Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Patent
1993-06-02
1997-04-08
Housel, James C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
4242491, 435871, A61K 31075
Patent
active
056185413
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a vaccinal pharmaceutical composition intended for the prevention of meningitis caused by Neisseria meningitidis.
Generally speaking, meningitis is either of viral origin or of bacterial origin. The bacteria mainly responsible are N. meningitidis and Haemophilus influenzae, which are implicated, respectively, in approximately 40 and 50% of cases of bacterial meningitis.
N. meningitidis accounts for approximately 600 to 800 cases of meningitis per annum in France. In the USA, the number of cases amounts to approximately 2,500 to 3,000 per annum.
The species N. meningitidis is subdivided into serogroups according to the nature of the capsular polysaccharides. Although a dozen serogroups exist, 90% of cases of meningitis are attributable to 3 serogroups: A, B and C.
There are effective vaccines based on capsular polysaccharides to prevent meningitis caused by N. meningitidis serogroups A and C. These polysaccharides, as such, exhibit little or no immunogenicity in infants under 2 years of age, and do not induce immune memory. However, these drawbacks may be overcome by conjugating these polysaccharides to a carrier protein.
On the other hand, the polysaccharide of N. meningitidis group B exhibits little or no immunogenicity in man, either in conjugated or in unconjugated form. Thus, it is seen to be highly desirable to seek a vaccine against meningitis induced by N. meningitidis, in particular of serogroup B, other than a vaccine based on polysaccharide.
To this end, various proteins of the outer membrane of N. meningitidis have already been proposed. Special attention has focused on the membrane receptor for human transferrin.
Generally speaking, the large majority of bacteria require iron for their growth, and have developed specific systems for acquiring this metal. As regards N. meningitidis in particular, which is a strict pathogen of man, the iron can be abstracted only from human iron-transport proteins such as transferrin and lactoferrin, since the amount of iron in free form is negligible in man (of the order of 10.sup.-18 M), and in any case insufficient to permit bacterial growth.
Thus, N. meningitidis possesses a human transferrin receptor and a human lactoferrin receptor, which enable it to bind these iron-chelating proteins and thereafter to take up the iron needed for its growth.
The transferrin receptor of N. meningitidis strain B16B6 has been purified by Schryvers et al. (WO 90/12591) from a membrane extract. This protein as purified evidently consists essentially of two types of polypeptide: a polypeptide of high apparent molecular weight of 100 kD and a polypeptide of lower apparent molecular weight of approximately 70 kD, as visualised after polyacrylamide gel electrophoresis in the presence of SDS.
The product of the purification carried out, in particular, by Schryvers is referred to, by arbitrary definition and for the requirements of the present patent application, as the transferrin receptor, and the polypeptides of which it consists are referred to as subunits. In the text below, the subunits of high molecular weight and of lower molecular weight are referred to as Tbp1 and Tbp2, respectively.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an SDS-PAGE gel with 7.5% acrylamide, in which columns A and B correspond to the receptors of N. meningitidis strains 2169 and 2394, respectively. The arrows pointing horizontally indicate the position of the reference proteins of known apparent molecular mass (94 kD, phosphorylase B; 67 kD, albumin).
It has now been found that there are at least two types of strain which differ in the constitution of their respective transferrin receptors. This was demonstrated by studying membrane extracts of several tens of strains of N. meningitidis of miscellaneous origins. These membrane extracts were first subjected to SDS-PAGE gel electrophoresis and then electrotransferred onto nitrocellulose sheets. These nitrocellulose sheets were incubated:
a) in the presence of a rabbit antiserum directed towards the transferrin receptor
REFERENCES:
N. Banerjee-Bhatnagar and Carle E. Frasch, "Expression of Neisseria meningitidis Iron-Regulated Outer Membrane Proteins, Including 1 70-Kilodalton Transferrin Receptor, and Their Potential for Use as Vaccines," Infection and Immunity, vol. 58, No. 9, Sep. 1990, pp. 2875-2881.
Anthony B. Schryvers and Leigh J. Morris, "Identification and Characterization of the Human Lactoferrin-Binding Protein from Neisseria meningitidis," Infection and Immunity, vol. 56, May 1988, pp. 1144-1149.
Griffiths et al; FEMS Microbiology Letters 69:31-36, 1990.
Saukkonen et al; Vaccine 7:325-328, 1989.
Schryvers et al; Can. J. Microbiol 35:409-415, 1989.
Mackinnen et al, Microbiol Pathogenesis 12:415-420, 1992.
Sacchi et al Vaccine 13(1):112-118, 1995.
Zollinger et al, Trans. Royal Soc. Trop. Med Hyg. 85 Suppl. 1 37-43, 1991.
Zollinger et al, Infect. Immun. 40(1):257-264, 1983.
Housel James C.
Krsek-Staples Julie
Pasteau Merieux Serums et Vaccins
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