Medeva Holdings Bv

Acambis Research Limited

Archimedes Development Limited

West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited

Celltech Pharma Europe Limited

Steven Neville Chatfield

Gordon Dougan

Lisbeth Illum

Mark Roberts

Carlos Estenio Hormaeche

Mohammed Anjam Khan

Mark Sydenham

Bernardo Villarreal-Ramos

There is provided vaccine compositions for intranasal administration, which compositions comprise one or more antigens and an effective adjuvant amount of a chitosan.

Vaccine compositions including chitosan for intranasal administration and use thereof

The invention relates to a vaccine comprising a bacterium attenuated by a non-reverting mutation in a gene encoding a protein which promotes folding of extracytoplasmic proteins. Such mutations were initially identified as being useful in vaccines from a bank of randomly inserted, transposon mutants in which attenuation was determined as a reduction in virulence of the organism in the mouse model of infection. Site directed mutation of the gene results in a strain which shows at least 4 logs of attenuation when delivered both orally and intravenously. Animals vaccinated with such a strain are protected against subsequent challenge with the parent wild type strain. Finally, heterologous antigens such as the non-toxic and protective, binding domain from tetanus toxin, fragment C, can be delivered via the mucosal immune system using such strains of bacteria. This results in the induction of a fully protective immune response to subsequent challenge with native tetanus toxin.

Vaccines containing attenuated bacteria

The invention provides a bacterium attenuated by a non-reverting mutation in each of the aroC gene, the ompF gene and the ompC gene. The bacterium is useful as a vaccine. The bacterium may, for example, be an attenuated strain ofuseful in vaccination against diarrhoea.

Bacteria attenuated by a non-reverting mutation in each of the aroC, ompF and ompC genes, useful as vaccines

The invention provides the use of Hepatitis A virus capsid, or a mucosally immunogenic fragment or epitope thereof, for the manufacture of a mucosal vaccine composition for administration to a mucosal surface of a patient to induce production of serum Immunoglobulin G antibody against Hepatitis A. Preferably the vaccine composition is administered by the intranasal route.

Vaccine compositions

The invention provides a DNA molecule comprising a promoter sequence operably linked to a DNA sequence encoding first and second proteins linked by a hinge region wherein in that the promoter sequence can be one having activity which is induced in response to a change in the surrounding environment and the first protein can be Tetanus toxin C fragment or one or more epitopes thereof. The invention also provides intermediate molecules having a promoter operably linked to a DNA sequence encoding a first antigenic sequence and a hinge region, and at or adjacent the 3&prime;-end thereof one or more restriction sites for the introduction of a second anti-genic sequence. In addition, the invention provides replicable expression vectors containing the DNA fusion proteins expressed therefrom, bacterial transformed with the vectors and the use of the bacteria, in vaccines.

Expression of recombinant fusion proteins in attenuated bacteria

The invention provides a DNA construct comprising a DNA sequence encoding a fusion protein of the formula: TetC-(Z) -Het, wherein: TetC is the C fragment of tetanus toxin, or a protein comprising the epitopes thereof; Het is a heterologous protein, Z is an amino acid, and a is zero or a positive integer, provided that (Z) does not include the sequence Gly-Pro. The invention also provides replicable expression vectors containing the constructs, bacteria transformed with the constructs, the fusion proteins per se and vaccine compositions formed from the fusion proteins or attenuated bacteria expressing the fusion proteins.

A variety of different types of nasal vaccine systems have been described including cholera toxin, microspheres, nanoparticles, liposomes, attenuated virus, and outer membrane proteins (proteosomes). The present invention is directed toward a novel nasal vaccine composition that utilizes the cationic polysaccharide, chitosan, as a delivery system. Chitosan is a polysaccharide comprising copolymers of glucosamine and N-acetylglucosamine. The term chitosan encompasses a series of chitosan polymers with different molecular weights (50 kDa-2,000 kDa) and degree of acetylation (40%-98%). Several vaccine animal studies were carried out employing influenza or pertussis antigens in combination with chitosan. Nasal administration of chitosan-antigen nasal vaccines induced significant serum IgG responses and secretory IgA levels. Animals vaccinated via the nasal route with various chitosan-antigen vaccines were also found to be protected against the appropriate challenge.

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Berkshire, United Kingdom

Steven Neville Chatfield