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Rational design and preclinical evaluation of glycoconjugate vaccines for infectious diseases

Objective



The social and economic value of vaccination was acknowledged by the EU when a specialised Task Force on Vaccines and Viral Diseases was established to promote research and development in this field. The new technology of saccharide-protein conjugated vaccines has proven extremely effective for the protection of infants and other risk groups against Haemophilus influenzae Type b (Hib) infection. This approach, in which the T-cell independent response to pure polysaccharide immunogens is converted to a T-cell dependent response, can obviously be applied to protect against other diseases. The full potential will not be realised, however, until the underlying structural principles governing immunogenicity are systematically defined. The aim of this proposal is to uncover these basic rules.
We will synthesise, characterise and evaluate the immunogenicity of a range of saccharideprotein conjugate vaccines designed to produce controlled protective responses against, initially, the bacterial pathogens Neisseria meningitidis and Streptococcus pneumoniae, which have been given high priority by WHO, and against tumours over-expressing the CaMBrl carbohydrate epitope. This project will explore the role of the experimental variables carbohydrate loading, oligosaccharide size and coupling chemistry - in defining the immunological responses and to optimise protective immunity. Saccharide structures will be optimised to enhance immunogenicity and stability, and to provide an appropriate spectrum of T-cell dependent and cellular responses. Animal models providing correlates with protection in infants and in-vitro techniques to monitor T-cell responses will be developed. The structure, stability and consistency of these vaccines will be delineated by physicochemical methods.
Chemically stabilised analogues of the carbohydrate haptens will be designed, and synthesised, and the conjugates produced and tested. Formulation conditions to ensure vaccine stability will be established.
The techniques developed will be applicable to other saccharide-protein conjugate vaccines and provide immunogens suitable for inclusion in novel delivery systems designed to produce immunity at mucosal surfaces or for inclusion in microencapsulated, single dose formulations.

Coordinator

N/A

Participants (4)

National Institute for Biological Standards and Control
United Kingdom
Address
Blanche Lane South Mimms
EN6 3QG Potters Bar
Stockholms Universitet
Sweden
Address

106 91 Stockholm
THE UNIVERSITY OF MILANO
Italy
Address
Via Venezian 21
20133 Milano
UTRECHT UNIVERSITY
Netherlands
Address
Padualaan 8
3584 CH Utrecht