Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1995-05-23
2002-07-16
Bansal, Geetha P. (Department: 1642)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S254110, C435S320100, C435S471000, C536S023100, C536S023700, C536S023400
Reexamination Certificate
active
06420134
ABSTRACT:
BACKGROUND
Haemophilus influenzae
are divided into two groups of strains, typable and nontypable. Strains which possess a known capsule are typed by the serological reaction of the capsule with reference antisera. Types a-f have been identified. Strains which fail to react with any of the reference antisera are nontypable.
H. influenzae
type b (Hib) is the most frequent cause of neonatal meningitis and other invasive infections in the United States (Fraser et al., 1974
, Am. J. Epidemiol
. 100:29-34). The major incidence of childhood meningitis occurs between the ages of one and five years. Sixty percent of the meningitis cases due to Hib occur in children under the age of two years (Fraser et al., supra).
It is now well established that nontypable
H. influenzae
also cause diseases including pneumonia, bacteremia, meningitis, postpartum sepsis, and acute febrile tracheobronchitis in adults (Murphy et al., 1985
, J. Infect. Diseases
152:1300-1307). In addition, nontypable
H. influenzae
are a frequent etiologic agent of otitis media in children and young adults. Indeed, about 20 to 40% of all cases of otitis media can be attributed to
H. influenzae
. Children may experience multiple infections of the same organism since infection confers no long lasting immunity. Currently, chronic or repeat otitis media is treated by administration of antibiotics and, if necessary, by drainage of the inner ear.
H. influenzae
strains have also been implicated as a primary cause of sinusitis (Cherry J. D. and J. P. Dudley, 1981, in Textbook of Pediatric Infectious Diseases, Feigin and Cherry eds., pp 103-105). Additionally, nontypable
H. influenzae
cause neonatal sepsis.
Antiserum produced against the capsular polysaccharide of Hib, polyribosyl ribitol phosphate (PRP), has been shown to be bactericidal and protective against Hib (Smith et al., 1973
, Pediatrics
52:637-644; Anderson, et al., 1972
, J. Clin. Inv
. 51:31-88). Anti-PRP antibody, however, is ineffective against nontypable
H. influenzae
infection.
Currently available vaccines against
H. influenzae
are all directed against Hib. All are effective by eliciting anti-PRP antibody. Anti-PRP antibody, however, is ineffective against nontypable
H. influenzae
, which by definition lack the PRP capsule. There is a long recognized need for a vaccine that will protect against nontypable
H. influenzae.
SUMMARY OF THE INVENTION
This invention pertains to the outer membrane protein “e” of
H. influenzae
and to peptides and proteins which have an epitope in common with protein “e”. Protein “e” is a lipoprotein which has a molecular weight of about 28,000 daltons and an amino acid sequence as set forth in FIG.
7
. The invention also pertains to the use of protein “e” and peptides and proteins having protein “e” epitopes for vaccination against nontypable and typable
H. influenzae
. The peptides and proteins can be used in univalent vaccines or in multivalent vaccines in conjunction with other antigens of typable or nontypable
H. influenzae
(e.g., as mixtures, fusion or conjugates therewith) or with antigens of other infectious bacteria, viruses or parasites. The peptides and proteins elicit biologically active (bactericidal and/or opsonic) antibody against
H. influenzae
. Importantly, protein “e” acts in synergy with other outer membrane proteins of
H. influenzae
in eliciting cross-reactive, bactericidal antibody responses, especially against nontypable strains of
H. influenzae
, and thus, the peptides or proteins of this invention are particularly effective when administered together with these proteins. In addition, antibody specific for epitopes of protein “e” can be used (either alone or in conjunction with antibody against epitopes of other outer membrane proteins) for passive immunization against
H. influenzae
and in diagnostic assays for the organism.
The invention also pertains to methods of producing native, purified protein “e”, and to various vaccine formulations containing them. Protein “e” can be obtained by purification from
H. influenzae
. This invention also provides a method of isolating and purifying protein “e” in native lipoprotein form from
H. influenzae
by differential detergent extraction to provide an essentially endotoxin-free preparation without the use of agents considered harmful to humans. Protein “e” can also be produced by recombinant DNA techniques in lipidated or nonlipidated form or by protein synthesis. Epitopic oligopeptides and other fragments of protein “e” and analogues of these can be produced by recombinant DNA techniques, chemical synthesis or chemical or enzymatic cleavage. These peptides or proteins, in turn, can be fused or conjugated to other antigens of
H. influenzae
or to antigens of other microorganisms (bacteria, viruses, fungi or parasites) by chemical or genetic coupling techniques to produce multivalent antigenic conjugates and fusion peptides or proteins. The peptides or proteins can be modified for conjugation such as by addition of amino acids or other coupling groups. For vaccination, the peptides or proteins, in any of the forms described, can be formulated in pharmaceutically acceptable vehicles with optional additives such as adjuvants.
The invention also pertains to isolated nucleic acid sequences which encode the native protein “e” or any of the various peptidic or proteinaceous derivatives of the protein “e”. The sequences can be incorporated into appropriate expression systems for production of protein “e” or any of the derived peptides and proteins of this invention. In addition, the gene fragments or oligonucleotides can be used as probes in nucleic acid hybridization assays.
REFERENCES:
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patent: 4220722 (1980-09-01), Rowley et al.
patent: 4356170 (1982-10-01), Jennings et al.
patent: 4661347 (1987-04-01), Muller-Eberhard et al.
patent: 4762713 (1988-08-01), Anderson
patent: 4830852 (1989-05-01), Marburg et al.
patent: 4873090 (1989-10-01), Clancy
Ausubel et al., ed., Current Protocols in Molecular Biology, vol. 1, Unit 6.8 (John Wiley & Sons, 1987).
Deich et al., J. Bacteriol., 170, 489-498 (1988).
Granoff et al., J. Pediatrics, 105, 22-27 (1984).
Gulig et al., Infection & Immunity, 49, 819-827 (1985).
Lam et al., Current Microbiol., 3, 359-364 (1980).
Lewin et al., Proc. Natl. Acad. Sci. USA, 77, 3998-4002 (1980).
Loeb, Infection & Immunity, 55, 2612-2618 (1987).
Moxon et al., J. Inf. Dis., 136, S186-S190 (1977).
Praxis Biologics, Inc., Annual Report for 1988.
Rothstein et al., Pediatric Research, 23, 380A (1988).
Saukkonen, Experimental Meningococcal Meningitis, 203-211 (1988).
Schneerson et al., J. Exp. Med., 152, 361-376 (1980).
Smith et al., Infection & Immunity, 8, 278-290 (1973).
Granoff et al. Journal of Infectious Diseases vol. 153 No. 3 1986.
Green Bruce A.
Zlotnick Gary W.
Bansal Geetha P.
Gordon Alan M.
Praxis Biologics, Inc.
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