Analog of Haemophilus Hin47 with reduced protease activity

Details Analog of Haemophilus Hin47 with reduced protease activity Analog of Haemophilus Hin47 with reduced protease activity

1996-06-20

1999-11-09

Martinell, James

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 237, C12N 1511

Patent

active

059815035

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to the field of immunology and is particularly concerned with immunogens and antigens from species of Haemophilus.


BACKGROUND TO THE INVENTION

Haemophilus influenzae is the organism responsible for a variety of serious human diseases, such as meningitis, epiglotitis, pneumonia and otitis media. Haemophilus influenzae type b (Hib) is a major cause of bacterial meningitis in children under the age of five years. Protective antibodies to the disease are induced by the capsular polysaccharide of the organism and vaccines have been developed that utilise the purified polyribosyl ribitol phosphate (PRP) as the antigen. This vaccine provides 90% protection in adults and in children over 24 months of age, but was ineffective in children under 24 months (Zangwill et al 1993). (The references are identified in a list of references at the end of this disclosure, each of which reference in the list is hereby incorporated by reference without further reference thereto). Like other polysaccharide antigens, PRP does not induce the proliferation of T-helper cells, and re-immunisation fails to elicit either a booster response or an increase in memory cells. Conjugation of the PRP polysaccharide with protein carriers confers T-cell dependent characteristics to the vaccine and substantially enhances the immunologic response to the PRP antigen. Currently, there are four PRP-carrier conjugate vaccines available. These are vaccines based upon H. influenzae type b capsular polysaccharide conjugated to diphtheria toxoid, tetanus toxoid, or Neisseria meningitidis outer membrane protein (reviewed in Zangwill et al, 1993). These H. influenzae b conjugate vaccines have dramatically reduced the incidence of bacterial meningitis (Schoendorf et al, 1994).
There are six serotypes of H. influenzae designated a to f, which are defined by their capsular polysaccharides. The current Haemophilus conjugate vaccines do not protect against other invasive typable strains (types a and c) and, importantly, do not protect against non-typable (NTHi) strains which are a common cause of postpartum and neonatal sepsis, pneumonia and otitis media. Otitis media is the most common illness of early childhood with approximately 70% of all children suffering at least one bout of otitis media before the age of seven. Chronic otitis media can lead to hearing, speech, and cognitive impairment in children. It is caused by bacterial infection with Streptococcus pneumoniae (approximately 50%), non-typable H. influenzae (approximately 30%), and Moraxella (Branhamella) catarrhalis (approximately 20%). In the United States alone, treatment of otitis media costs between 1 and 2 billion dollars per year for antibiotics and surgical procedures, such as tonsillectomies, adenoidectomies and insertion of tympanostomy tubes. To achieve universal protection against H. influenzae related diseases, particularly in the two to six month age group and certain high risk groups, the provision of conserved, cross-reactive non-capsular H. influenzae immunogens is desirable. Non-typable strains of H. influenzae are also important pathogens responsible for pneumonia in the elderly and other individuals who are particularly susceptible to respiratory infections. There is thus a need for antigens from H. influenzae which are useful as components in immunogenic preparations that provide protection against the many serotypes of H. influenzae. PCT application WO 92/10936, published Jul. 9, 1992 and incorporated herein by reference thereto, describes a 47,000 molecular weight outer membrane protein obtained from H. influenzae that is reported to be an adhesin and has been termed Hin47 that is immunologically conserved between non-typable, type b and non-typed clinical isolates of H. influenzae. The amino acid sequence of Hin47 and the nucleotide sequence of the gene encoding Hin47 were presented at the American Society of Microbiology (ASM) conference held in New Orleans, May 26-30, 1992. These sequences have also been published in PCT

REFERENCES:
Zangwill et al, 1993 MMWR 42:1-15.
Schoendorf et al, 1994 Pediatrics 93:663-8.
Brenner S., 1988 Nature 334:528-530.
O'Hagan 1992 Clin. Pharmokinet. 22:1-10.
Ulmer et al, 1993 Curr. Opinion. Invest. Drugs 2:983-989.
Chang et al, 1978 Nature 275:617-624.
Goeddel et al 1980 Nucl. Acid. Res. 8:4057-4074.
Harkness et al, 1992 J. Bacteriol. 174:2425-2430.
Loeb M.R., 1987 Infec. Immun. 55:2612-2618.
Holmes and Quigley 1981. Analyt. Biochem. 114:193-197.
Young and Davis, 1983 Proc. Natl. Acad. Sci. USA 80: 1194-1196.
Panezutti et al, 1993 Infec. Immun. 61:1867-1872.
Lipinska et al, 1985 Bacteriol. 171:1574-1584.
Barenkamp et al, 1986 Infect. Immun. 52:572-578.
Crowl et al, 1985 Gene 38:31-38.

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