Compositions and methods comprising DNA sequences encoding...

Details Compositions and methods comprising DNA sequences encoding... Compositions and methods comprising DNA sequences encoding...

1995-05-31

2002-02-05

Bui, Phuong T (Department: 1638)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023400, C435S252300, C435S320100, C435S069100, C435S069300, C435S071100, C435S071200, C424S203100, C424S200100, C424S190100, C424S192100, C424S184100, C424S185100

Reexamination Certificate

active

06344552

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to compositions and methods useful for the prevention, treatment and diagnosis of Lyme disease in humans and other animals. More particularly, this invention relates to OspA and OspB polypeptides which are able to elicit in a treated patient, the formation of an immune response which is effective to treat or protect against Lyme disease. This invention also relates to a screening method for selecting the OspA and OspB polypeptides of this invention which are able to elicit such an immune response. Also within the scope of this invention are antibodies directed against the OspA and OspB polypeptides and diagnostic kits comprising the antibodies or the polypeptides.
BACKGROUND OF THE INVENTION
Lyme borreliosis is the most common vector-borne infection in the United States [S. W. Barthold, et al., “An Animal Model For Lyme Arthritis”,
Ann. N.Y. Acad. Sci
., 539, pp. 264-73 (1988)]. It has been reported in every continent except Antarctica. The clinical hallmark of Lyme Disease is an early expanding skin lesion known as erythema migrans, which may be followed weeks to months later by neurologic, cardiac, and joint abnormalities.
The causative agent of Lyme disease is a recently recognized spirochete known as
Borrelia burgdorferi
, transmitted primarily by ixodes ticks that are part of the
Ixodes ricinus
complex.
B. burgdorferi
has also been shown to be carried in other species of ticks and in mosquitoes and deer flies, but it appears that only ticks of the
I. ricinus
complex are able to transmit the disease to humans.
Lyme disease generally occurs in three stages. Stage one involves localized skin lesions (erythema migrans) from which the spirochete is cultured more readily than at any other time during infection [B. W. Berger et al., “Isolation And Characterization Of The Lyme Disease Spirochete From The Skin Of Patients With Erythema Chronicum Migrans”,
J. Am. Acad. Dermatol
., 3, pp. 444-49,(1985)]. Flu-like or meningitis-like symptoms are common at this time. Stage two occurs within days or weeks, and involves spread of the spirochete through the patient's blood or lymph to many different sites in the body including the brain and joints. Varied symptoms of this disseminated infection occur in the skin, nervous system, and musculoskeletal system, although they are typically intermittent. Stage three, or late infection, is defined as persistent infection, and can be severely disabling. Chronic arthritis, and syndromes of the central and peripheral nervous system appear during this stage, as a result of the ongoing infection and perhaps a resulting auto-immune disease [R. Martin et al., “
Borrelia burgdorferi
—Specific And Autoreactive T-Cell Lines From Cerebrospinal Fluid In Lyme Radiculomyelitis”,
Ann Neurol
., 24, pp. 509-16 (1988)].
B. burgdorferi
is much easier to culture from the tick than from humans, therefore at present, Lyme disease is diagnosed primarily by serology. The enzyme-linked immunosorbent assay (ELISA) is one method of detection, using sonicated whole spirochetes as the antigen [J. E. Craft et al., “The Antibody Response In Lyme Disease: Evaluation Of Diagnostic Tests”,
J. Infect. Dis
., 149, pp. 789-95 (1984)]. However, serologic testing is not yet standardized, and results may vary between laboratories and commercial kits, causing false negative and, more commonly, false positive results. In addition, the disease often goes unrecognized, as the ticks are small and easy to miss, and the characteristic rash only occurs in 60-80% of cases and may be misinterpreted when it does occur.
At present, all stages of Lyme disease are treated with antibiotics. Treatment of early disease is usually effective, however the cardiac, arthritic, and nervous system disorders associated with the later stages often do not respond to therapy [A. C. Steere, “Lyme Disease”,
New Eng. J. Med
., 321, pp. 586-96 (1989).
Two lines of evidence suggest that the host immune response to specific antigens of
B. burgdorferi
may be partially responsible for the pathogenicity of Lyme disease. First, patients treated with corticosteroids (which suppress the immune system) show improvement of their symptoms [A. C. Steere et al., “Lyme Carditis: Cardiac Abnormalities Of Lyme Disease”,
Ann. Intern. Med
., 93, pp. 8-16 (1980)]. Second, some patients that do not respond to antibiotics appear to manifest an autoimmune disorder initiated by infection with
B. burgdorferi.
Like
Trepnema pallidum
, which causes syphilis, and leptospirae, which cause an infectious jaundice, Borrelia belong to the eubacterial phylum of spirochetes [A. G. Barbour and S. F. Hayes, “Biology Of Borrelia Species”,
Microbiol. Rev
., 50, pp. 381-400 (1986)].
Borrelia burgdorferi
have a protoplasmic cylinder that is surrounded by a cell membrane, then by flagella, and then by an outer membrane. Embedded in the outer membrane are two major proteins, a 31 kd outer-surface protein A (OspA) [A. G. Barbour et al., “Lyme Disease Spirochetes And Ixodid Tick Spirochetes Share A Common Surface Antigenic Determinant Defined By A Monoclonal Antibody”,
Infect. Immun
., 41, pp. 795-804 (1983); J. L. Benach et al., “A Murine IgM Monoclonal Antibody Binds An Antigenic Determinant In Outer Surface Protein A, An Immunodominant Basic Protein Of The Lyme Disease Spirochete”,
J. Immunol
., 140, pp. 265-72 (1988)] and a 34 kd outer surface protein B (OspB) [A. G. Barbour et al., “Variation In A Major Surface Protein Of Lyme Disease Spirochetes”,
Infect. Immun
., 45, pp. 94-100 (1984)]. The two proteins have been shown to vary from different isolates or from different passages of the same isolate as determined by their molecular weights and reactivity with monoclonal antibodies. In addition, OspB may not be produced at all in culture [T. G. Schwan et al., “Changes In Infectivity And Plasmid Profile Of The Lyme Disease Spirochete,
Borrelia Burgdorferi
, As A Result Of In Vitro Cultivation”,
Infect. Immun
., 56, pp. 1831-36 (1988)].
Early in human infection, antibodies are generated primarily against a 41 kd flagella-associated antigen. Later on, high titer antibodies to both OspA and OspB appear [J. E. Craft et al., “Antigens Of
Borrelia Burgdorferi
Recognized During Lyme Disease: Appearance Of A New Immunoglobulin M Response And Expansion Of The Immunoglobulin G Response Late In The Illness”,
J. clin. Invest
., 78, pp. 934-39 (1986)]. However, this humoral immune response is generally not sufficient to clear the system of the infective agent in experimentally infected laboratory rats. [K. D. Moody et al., “Experimental Chronic Lyme Borreliosis In Lewis Rats”,
Am. J. Troy. Med. Hyg
. in press (1990)]. In addition, humans have been shown to be persistently infected for months or years. It has thus been suggested that the spirochete may be able to sequester itself in certain intracellular sites where it remains unavailable to circulating antibody molecules.
Development of a laboratory model for Lyme disease has proved elusive. Several groups have found spirochetemia in rabbits, Peromyscus mice, and Syrian hamsters after inoculation with
B. burgdorferi
, but no other manifestations of Lyme disease have been found. [W. Burgdorfer, “The New Zealand White Rabbit: An Experimental Host For Infecting Ticks With Lyme Disease Spirochetes”,
Yale J. Biol. Med
., 57, pp. 609-12 (1984); A. N. Kornblatt et al., “Experimental Lyme Disease In Rabbits: Spirochetes Found In Erythema Migrans And Blood”,
Infect. Immun
., 46, pp. 220-23 (1984); A. N. Kornblatt et al., “Infection In Rabbits With The Lyme Disease Spirochete”,
Yale J. Biol. Med
., 57, pp. 613-14 (1984); J. L. Benach et al., “Experimental Transmission Of The Lyme Disease Spirochete To Rabbits”,
J. Infect. Dis
., 150, pp. 786-87 (1984); J. G. Donahue et al., “Reservoir Competence Of White-Footed Mice For Lyme Disease Spirochetes”,
Am. J. Troy. Med. Hyg
., 36, pp. 92-96 (1987); E. C. Burgess et al.,

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