Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1997-01-21
2001-11-13
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S203100, C424S282100, C424S184100, C424S093400, C424S093100, C424S009200, C424S828000, C514S825000
Reexamination Certificate
active
06316005
ABSTRACT:
BACKGROUND OF THE INVENTION
Lyme disease was first described by Steere et al. in 1977 who reported an epidemic of arthritis in Lyme, Old Lyme and East Haddam, Connecticut. In 1982, Dr. Willy Burgdorfer discovered a new spirochete in the midgut of
Ixodes dammini
ticks (see Burgdorfer, W. A. et al., (1982) Science 216: 1317-1319). This spirochete was subsequently shown to elicit an immune response in infected rabbits which paralleled that in humans with Lyme disease, and is now known to be the etiological agent of the disease. The spirochete was subsequently named
Borrelia burgdorferi.
While Ixodes ticks are the most commonly encountered vectors of
Borrelia burgdorferi
, the spirochetes have also been found in deerflies, horseflies and mosquitoes. Spirochetes enter an animal host when the animal is bitten by the vector. The
B. burgdorferi
spirochetes reside in various tissues of the host animal, where they may lead to long term infection.
Borrelia burgdorferi
have recently been shown to possess a unique type of extra chromosomal DNA, linear plasmids, which range in length from 0.5 to 50 kb (Bergstrom, S. et al., (1991) Scand. J. Infect. Dis.—Suppl. 77: 102-107). These plasmids contain the genes encoding the two major outer surface proteins (Osp) expressed by
B. burgdorferi
, OspA and Osp B (Bergstrom et al., 1991). These proteins are believed to be major antigens involved in the immunity to
B. burgdorferi
infection. Schwan and Simpson (Schwan, T. G. and Simpson, W. J., (1991) Scand. J. Infect. Dis.—Suppl. 77: 94-101) report heterogeneity of the Osp A and B proteins amongst different
B. burgdorferi
isolates, as well as on the same isolate grown at different temperatures in vivo and studies at different stages during the infection of mice.
The initial stage of Lyme disease is characterized by an expanding skin lesion, erythema chronicum migrans (Asbrink, E. and Hovmark, A.,(1988) Ann. N.Y. Acad. Sci. 539: 4-15; Halperin, J. J., (1991) Scand. J. Infect. Dis.—Suppl. 77: 74-80). Subjects also frequently develop arthritis. However, in only a small percentage of these subjects is the arthritis chronic (Steere, A. C., (1991) Scand. J. Infect. Dis.—Suppl. 77: 51-54).
Borrelia burgdorferi
may also infect the heart muscle. Cardiac involvement in Lyme disease has mainly been reported as transitory. However, animal studies revealed that skeletal and heart muscles are regularly affected and that the spirochetes appeared to be located within the muscle fibers. This observation suggests that the spirochetes are able to maintain long-term survival in hosts and may thus be able to cause chronic heart complications (Stanek, G. et al. (1991) Scand J. Infect. Dis.—Suppl. 77: 85-87).
B. burgdorferi
also infects the nervous system in a high percentage of cases, leading to a wide range of acute, chronic and progressive central and peripheral nervous system disorders (Reik, L. et al. (1991) Ann. N.Y. Acad. Sci. 539: 1-3). Published reports have indicated that European populations afflicted with the disease experience dramatic clinical phenomena of neurological disorder, while North American patients develop milder forms of nervous system involvement. (Halperin, 1991; Halperin, J. J. et al., (1988) Ann. N.Y. Acad. Sci. 539: 24-34). However, Halperin (1991) report that it is becoming increasingly clear that at least as far as nervous system involvement is concerned, the same range of neurological phenomena occur in both populations. Diagnosis of Lyme disease depends upon a combination of the recognition of the clinical characteristics presented and also of the probability of exposure in endemically infected areas. However, the development of arthritis is often attributed to other causes and not correlated with a spirochete infection. The neurological symptoms which may be the result of
B. burgdorferi
infection can mimic a variety of other neurological conditions (Reik et al., 1988). Adding to these diagnostic complications is the difficulty of detecting the spirochetes in affected tissues.
Borrelia infection has been combatted with antibiotics, e.g., tetracycline, penicillin, amoxycilin, doxycilin, erythromycin and phenoxymethylpenicillin (Neu, H., (1988) Ann. N.Y. Acad. Sci., 539: 314-316; Skoldenberg, B. et al. (1988) Ann. N.Y. Acad. Sci. 539: 317-323; Weber, K. et al. (1988) Ann. N.Y. Acad. Sci. 539: 325-345; Luft., B. J. et al. (1988) Ann. N.Y. Acad. Sci, 539: 352-361). Ceftriaxone, and chemically similar compounds, have also been useful as chemotherapeutic agents (Neu, 1988). However, the establishment of protocols for effective chemical treatment of Lyme disease has been hampered by the lack of data with which an appropriate time period for treatment could be established. Additionally, there has been a lack of studies of the effectiveness of drugs in human patients. Further complicating the therapeutic picture is the need to establish and maintain sufficiently high tissue concentrations of antibiotics to combat chronic Borrelia infection (Neu, 1988; Skoldenberg et al., 1988).
Given this difficulty in the detection and treatment of Lyme disease, as well as the impracticability of managing the spread of spirochete vectors, there has been a recognized need for a vaccine capable of immunizing susceptible animals and humans against
Borrelia burgdorferi
infection. Vaccines have been studied in hamster (Johnson, R. C. et al. (1988) Ann. N.Y. Acad. Sci, 539: 258-263) and rat (Barthold, S. W. et al. (1988) Ann. N.Y. Acad. Sci. 539: 264-273) models. A whole cell
Borrelia burgdorferi
bacterin for use in domestic animals has been developed (U.S. Pat. No. 4,721,617). Vaccines based upon the
B. burgdorferi
Osp A and/or B proteins have also been developed. However, these whole cell and subunit vaccines contain, or are derived from, only one
B. burgdorferi
isolate. By contrast, the bacterin of this invention contains, or is derived from, at least two non-crossprotective
B. burgdorferi
isolates. The bacterin of this invention therefore will provide immune protection against two different types of
B. burgdorferi
isolate, while previously described bacterins provide protection against only one type of isolate. Accordingly, the bacterin provided by this invention will be more useful to vaccinate animals against Lyme disease.
SUMMARY OF THE INVENTION
This invention provides a bacterin which comprises per dose an effective immunizing amount of two non-crossprotective isolates of inactivated
Borrelia burgdorferi
, an adjuvant in an amount effective to enhance the immunogenicity of the inactivated
Borrelia burgdorferi
and a suitable carrier. The non-crossprotective isolates of
Borrelia burgdorferi
may be selected from the Wisconsin, Chicago and European seroprotective groups of
Borrelia burgdorferi
isolates. Presently preferred are isolates from the Wisconsin and Chicago groups. However, isolates belonging to other seroprotective groups may also be used. The bacterin may further comprise a third non-crossprotective inactivated
Borrelia burgdorferi
isolate.
This invention also provides a method of immunizing an animal against infection by
Borrelia burgdorferi
which comprises administering to the animal a dose of the bacterin provided. The animal may be a mammal including, but not limited to, humans and dogs. This invention contemplates administering an additional dose of vaccine to the animal at a suitable interval of time after administration of the preceding dose.
This invention further provides a bacterin which comprises per dose an effective immunizing amount of an antigenic subunit derived from a first
Borrelia burgdorferi
isolate, an effective immunizing amount of an antigenic subunit derived from a second, non-crossprotective
Borrelia burgdorferi
isolate, an adjuvant in an amount effective to enhance the immunogenicity of the antigenic subunits and a suitable carrier. The bacterin may further comprise an effective immunizing amount of an antigenic subunit of a third, non-crossprotective
Borrelia burgdorferi
isolate. This invention provides a method of immunizing an anim
Callister Steven M.
Korshus Jon B.
Runnels Paul L.
Schell Ronald F.
Sharpee Richard L.
Darby & Darby
Devi S.
Solvay Animal Health, Inc.
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