Subunit vaccine against Neisseria meningitidis infections and co

Details Subunit vaccine against Neisseria meningitidis infections and co Subunit vaccine against Neisseria meningitidis infections and co

1993-05-25

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 39095

Patent

active

056185405

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.
Surprisingly, it has now been found that the high molecular weight subunit could not induce the production of neutralising type antibodies. Only the smaller of the 2 subunits of the receptor appears to be capable of fulfilling this function.
Consequently, the invention provides for: a strain of N. meningitidis, a fragment or an analogue of the said subunit, in purified form; that is to say dissociated and isolated from the high molecular weight subunit of the said receptor; and agent, the lower molecular weight subunit of the human transferrin receptor of at least one strain of N. meningitidis, a fragment or an analogue of the said subunit; in the absence of the high molecular weight subunit of the said receptor; transferrin receptor of at least one strain of N. meningitidis, a fragment or an analogue of the said subunit; in the absence of the high molecular wei

REFERENCES:
Griffiths et al, FEMS Microbiology Letters 69:31-36, 1990.
Zollinger et al, Infect & Immunity 40(1): 257-264, 1983.
Zollinger et al, Transactions of the Royal Society of Tropical Medicine & Hygiene 85: Supplement 1, 37-43, 1991.
Pettersson et al, Infection & Immunity 58(9):3036-3041, 1990.
Geysen et al, J. Molecular Recognition, 1(1): 32-41, 1988.
Saukkonen et al, Vaccine 7: 325-328, 1989.
Schuyvers et al, Molecular Microbiology 2(2): 281-288, 1988.
Nirupama Banerjee-Bhatnagar et al, "Expression of Neisseria meningitidis Iron-Regulated Outer Membrane Proteins, Including a 70-Kilodalton Transferrin Receptor, and Their Potential for Use as Vaccines," Infection and Immunity, vol. 58, No. 9, 1990, pp. 2875-2881.
Anthony B. Schryvers et al, "Identification and Characterization of the Human Lactoferrin-Binding Protein from Neisseria meningitidis," Infection and Immunity, vol. 56, No. 5, 1988, pp. 1144-1149.
Anthony B. Schryvers et al, Chemical Abstract No. 150244, "Identification and Characterization of the Transferrin Receptor from Neisseria meningitidis, " by Schryvers et al., Microbial Biochem., vol. 111, No. 17, 1989, p. 389.

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