Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1996-06-27
2002-11-26
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S234100, C424S202100
Reexamination Certificate
active
06486130
ABSTRACT:
The present invention relates to the prevention and treatment of Lyme disease in mammals and in particular to immunogenic formulations comprising different serological forms of OspC to retard or prevent the development of Lyme disease. The invention also comprises recombinant methods for the preparation of novel antigens.
BACKGROUND OF THE INVENTION
Lyme disease or Lyme borreliosis are terms used to describe the diverse clinical symptoms associated with tick-borne spirochetal infections caused by Lyme Disease Borrelia. Common manifestations of Lyme disease include disorders affecting the skin [erythema migrans (EM) or acrodermatitis chronica atrophicans (ACA)], nervous system (neuro-borreliosis), and joints (arthritis) but other organs and tissues may become infected and diseased. Lyme disease has a world-wide distribution and is the most prevalent tick-borne disease in both the United States and Europe. The range of clinical symptoms commonly associated with Lyme disease in Europe is broader than that in the United States, with skin and nervous system disorders being common in Europe but rare in the United States, whereas arthritis is more common in the United States than in Europe. The clinical symptoms in North America appear to be a subset of those observed in Europe.
Lyme disease is typically treated with antibiotics. Treatment may be delayed, however, due to the often complex clinical picture and the lack of widely available, reliable diagnostic tests. If the disease is allowed to proceed to a chronic condition, treatment with antibiotics is more difficult and is not always successful. Furthermore the prospect that permanent damage is induced is likely to be increased during the course of a prolonged infection. Accordingly, a vaccine to prevent Lyme disease is desirable.
Two antigens from Lyme disease Borrelia have been described that can protect against infection/disease by this organism as determined in animal models of Lyme disease. These antigens, OspA and OspC (or “pC”), therefore are likely candidates for inclusion in any vaccine designed to protect against Lyme disease. See Simon et al., European patent No. 418,827; Fikrig et al., Science 250: 553-56 (1990); Preac-Mursic et al., Infection 20: 342-49 (1992). OspA and OspC share many characteristics. Both are lipoproteins that are exposed at the cell-surface, (Howe et al., Science 227: 645-46 (1985); Bergstrom et al. Mol. Microbiol. 3: 479-486 (1989)), both are plasmid-encoded (Barbour et al., Science 237: 409-11 (1987); Marconi et al., J. Bacteriol. 175: 926-32 (1993)), the genes for these proteins are present in most strains (Barbour et al., J. Infect. Dis. 152: 478-84 (1985); Marconi et al., J. Bacteriol. 175: 926-32 (1993)), and both exist in multiple serologically distinct forms (Wilske et al., (1989)).
The existence of multiple, serologically distinct forms of these antigens is an obstacle to the development of an OspA and/or OspC vaccine to protect against most, if not all, forms of Lyme disease. For instance, it has been demonstrated by Fikrig et al., J. Immun. 148: 2256-60 (1992), that immunization with one serological form of OspA, such as recombinant OspA of strain N40, need not protect against a challenge with a strain expressing a different OspA, for example, strain 25015. Consequently, it is necessary to develop typing schemes to classify and group the different variants of the antigen i.e., OspA and/or OspC) such that the optimal mixture of serologically distinct forms of the antigen(s) that are needed to give broad protection can be determined.
A serotyping system for OspA has been developed using a limited number of monoclonal antibodies as the typing tools and 7 serotypes of OspA have been described using this methodology. Wilske et al., Ann. N.Y. Acad. sci. 539: 126-43 (1988). Restriction fragment length polymorphism (RFLP) analysis of OspA genes from 55 different European and North American strains identified six distinct genogroups. Wallich et al., Infection and Immunity 60: 4856-66 (1992). OspA proteins from North American isolates seem to be reasonably uniform since twelve of fourteen OspA's belonged to OspA type I and two to OspA type III. By contrast, the OspA's from European isolates are much more heterogeneous and include representatives of OspA types I (18), II (17), IV (4) and V (1). Construction of a phylogenetic tree based on sequence data for twelve OspA proteins from individual strains of
B. burgdorferi
supports the findings of the RFLP analysis but sequence information from isolates from two of the six genogroups is still lacking. At present no typing system exists for OspC.
Another consideration when selecting the appropriate antigens for inclusion in a vaccine is whether they are derived from strains that are epidemiologically important for the disease. In the mid-1970's it was postulated that pathogenic bacteria arise from a limited number of clones of highly related bacteria that in some way have a selective advantage in causing disease. This clonal hypothesis has since been confirmed. See Achtman et al., J. Infect. Dis. 165: 53-68 (1992). Thus, it is highly likely that among the numerous strains of Lyme disease Borrelia found in nature, only a limited number of “clones” exist that are highly adapted to causing mammalian, and in particular human, disease. In developing a vaccine to protect against disease in mammals and hence also in humans, it is of paramount importance to identify disease associated clones so that efforts can be concentrated against them. Thus it is necessary to elucidate the population structure of the species Lyme disease Borrelia and identify disease associated clones.
To date, a number of methods have been used to resolve the population structure of Lyme disease Borrelia, including (A) RFLP analysis of genomic DNA or of specific genes (LeFebvre et al., J. Clin. Micriobiol. 27: 636-39 (1989); Marconi & Garon, J. Bacteriol 174: 241-44 (1992); Postic et al., Res. Micriobiol. 141: 465-75 (1990); Stahlhammar-Carlemalm et al., Zbl. Bak 274: 28-39 (1990); Adam et al., Infect. Immun. 549: 2579-85 (1991); Wallich et al., Infect. Immun. 60: 4856-66 (1992)), (B) DNA-DNA hybridization (LeFebvre et al., J. Clin. Micriobiol. 27: 636-39 (1989); Postic et al., Res. Micriobiol. 141: 465-75 (1990)), (C) analysis of 16S rRNA by hybridization to oligonucleotide probes (Marconi et al., J. Clin. Micriobiol 30: 628-32 (1992) or by sequencing (Adam et al., Infect. Immun. 59: 2579-85 (1991); Marconi & Garon, J. Bacteriol. 174: 241-44 (1992)), (D) fingerprinting by an arbitrarily primed polymerase chain reaction (Welsh et al., Int. J. System. Bacteriol. 42: 370-77 (1992)), (E) multi-locus enzyme electrophoresis (Boerlin et al., Infect. Immun. 60: 1677-83 (1992)) and (F) serotyping of isolates (Peter & Bretz, Zbl. Baktk. 277: 28-33 (1992)).
There is broad agreement between the results obtained by these different procedures. In general, it appears that Lyme disease Borrelia isolates can be divided into at least three major groups. Indeed, some investigators believe that the genetic distances between members of these groups is sufficient to merit differentiating them into three separate species:
B.burgdorferi
sensu stricto (type strain B31),
B.garinii
sp. nov. (type strain 20047) and a species designated
B.afzelii
or the “group VS461 Borrelia.” See Baranton et al., Int. J. Syst. Bacteriol. 42: 378-383, 1992; Marconi & Garon, supra.
The significance of the existence of these different groups for vaccine development remains to be fully elucidated. It is clear from the data of Wallich et al., Infection & Immunity 60: 4856-66 (1992), that there is a strong association between the genogroup to which an isolate belongs and the type of OspA that is produced: isolates from the group containing strain B31 (genogroup AAA or
B.burgdorferi
sensu stricto) produce a type I OspA (all of thirty strains analyzed), isolates from the group containing strain 20047 (genogroup BBB or
B.garinii
sp. nov.) usually produce a type II (17/19) OspA but types V (1/19) and VI (
Crowe Brian
Dorner Friedrich
Livey Ian
Baxter Vaccine AG
Heller Ehrman White & McAuliffe
Portner Ginny Allen
Smith Lynette R. F.
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