Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1997-11-13
2001-09-11
Graser, Jennifer (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S249100, C424S184100, C424S185100, C424S190100, C530S300000, C530S350000, C536S023700
Reexamination Certificate
active
06287574
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to a highly conserved, immunologically accessible antigen at the surface of
Neisseria meningitidis
organisms. This unique antigen provides the basis for new immunotherapeutic, prophylactic and diagnostic agents useful in the treatment, prevention and diagnosis of
Neisseria meningitidis
diseases. More particularly, this invention relates to a proteinase K resistant
Neisseria meningitidis
surface protein having an apparent molecular weight of 22 kDa, the corresponding nucleotide and derived amino acid sequences (SEQ ID NO:1 to SEQ ID NO:26), recombinant DNA methods for the production of the
Neisseria meningitidis
22 kDa surface protein, antibodies that bind to the
Neisseria meningitidis
22 kDa surface protein and methods and compositions for the diagnosis, treatment and prevention of
Neisseria meningitidis
diseases.
BACKGROUND OF THE INVENTION
Neisseria meningitidis
is a major cause of death and morbidity throughout the world.
Neisseria meningitidis
causes both endemic and epidemic diseases, principally meningitis and meningococcemia [Gold,
Evolution of meningococcal disease,
p. 69, Vedros N. A., CRC Press (1987); Schwartz et al.,
Clin. Microbiol. Rev.,
2, p. S118 (1989)]. In fact, this organism is one of the most common causes, after
Haemophilus influenzae
type b, of bacterial meningitis in the United States, accounting for approximately 20% of all cases. It has been well documented that serum bactericidal activity is the major defense mechanism against
Neisseria meningitidis
and that protection against invasion by the bacteria correlates with the presence in the serum of anti-meningococcal antibodies [Goldschneider et al.,
J. Exp. Med.
129, p. 1307 (1969); Goldschneider et al.,
J. Exp. Med.,
129, p. 1327 (1969)].
Neisseria meningitidis
are subdivided into serological groups according to the presence of capsular antigens. Currently, 12 serogroups are recognized, but serogroups A, B, C, Y, and W-135 are most commonly found. Within serogroups, serotypes, subtypes and immunotypes can be identified on outer membrane proteins and lipopolysaccharide [Frasch et al.,
Rev. infect. Dis.
7, p. 504 (1985)].
The capsular polysaccharide vaccines presently available are not effective against all
Neisseria meningitidis
isolates and do not effectively induce the production of protective antibodies in young infants (Frasch,
Clin. Microbiol. Rev.
2, p. S134 (1989); Reingold et al.,
Lancet,
p. 114 (1985); Zollinger, in Woodrow and Levine,
New generation vaccines,
p. 325, Marcel Dekker Inc. N.Y. (1990)]. The capsular polysaccharide of serogroups A, C, Y and W-135 are presently used in vaccines against this organism. These polysaccharide vaccines are effective in the short term, however the vaccinated subjects do not develop an immunological memory, so they must be revaccinated within a three-year period to maintain their level of resistance.
Furthermore, these polysaccharide vaccines do not induce sufficient levels of bactericidal antibodies to obtain the desired protection in children under two years of age, who are the principal victims of this disease. No effective vaccine against serogroup B isolates is presently available even though these organisms are one of the primary causes of meningococcal diseases in developed countries. Indeed, the serogroup B polysaccharide is not a good immunogen, inducing only a poor response of IgM of low specificity which is not protective [Gotschlich et al.,
J. Exp. Med.,
p. 129, 1349 (1969); Skevakis et al.,
J. Infect. Dis.,
149, p. 387 (1984); Zollinger et al.,
J. Clin. Invest.,
63, p. 836 (1979)]. Furthermore, the presence of closely similar, crossreactive structures in the glycoproteins of neonatal human brain tissue [Finne et al.,
Lancet,
p. 355 (1983)] might discourage attempts at improving the immunogenicity of serogroup B polysaccharide.
To obtain a more effective vaccine, other
Neisseria meningitidis
surface antigens such as lipopolysaccharide, pili proteins and proteins present in the outer membrane are under investigation. The presence of a human immune response and bactericidal antibodies against certain of these proteinaceous surface antigens in the sera of immunized volunteers and convalescent patients was demonstrated [Mandrell and Zollinger,
Infect. Immun.,
57, p. 1590 (1989); Poolman et al.,
Infect. Immun.,
40, p. 398 (1983); Rosenquist et al.,
J. Clin. Microbiol.,
26, p. 1543 (1988); Wedege and Froholm,
Infect. Immun.
51, p. 571 (1986); Wedege and Michaelsen,
J. Clin. Microbiol.,
25, p. 1349 (1987)].
Furthermore, monoclonal antibodies directed against outer membrane proteins, such as class 1, 2/3 and 5, were also reported to be bactericidal and to protect against experimental infections in animals [Brodeur et al., Infec.
Immun.,
50, p. 510 (1985); Frasch et al,
Clin. Invest. Med.,
9, p. 101 (1986); Saukkonen et al.
Microb. Pathogen.,
3, p. 261 (1987); Saukkonen et al.,
Vaccine,
7, p. 325 (1989)].
Antigen preparations based on
Neisseria meningitidis
outer membrane proteins have demonstrated immunogenic effects in animals and in humans and some of them have been tested in clinical trials [Bjune et al.,
Lancet, p.
1093 (1991); Costa et al.,
NIPH Annals,
14, p. 215 (1991); Frasch et al.,
Med. Trop.,
43, p. 177 (1982); Frasch et al.,
Eur. J. Clin. Microbiol.,
4, p. 533 (1985); Frasch et al. in Robbins,
Bacterial Vaccines,
p. 262, Praeger Publications, N.Y. (1987); Prasch et al,
J. Infect. Dis.,
158, p. 710 (1988); Moreno et al.
Infec. Immun.,
47, p. 527 (1985); Rosenqvist et al.,
J. Clin. Microbiol.,
26, p. 1543 (1988); Sierra et al.,
NIPH Annals,
14, p. 195 (1991); Wedege and Froholm,
Infec. Immun.
51, p. 571 (1986); Wedege and Michaelsen,
J. Clin. Microbiol.,
25, p. 1349 (1987); Zollinger et al.,
J. Clin. Invest.,
63, p. 836 (1979); Zollinger et al.,
NIPH Annals,
14, p. 211 (1991)]. However, the existence of great interstrain antigenic variability in the outer membrane proteins can limit their use in vaccines [Frasch,
Clin. Microb.,
Rev. 2, p. S134 (1989)]. Indeed, most of these preparations induced bactericidal antibodies that were restricted to the same or related serotype from which the antigen was extracted [Zollinger in Woodrow and Levine,
New Generation Vaccines, p.
325, Marcel Dekker Inc. N.Y. (1990)]. Furthermore, the protection conferred by these vaccines in young children has yet to be clearly established. The highly conserved
Neisseria meningitidis
outer membrane proteins such as the class 4 [Munkley et al.
Microb. Pathogen.,
11, p. 447 (1991)] and the lip protein (also called H.8) [Woods et al.,
Infect. Immun.,
55, p. 1927 (1987)] are not interesting vaccine candidates since they do not elicit the production of bactericidal antibodies. To improve these vaccine preparations, there is a need for highly conserved proteins that would be present at the surface of all
Neisseria meningitidis
strains and that would be capable of eliciting bactericidal antibodies in order to develop a broad spectrum vaccine.
The current laboratory diagnosis of
Neisseria meningitidis
is usually done by techniques such as Gram stain of smear preparations, latex agglutination or coagglutination, and the culture and isolation on enriched and selective media [Morello et al., in Balows,
Manual of Clinical Microbiology,
p. 258, American Society for Microbiology, Washington (1991)]. Carbohydrate degradation tests are usually performed to confirm the identification of
Neisseria meningitidis
isolates. Most of the described procedures are time-consuming processes requiring trained personnel. Commercial agglutination or coagglutination kits containing polyvalent sera directed against the capsular antigens expressed by the most prevalent serogroups are used for the rapid identification of
Neisseria meningitidis.
However, these polyvalent sera often nonspecifically cross-reac
Brodeur Bernard R.
Hamel Josee
Martin Denis
Rioux Clement
Biochem Pharma Inc.
Foley & Lardner
Graser Jennifer
LandOfFree
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