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
2000-04-20
2003-12-23
Swartz, Rodney P (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S009200, C424S184100, C424S234100, C424S236100, C424S262100, C530S300000, C530S350000, C536S023100, C536S023700
Reexamination Certificate
active
06667038
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and method related to
Borrelia burgdorferi
toxins, in particular, the present invention provides methods and compositions for the diagnosis, treatment and prevention of Lyme disease.
BACKGROUND OF THE INVENTION
Lyme disease is a potentially severe and complex multisystem disorder associated with the tick-borne spirochete
Borrelia burgdorferi
. The disease is transmitted to humans and other animals through arthropod bites. Indeed, with few exceptions (e.g.,
B. recurrentis
and
B. duttonii
), all Borrelia species are maintained in nature by cycling through the wild animals (e.g., deer, rodents and fowl) and the ticks that feed upon them. Lyme disease was first officially recognized in North America in 1975, and has become recognized as the most prevalent tick-borne disease in the U.S. This recognition was due to an outbreak of disease in children in Lyme, Conn. The disease is now recognized as having a worldwide distribution, with cases recorded in may countries around the world. Lyme disease seems to be more severe than erythema chronicum migrans, a tick-borne syndrome reported in Europe, as early as 1908. The etiologic agent,
B. burgdorferi
remained unidentified until 1981, when it was isolated from
Ixodes scapularis
(
I. dammini
) from New York and later in the European tick vector
I. ricinus
(See, Schwan, et al., “Borrelia” in Murray, et al., [eds].
Manual of Clinical Microbiology
, 6th ed., ASM Press, Washington, D.C., 1995, pp. 625-635). In addition to infection acquired through tick bites, infected tissues of mammalian reservoirs or patients may also transmit disease.
In the northeastern United States, Wisconsin and Minnesota, the deer tick,
Ixodes dammini
is the primary vector, while in the western United States and Europe,
I. pacifious
and
I. ricinus
are the main vectors, respectively. It is also possible that ticks of other genera may transmit the disease (See, Schwan, et al., “Borrelia” in Murray, et al., [eds].
Manual of Clinical Microbiology
, 6th ed., ASM Press, Washington, D.C., 1995, pp. 625-635). The prevalence of infected ticks appears to vary widely among geographic regions, and is directly proportional to the reported number of lyme disease cases in a given location (See, e.g., Persing, et al.,
J. Clin. Microbiol
., 1990, 28, 566-572).
Although there is not universal agreement, it appears that the Lyme disease spirochete,
B. burgdoferi
sensu lato, may be divided into three separate species,
B. burdorferi
sensu stricto,
B. garinii
, and
B. afzelii
. There appears to be no vector specificity among these proposed species, nor it is clear as to whether they cause identical diseases. However, preliminary studies conducted in Europe have indicated that different clinical manifestations may be associated with these three species (See, Schwan, et al., “Borrelia” in Murray, et al., [eds].
Manual of Clinical Microbiology
, 6th ed., ASM Press, Washington, D.C., 1995, pp. 625-635).
The clinical symptoms of Lyme disease vary among individuals and during the time course of infection, and range from a relatively benign skin rash to severe arthritic, neurologic and cardiac manifestations. The most common clinical manifestation is the distinctive skin rash (“erythema migrans,” “erythema chronicam migrans,” or “ECM”) which follows the bite of an infected tick. This rash is often accompanied by headache, stiff neck, myalgias, arthralgias, malaise, fatigue, and/or lymph node swelling. Weeks to months later, some infected patients develop meningoencephalitis, myocarditis, or migrating musculoskeletal pain. Even later in the course of disease, patients may experience intermittent attacks of oligoarticular arthritis or chronic arthritis in large joints, particularly in the knee. While Lyme disease appears to progress to dermatologic and neurologic manifestations more frequently in Europe, arthritis is a more common late manifestation observed in U.S. patients (See, Rose, et al.,
J. Clin. Microbiol
., 1991, 29:524-432). Other clinical syndromes reported in Europe that may have the same etiologic agent include lymphocytoma (lymphadenosis benigna cutis), acrodermalitis chronica atrophicans, tick-borne meningoradiculitis (Garin-Bujadoux-Bannwarth's syndrome), and myositis. Due to increased awareness and reporting, reported cases of Lyme disease have increased over time. Between 1982 and 1992, approximately 50,000 cases of Lyme disease were reported to the Centers for Disease Control (CDC), with 48 states reporting cases by 1992.
Treatment of Lyme disease typically consisting of oral antimicrobial therapy at the initial stages and high dosage intravenous antimicrobial therapy for the later manifestations. While treatment is often successful, symptoms sometimes persist or reappear after treatment, particularly during the later stages of disease (See, e.g., Rose and Schwan,
J. Infect. Dis
., 1989, 160:1018-1029). Chronic Lyme disease is difficult to treat with current antimicrobial regimes (Donta, et al.,
Clin. Infect. Dis
., 1997, 25:552-555).
With the dramatic increase in public awareness of the disease, its prevalence and geographical distribution of Lyme borreliosis, a tremendous new demand has been placed on laboratories to confirm cases using methods such as serology (See, Simpson, et al.,
J. Clin. Microbiol
., 1990, 28:1329-1337). However, diagnosis of Lyme disease is often not straightforward. For example, there are well-documented Lyme disease cases for which knowledge of tick bite, skin rash, or positive serology are lacking. Most of the systemic manifestations of advanced Lyme disease are not unique to the disease and observation of spirochetes in patients is difficult (See, Rosa and Schwan,
J. Infect. Dis
., 1989, 160:1018-1029; Rosa, et al.,
J. Clin. Microbiol
., 1991, 29:524-532). In addition, strong, specific immunologic responses are not always observed.
Furthermore, many problems have been reported with currently available serological tests, including both false positives and false negatives. Some tests have focused on the flagellar protein of
B. burgdorferi
as a means to increase the sensitivity of the serological tests because early studies indicate that the 41 kD flagellar subunit (flagellin) generated the earliest immune response in infected humans (See, e.g., Simpson, et al.,
J. Clin. Microbiol
., 1990, 28:1329-1337 for a brief review). However, potential factors have been considered problematic with the use of flagellar protein, including the cross-reactivity of antibodies to flagella of other Borrelia species, as well as other organisms such as
Treponema pallidum
. This has led others to investigate the use of a 39 kDa non-flagellar
B. burgdoferi
antigen that is immunoreactive with many sera from human Lyme disease patients (See, Simpson, et al.,
J. Clin. Microbiol
., supra).
Additional factors complicate the serologic diagnosis of Lyme disease. For example, serology is often less useful during the early stages of disease (i.e., during primary Lyme disease), as many patients with ECM have not formed sufficient antibody levels to be detectable in many assays (See, e.g., Coleman and Benach,
J. Infect. Dis
., 1987, 155:756-765). Antigen detection in urine, blood, and other tissues by a dot blot immunoassay and an antigen capacity assay using colloidal gold-immune electron microscopy have also been tried. However, these antigen detection methods are apparently no longer available (See, Schwan, et al., “Borrelia,” in Murray, et al., [eds],
Manual of Clinical Microbiology
, 6th ed., ASM Press, Washington, D.C., 1995, pp.626-635).
In sum, much remains to be learned regarding Lyme disease and the pathogenic mechanisms associated with the disease. In addition, much remains to be learned regarding the organisms themselves. One complicated factor is the difficulty of culturing the organisms in the laboratory. Indeed, the maintenance of infectious spirochetes, requires the use of laboratory animals (e.g., rats, mice, or live
Cartwright Mark J.
Donta Sam T.
Boston Medical Center Corp.
Swartz Rodney P
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