Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-09-29
2003-10-14
Smith, Lynette R. F. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S009200, C424S130100, C424S164100, C424S178100, C424S184100, C424S197110, C424S234100, C424S278100, C424S282100, C435S243000, C435S252100, C435S253600, C435S002000
Reexamination Certificate
active
06632439
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a vaccine, and an in-vitro method for developing such a vaccine, for establishing resistance to
Fusobacterium necrophorum
bacteria that is responsible for footrot and liver abscesses in the bovine species.
DESCRIPTION OF THE PRIOR ART
The infectious disease “footrot” is caused by colonization of
F. necrophorum
bacteria and typically occurs when the colonization locates in the area of a trauma site to the foot followed by exposure to a wet and slushy environment. The disease most commonly occurs in cattle and sheep, with the disease, usually acute, being characterized by painful inflammation of the interdigital skin of the infected subject. Outward characterizations of the footrot disease include lameness in one or more legs, loss of appetite, loss of weight, and occasional mortality.
In cattle, the
F. necrophorum
bacteria that causes footrot may also cause liver abscesses. The etiological pathway for such an
F. necrophorum
infection leading to liver abscesses is different than that associated with footrot. When
F. necrophorum
induced liver abscess occurs in ruminants, especially cattle, it typically is the result of a pathway provided to the bloodstream by an ulcerated rumen (stomach), through which pathway the
F. necrophorum
bacteria, otherwise indigenous as a microflora present in the gastro-intestinal tract, passes. Once in the bloodstream, the bacteria continue through the portal vein and invade the liver causing abscesses.
Because of the severe economic losses caused to the cattle industry by footrot and liver abscess diseases, there is a need for an easily administered vaccine for cattle that readily inhibits propagation of
F. necrophorum
bacteria. Such a vaccine is most desirable if it establishes optimal resistance in inoculated members to reduce the number of instances of footrot and liver abscesses in cattle.
Conventional vaccines use various killed strains of
F. necrophorum
bacteria including, for example, the biotype A strains [
F. necrophorum
subspecies
necrophorum
(FNN)], to prevent footrot, liver abscesses, and other infectious diseases resulting from colonization by the bacteria. While conventional vaccines experience some degree of success in preventing colonization and infection with the
F. necrophorum
bacteria, suitable prevention and inhibition of colonization and infection by the bacteria in cattle is still lacking for various reasons. First, some conventional vaccines are derived from a bacteria colony supernatant created from the physical separation of a bacteria colony grown in-vitro from its growth media. It is important and desirable, therefore, that after the separation is complete, the supernatant from which the vaccine is generated, contain certain key proteins. The physical separation process, however, typically separates antigenic proteins found in the growth media from the supernatant used to generate the vaccine. If for any reason, key bacterial proteins are removed from the supernatant during separation—which can occur if such key proteins are in the form of solids which do not remain suspended in liquid, then a vaccine created from the supernatant will necessarily lead to a non-optimum antigenic response in the vaccinated animal. Conventional vaccine production methodologies typically produce vaccines which do not illicit a maximum antigenic response in an inoculated host because of this undesirable method.
The reduction of a vaccine's antigenic response from optimal to insufficient can be brought about by the internal physical stresses imposed on the bacterial cell structure by centrifuge techniques used to separate the bacteria initially suspended in its liquid growth media. Centrifuge-induced stress imposed on the bacteria cells can result in undesirable detachment or division of cell components from the remaining bacteria cell structure. Thus, if the cell wall, for example, ruptures—permitting the cell contents to flow out of the cell wall, then the solid but damaged cell wall will, as part of the separation process, settle as a solid from the supernatant created by the centrifugation process and used to form the vaccine. Any antigenic properties associated with the cell wall will, thus, be lost, producing a less than optimal immune response to the vaccine.
A less than optimum immune response to conventional vaccines also occurs in cattle vaccine production methodologies using bacteria strains isolated from host members other than cattle. For example, a vaccine derived from bacteria isolated from sheep may cause less than a full immune response in cattle because the phenotypic characteristics of the particular bacterial strain derived from sheep may be slightly different than that associated with strains obtained from cattle.
It has also been discovered that the efficacy of a vaccine can be negatively influenced by harvesting the in-vitro bacterial culture during an inappropriate time frame within the bacterial culture growth phase. As a bacterial culture grows and matures, certain desirable proteins, important for vaccine production, are produced in greater quantities during certain phases of culture growth.
Turning now to certain specific prior art patents relating to the present invention, U.S. Pat. Nos. 5,455,034 ('034) and 5,492,694 ('694) to Nagaraja et al. disclose a
Fusobacterium necrophorum
leukotoxoid vaccine derived bacteria grown for a maximum of 10 hours, preferably 6-9 hours, while maintaining the culture pH in a range between 6.5 and 8, in order to maximize the production of leukotoxin—a specific protein generated by the bacteria. The leukotoxin supernatant is separated from the bacteria and inactivated for use in the vaccine. The leukotoxin protein is specifically isolated and the rest of the bacterial culture is discarded, with only a specific portion of the bacterial culture used to form the vaccine. The '694 Patent thus discloses a vaccine production methodology in connection with which bacterial cultures are grown for specific periods of time, after which very specific portions of the bacterial culture are isolated. In the '034 Patent, a vaccine production methodology is disclosed in which an inactivated cell culture product of
Actinomyces pyogenes
was added as an additional component.
In European Patent EP0460480, entitled Bacterin for the Treatment of
necrophorum
Diseases and a Method for the Production Thereof, invented by Berg, a method is disclosed that uses whole-cell suspensions of
F. necrophorum
which have been inactivated using &bgr;-propiolactone (BPL). The patent further discloses a method whereby the bacteria are cultured until fermentation is complete, which is approximately 18 hours or greater. The longer fermentation period is believed to result in the enzymatic breakdown of various proteins that may be important to the efficacy or antigenic properties of the vaccine. Also, the isolate used is derived from an ovine species as opposed to a bovine, which is likely less effective in cattle than an isolate from a bovine species. A problem associated with the Berg patent is that it requires a higher dosage of vaccine to be administered to a subject. The higher vaccine dosage−2 to 6 ml, increases the chances of lesions forming at the inoculation point.
For the above reasons, there is a need for a vaccine which induces an optimal immune response in an inoculated host to substantially prevent diseases such as footrot or liver abscesses. It is also desired to have a vaccine that can be administered in smaller dosages so that the chances for lesion formation at the inoculation point is lessened. Such a vaccine should be economical to produce, as many known methods for forming the vaccines require numerous steps and expensive equipment.
SUMMARY OF THE INVENTION
The present invention relates to a vaccine, and method for forming the vaccine, for administration to ruminants, most preferably bovines, for establishing resistance to infectious diseases of footrot and liver abscesses caused by the
F.
Anderson Gary A.
Liem Adrian
Stine Douglas L.
Hines Ja'Na
Lee Michael
Marks David L.
Novartis Animal Health, Inc.
Smith Lynette R. F.
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