Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1996-02-08
2000-10-10
Marschel, Ardin H.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4242041, 435 691, 4352351, 4353201, 536 271, 536 2372, A61K 3929, C12Q 170
Patent
active
061299227
DESCRIPTION:
BRIEF SUMMARY
RELATED APPLICATIONS
This application is a national stage application under 35 U.S.C. .sctn.371 of PCT/GB94/01646, filed Jun. 29, 1994. This application claims priority under 35 U.S.C. .sctn.119 to Great Britain application 9316745.0, filed Aug. 12, 1993.
The present invention relates to vaccine compositions for delivery to mucosal surfaces, and to a method of inducing, in a mammal, an immune response to an antigen by delivering the antigen to a mucosal surface of the mammal. More particularly, the present invention relates to vaccine compositions for inoculating a mammal such as a human against picornavirus infection and particularly Hepatitis A infection.
Hepatitis A is an acute disease caused by infection with a small picornavirus closely related to the poliovirus. Infection is spread by the faecal/oral route and consequently the disease in endemic in areas where hygiene and sanitation standards are low. The risk of travellers to developing countries acquiring Hepatitis A is far greater than that of contracting typhoid and cholera (40 and 800 times respectively).
The virus itself is not directly cytopathic. The liver damage resulting from Hepatitis A virus (HAV) infection arises from destruction of virally infected cells by the host's cytotoxic T-lymphocytes. There is only a single serotype of HAV and infection results in long-term immunity, characteristics that are ideal for developing Hepatitis A prophylaxis. Protection is mediated by neutralising antibodies that prevent entry of hepatitis A virus into hepatocytes. Passive immunisation with purified human serum .gamma.-globulin provides short term protection against the disease and until recently this was the only means of preventing hepatitis A.
In recent years, HAV vaccines have been developed but development has focused on inactivated and live attenuated vaccines. Both types of vaccines are prepared from HAV propagated in tissue culture cells. HAV replication is slow and the majority of the virus remains cell associated, and consequently the viral yields are low and relatively commercially unattractive. The problem of low viral yield could be overcome by using recombinant techniques which allow for the production of large quantities of proteins. However, it is important to ensure correct processing and folding of HAV proteins because the known neutralising epitopes are conformationally dependent. It has proved difficult so far to obtain recombinant HAV antigens that elicit appropriate immune responses.
One recombinant HAV antigen that has proved successful in inducing protection against HAV when injected parenterally is the HAV capsid preparation developed by American Biogenetic Sciences. American Biogenetic Sciences have succeeded in producing empty HAV capsids in eucaryotic cells using vaccinia and baculovirus expression vectors. The recombinant capsids are recognised by neutralising monoclonal antibodies, induce protection against HAV in chimpanzees when injected parenterally and are produced in considerably larger quantities than that obtained by conventional means. The HAV capsids are disclosed in International Patent Application WO-A-9301279, the disclosure in which is incorporated herein by reference.
A disadvantage with many vaccination regimens is that it is frequently necessary to administer the vaccine composition by means of injection, a factor which has a potential deterrent effect to many people, particularly when follow-up or booster injections are required to complete a course of treatment. One way of overcoming this problem would be to administer the vaccine composition to the oral or nasal mucosa, but although immunisation by the oral or intranasal route has been explored with certain other antigens, it has been found usually to be less effective in evoking serum antibodies than parenteral immunisation. For example, the article by M. H. Sjogren et al, Vaccine, Vol. 10, Suppl. 1, S135-S137, 1992, describes the administration of a live attenuated hepatitis A vaccine by either the oral route or the intramuscular route. Whereas intra
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Chatfield Steven Neville
Roberts Mark
Marschel Ardin H.
Medeva Holdings B.V.
Zeman Mary K
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