate their development. TBVAC2020 proposes to achieve this by combining creative “bottom-up” approaches for vaccine discovery (WP1), new preclinical models addressing clinical challenges (WP2) and identification and characterisation of correlates of protection (WP5) with a directive “top-down” portfolio management approach aiming to select the most promising TB vaccine candidates by their comparative evaluation using objective gating and priority setting criteria (WP6) and by supporting direct, head-to head or comparative preclinical and early clinical evaluation (WP3, WP4). This approach will both innovate and diversify the existing TB vaccine and biomarker pipeline as well as accelerate development of most promising TB vaccine candidates through early development stages. The proposed approach and involvement of many internationally leading groups in the TB vaccine and biomarker area in TBVAC2020 fully aligns with the Global TB Vaccine Partnerships (GTBVP).
In the course of the project several vaccination experiments in guinea pigs were performed. With cationic liposome formulations we demonstrated robust induction of antigen specific T cells. During the final reporting period we have continued and extended the studies with subunit vaccine immunized guinea pigs: Together with TBVAC2020 partners LUMC, SSI and PHA Porton Down we studied several formulations of a subunit vaccine containing a fusion protein of Ag85, ESAT6 and Rv2034. However, we noted a striking difference in the response to the subunit vaccine compared to BCG. While BCG vaccinated guinea pigs responded well to total lipid extracts and defined lipids, such as PIM6, no lipid reactivity whatsoever was observed in subunit vaccine immunized animals. We therefore tested a prime-boost regimen by vaccinating guinea pigs first with BCG followed by subunit vaccination. We could show that this approach results in an improved immune response covering both, protein and lipid reactivities. In addition to vaccination studies we also compared immune profiles of BCG vaccinated guinea pigs with immune profiles of guinea pigs that were infected with virulent Mycobacterium tuberculosis. At least during the early phase (within 4 weeks) only BCG induced T cell responses to total lipid extracts and defined lipids (i.e. PIM6). Mtb-infected guinea pigs were not able to control mycobacterial growth and showed only weak proliferative T cell responses to the immunogenic protein antigen, ESAT6. Part of the data has been published (Kaufmann et al., J Immunol, 2016), another manuscript is in preparation. Several aspects described above have been presented at the Keystone Conference in Banff, January 2019: Tuberculosis: Mechanisms, Pathogenesis and Treatment; and at the EMBO Workshop in Oxford, September 2019: CD1-MR1: beyond MHC restricted lymphocytes.
Section overview
Subjects
- Animal health
Framework programme
Funding programme
Excutive institution
Friedrich-Loeffler-Institute - Federal Research Institute for Animal Health (FLI)
