Tuberculosis, a disease caused by the bacterium Mycobacterium tuberculosis, kills 2-3 million people per year. Although an attenuated strain of M.bovis called BCG is widely used as vaccine against TB, its effectiveness is generally considered as insufficient. Our new approach for BCG improvement is to add a novel type of adjuvant, based on genetically engineered versions of the lipopolysaccharide (LPS) from Neisseria meningitidis (Nm). The modifications aim at (i) specific targeting to dendritic cells where an immune response is initiated, and (ii) reduction of toxicity by making the lipid A part less active for the LPS receptor TLR4/MD2. The inactivation of the lgtB gene results in Nm LPS with a truncated oligosaccharide lacking the terminal galactose which specifically binds to the receptor DC-SIGN on human dendritic cells and this binding skews the resulting T-cell response in a Th1-direction. Heterologous expression in N.meningitidis of the pagL gene from Bordetella bronchiseptica, which encodes a lipid A deacylase, results in penta-acylated Nm LPS of strongly reduced TLR4-activating ability. By controlling the degree of PagL-mediated deacylation, different ratios between penta- and hexa-acylated forms can be obtained which display a continuous range of TLR4-activating capacity. Moreover, mass spectrometric analyses of the Nm LPS have shown that, in addition to penta- and hexa-acylated LPS forms, at least eight other structural variations in the molecular species may occur. At present, the relevance of these structural variants for adjuvant activity and reactogenicity is only partially known. Therefore we will develop a methodology to isolate and structurally identify the different LPS molecular species and test them for the desired level of adjuvant activity without concomitant high reactogenicity. This novel LPS-based targeted adjuvant will be investigated in the context of BCG improvement, but if successful will find application for many other vaccines.
Field of science
- /medical and health sciences/clinical medicine/pneumology/tuberculosis
- /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug/vaccines
Call for proposal
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Funding SchemeMC-IEF - Intra-European Fellowships (IEF)
2500 EJ Den Haag