Hybrid protein between CS from plasmodium and HBSAG

Details Hybrid protein between CS from plasmodium and HBSAG Hybrid protein between CS from plasmodium and HBSAG

1997-09-18

2001-01-02

Minnifield, Nita (Department: 1645)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C536S023720, C536S023700, C435S320100, C435S255300, C435S069300, C435S069900, C435S069100, C435S254100, C435S242000, C530S202000

Utility Patent

active

06169171

ABSTRACT:

The present invention relates to a novel hybrid protein, its use in medicine, particularly in the prevention of malaria infections and vaccines containing it.
Malaria, is one of the world's major health problems with 2 to 4 million people dying from the disease each year. One of the most acute forms of the disease is caused by the protozoan parasite,
Plasmodium falciparum
which is responsible for most of the mortality attributable to Malaria.
The life cycle of
P. falciparum
is complex, requiring two hosts, man and mosquito for completion. The infection of man is initiated by the inoculation of sporozoites in the saliva of an infected mosquito. The sporozoites migrate to the liver and there infect hepatocvtes where they differentiate, via the exoerythrocytic intracellular stage, into the merozoite stage which infects red blood cells (RBC) to initiate cyclical replication in the asexual blood stage. The cycle is completed by the differentiation of a number of merozoites in the RBC into sexual stage gametocytes which are ingested by the mosquito, where they develop through a series of stages in the midgut to produce sporozoites which migrate to the salivary gland.
The sporozoite stage of
P. falciparum
has been identified as a potential target of a malaria vaccine. The major surface protein of the sporozoite is known as circumsporozoite protein (CS Protein). This protein from strain 7G8 has been cloned, expressed and sequenced (Dame et al
Science
225 (1984) p593). The protein from strain 7G8 is characterised by having a central immunodoninant repeat region comprising a tetrapeptide Asn—Ala—Asn—Pro repeated 37 times but interspersed with four minor repeats Asn—Val—Asp—Pro. In other strains the number of major and minor repeats vary as well as their relative position. This central portion is flanked by an N and C terminal portion composed of non-repetitive amino acid sequences designated as the repeatless portion of the CS protein.
It has been shown that irradiated sporozoites can provide significant protection against experimental human malaria (Am. J. Trop. Med. Hyg. 24: 297-402, 1975). However, production difficulties makes the use of irradiated sporozoite impractical from the point of view of producing a vaccine.
Several groups have proposed subunit vaccines based on the circumsporozoite protein. Two of these vaccines have undergone clinical testing; one is a synthetic peptide, the other is a recombinant protein (Ballou et al Lancet: i 1277 (1987) and Herrington et al Nature 328:257 (1987).
These vaccines were successful in stimulating an anti-sporozoite response. Nonetheless, the magnitude of the response was disappointing, with some vaccinees not making a response at all. Furthermore, the absence of “boosting” of antibody levels on subsequent injections and results of in vitro lymphocyte proliferation assays suggested that T-cells of most of these volunteers did not recognise the immuno-dominant repeat. Nonetheless, one vaccinee in each study did not develop parasitemia.


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