Rational design of a lipopolysaccharide adjuvant for tuberculosis vaccines

Objective

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.

Fields of science (EuroSciVoc)

CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.

• natural sciences biological sciences microbiology bacteriology
• medical and health sciences basic medicine immunology
• natural sciences biological sciences biochemistry biomolecules lipids
• medical and health sciences clinical medicine pneumology tuberculosis
• medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs vaccines

Programme(s)

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• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Topic(s)

Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.

• FP7-PEOPLE-2009-IEF - Marie Curie Action: "Intra-European Fellowships for Career Development"

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP7-PEOPLE-2009-IEF
See other projects for this call

Funding Scheme

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MC-IEF - Intra-European Fellowships (IEF)

Coordinator

Participants (1)