ADJUTUB

Rational design of a lipopolysaccharide adjuvant for tuberculosis vaccines

Coordinatore	RIJKSINSTITUUT VOOR VOLKSGEZONDHEIDEN MILIEU*NATIONAL INSTITUTEFOR PUBLIC HEALTH AND THE ENVIRONMENTEN    more  Organization address address: Antonie Van Leeuwenhoeklaan 9 city: BILTHOVEN postcode: 3721 MA contact info Titolo: Dr. Nome: Peter Cognome: Van Der Ley Email: send email Telefono: +31 30 2742533
Nazionalità Coordinatore	Netherlands [NL]
Totale costo	222˙885 €
EC contributo	222˙885 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2009-IEF
Funding Scheme	MC-IEF
Anno di inizio	2010
Periodo (anno-mese-giorno)	2010-12-01   -   2012-11-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	RIJKSINSTITUUT VOOR VOLKSGEZONDHEIDEN MILIEU*NATIONAL INSTITUTEFOR PUBLIC HEALTH AND THE ENVIRONMENTEN  Organization address address: Antonie Van Leeuwenhoeklaan 9 city: BILTHOVEN postcode: 3721 MA contact info Titolo: Dr. Nome: Peter Cognome: Van Der Ley Email: send email Telefono: +31 30 2742533	NL (BILTHOVEN)	coordinator	222˙885.60
2	"MINISTERIE VAN VOLKSGEZONDHEID, WELZIJN EN SPORT"  Organization address address: PARNASSUSPLEIN 5 city: DEN HAAG postcode: 2500 EJ contact info Titolo: Dr. Nome: Corine Cognome: Kruiswijk Email: send email Telefono: +31 30 2743403 Fax: +31 30 2744429	NL (DEN HAAG)	participant	0.00

Mappa

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 Obiettivo del progetto (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.'