Heat shock genes and proteins from Neisseria meningitidis,...

Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...

Reexamination Certificate

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C435S006120, C435S007100, C435S091100, C435S091200, C530S350000, C536S022100, C536S023100, C536S024300, C536S023400, C536S024310, C536S024320

Reexamination Certificate

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06497880

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to heat shock proteins of the Hsp60 family from
Candida glabrata
and
Aspergillus fumigatus
and a heat shock protein of the Hsp70 family from
Neisseria meningitidis,
including fragments thereof, and uses of such proteins and nucleic acid molecules encoding these proteins.
BACKGROUND OF THE INVENTION
Meningitis is an infection of the fluid of the spinal cord and the fluid that surrounds the brain. The disease is caused either by a viral or a bacterial infection. Viral meningitis is typically less severe than bacterial meningitis and resolves without specific treatment. In contrast, bacterial meningitis can be rather severe and can cause brain damage, hearing loss or learning disability. Symptoms of meningitis are high fever, headache and stiff neck. These symptoms may develop over a span of several hours, or may take 1-2 days. Other symptoms may be nausea, vomiting, discomfort looking into bright light, confusion or sleepiness. In young children, the classical symptoms may be absent or may not be easily detected, and the child may appear to be slow, inactive, irritable, vomiting or feeding poorly. As the disease progresses, seizures may occur.
Bacterial meningitis may be caused by
Haemophilus influenzae, Streptococcus pneumoniae
or
Neisseria meningitidis.
Because all children (in the U.S.) are now given a vaccine against
Haemophilus influenzae
in the course of their routine immunizations, meningitis due to this organism is now relatively uncommon. Thus, the major bacterial disease-causing agents are now
Streptococcus pneumoniae
and
Neisseria meningitidis.
Early diagnosis and treatment are critically important. It must be determined whether symptoms are due to a viral or bacterial agents, and, if they are caused by a bacterial agent, which bacterium is involved. Present methods of diagnosis are relatively slow. They involve obtaining spinal fluid by performing a spinal tap. Bacteria are identified by cultivation of spinal fluid.
Bacterially-caused meningitis can be treated by antibiotics. However, it is critically important that treatment commence early in the course of the disease. Obviously, antibiotic therapy may be jeopardized by the development of antibiotic-resistant strains of disease-causing bacteria. Because of this concern, and also because of cost-benefit considerations, vaccination against the bacteria causing the disease would be preferable, at least in regions, in which the disease is endemic. As discussed before, U.S. children are routinely vaccinated against
Haemophilus influenzae,
but not against
Neisseria meningitidis
and
Streptococcus pneumoniae.
One such vaccine protects against four strains of
Neisseria meningitidis.
However, the vaccine appears not to be effective in children under 18 months of age. Similarly, a vaccine containing polysaccharide antigens for 14 of the 83 capsular types of
Streptococcus pneumoniae
was developed. The vaccine was found to be 57% effective in two large studies. As with the
Neisseria
vaccine, children under the age of two years do not appear to be protected by the vaccine. Thus, there is a need for improved vaccine against the latter two species of bacteria. The information provided here was obtained from publications by the Division of Bacterial and Mycotic Diseases of the National Center for Infectious Diseases, and the Centers for Disease Control and prevention, by Lonks and Medeiros, Antimicrobial Therapy 1 79:523-535, 1995, by Butler et al., JAMA 270:1826, 1993, and by Gotschlich et al., Antibodies in Human Diagnosis and Therapy 391-402 (Haber and Krause eds., 1977).
Aspergillosis is an opportunistic infection occurring in compromised individuals and is caused by molds of the genus Aspergillus, of which
Aspergillus fumigatus
is an important species. Aspergillus is ubiquitous and is distributed worldwide. Infection generally involves inhalation of fungal elements. Aspergillosis has several clinical manifestations, including colonization of the ear or the lungs, allergic pulmonary involvement, and invasive pulmonary and disseminated infections. The pulmonary invasive and disseminated forms of infections have a grave prognosis, including a high rate of mortality. Susceptible hosts include cancer patients, patients treated with immunosuppressive or cytotoxic drugs, and those otherwise debilitated such as AIDS patients, neutropenic cancer patients, or patients receiving adrenal corticosteroid drugs. Segal, Vaccines against Fungal Infections, CRC Crit. Rev. Microbiology 14:229, 1987. Rolston and Bodey, Infections in patients with cancer, Cancer Medicine (Holland et al. eds), 1997. The true incidence of aspergillosis is not known in the HIV/AIDS population, in part because the condition is frequently not diagnosed. However, it is clear that the incidence is increasing. Ampel has reported that more than 75 cases have been documented in the literature. Ampel, Emerging disease issues and fungal pathogens associated with HIV infection, Emerging Infectious Diseases 2:109-116, 1996. Aspergillosis has been reported to occur in 20-50% of patients with acute leukemia. It is noted that many cases of Aspergillus infection in cancer patients are not diagnosed until an autopsy is performed after death. Clearly, aspergillosis is becoming increasingly common among neutropenic patients and in cancer patients receiving corticosteroid drugs. Rolston and Bodey, supra. An article in 1992 by Bodey et al. reports on the incidence of fungal infections based on an international autopsy survey. Bodey et al., Fungal Infections In Cancer Patients, An International Autopsy Survey, Eur. J. Clin. Microbiol. Infect. Dis. 11:99-109, 1992. Countries included are Austria, Belgium, Canada, Germany, Italy, Japan, Netherlands and the UK. It was concluded that 25% of leukemia patients had fungal infections. Of these infected patients, 66% had candidiasis, and 34% aspergillosis. Estimates of rates of fungal infections in organ transplant patients as high as about 40% were published. Paya, Clin. Infect. Dis. 16:677-688, 1993. More than 80% of these infections were due to Candida and Aspergillus. As alluded to before, diagnosis of aspergillosis is not infrequently missed, and there is therefore a need for improved methods of diagnosis.
Candidiasis is a fungal infection caused by yeasts of the genus Candida. Among the more than 80 known species, only seven species appear to be pathogenic. The major disease-causing species is
Candida albicans.
Among the pathogenic species s also found
Candida glabrata,
formerly known as
Torulopsis glabrata.
Clinical manifestations of Candida infection range from superficial cutaneous infections to disseminated disease. Infections range from acute to chronic. They can involve skin and nails, the mucosal membranes of the mouth and vagina, and various internal organs such as the lungs, gastrointestinal tract, and circulatory and central nervous systems. Manifestations can be oral thrush, vaginitis, balanitis, diaper rash, chronic mucocutaneous conditions, bronchitis or pneumonia, meningitis, endocarditis, and septicemia. While the superficial forms of candidiasis have been well known since antiquity, the incidence of the disseminated forms has increased recently, presumably because of the extensive use of antibiotics, corticosteroids, cytotoxic drugs, organ transplantation and other complex surgical procedures. It is important to note that today the majority of systemic or invasive fungal infections are due to Candida species. Segal, supra. Stringer, Mass. High Tech. 14:3, 1997.
Mortality from systemic candidiasis remains high, in the order of 38-59%. The mainstay for treatment is amphotericin B, and an alternative is fluconazole. In a multicenter trial, amphotericin B was 79% effective, and fluconazole 70%. Note that
Candida glabrata
is resistant to fluconazole. Because mortality remains high, an effective vaccine against candidiasis to be used in high-risk populations would be desirable.
Since
Candida albicans
is the major cause of candidiasis, e

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