Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-11-12
2003-12-02
Graser, Jennifer E. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S234100, C424S235100, C435S173300, C435S243000
Reexamination Certificate
active
06656478
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to salmonella vaccines that are useful against Salmonellosis caused by heterologous serotypes of Salmonella in mammals. More specifically, the invention relates to salmonella vaccines for swine incorporating
Salmonella cholerasuis
which provides cross protection against disease caused by heterologous Salmonella species including but not limited to
Salmonella typhimurium.
BRIEF DESCRIPTION OF THE PRIOR ART
Salmonellosis of swine is one of the most economically important of the enteric and septicemic diseases affecting young pigs. Although many serotypes of Salmonella have been isolated from pigs,
S. cholerasuis
var kunzendorf and
S. typhimurium
are the two most frequently isolated serotypes associated with clinical disease.
S. cholerasuis
is host-adapted to swine and most often causes fatal septicemic disease with little involvement of the intestinal tract. On the other hand,
S. typhimurium
typically causes enteroinvasive disease characterized primarily or exclusively by diarrhea. The initial signs of the disease include watery, yellowish diarrhea without mucin or melena. Affected pigs often exhibit anorexia, lethargy, and fever ranging from 105 to 107 degrees Fahrenheit. Mortality is usually low and occurs only after several days of diarrhea, presumably the result of hypokalemia and dehydration. Literature clearly notes that both the type of infection and host range vary significantly between
S. cholerasuis
and
S. typhimurium.
It has been known to use
Salmonella cholerasuis
vaccines such ARGUS SC™ vaccine (Intervet Inc., Millsboro, Del.) to protect pigs against diseases caused by infection from
S. cholerasuis
(homologous protection). The vaccine of the present invention incorporates a modified live
S. cholerasuis
, the composition of which is described generally in U.S. Pat. No. 5,468,485. More specifically, the patent discloses a vaccine for the immunization of vertebrates or invertebrates comprising an avirulent derivative of
S. cholerasuis
. The derivative is substantially incapable of producing functional adenylate cyclase (cya gene deletion) and/or cyclic AMP receptor protein (crp). The patent also discloses a vaccine for immunization of a vertebrate or invertebrate comprising a virulent derivative of a pathogenic microbe, which is substantially incapable of producing functional adenylate cyclase and/or cyclic AMP receptor protein. Said pathogenic microbe is capable of expressing a recombinant gene derived from a pathogen of said vertebrate to produce an antigen capable of inducing an immune response in said vertebrate against said pathogen. This patent describes construction of various avirulent Salmonella species but does not disclose or claim use of a
S. cholerasuis
vaccine to protect pigs against disease caused by a heterologous Salmonella such as
S. typhimuirum.
U.S. Pat. No. 5,804,194 discloses vaccines containing Salmonella bacteria attenuated by mutation of the HTRA gene. This mutation also produces avirulent salmonella vaccines which appear to be safe when injected into mice. Also described is vaccination of mice by a vaccine of the invention followed by challenge with a homologous
S. typhimurium
strain. There is no description or claim of a
S. cholerasuis
vaccine having the capability to cross protect against diseases caused by heterologous Salmonella species.
U.S. Pat. No. 5,843,426 discloses salmonella vaccines containing salmonella organisms, the virulence of which is attenuated by a deletion of a portion of the PhQ gene and Salmonella organisms having a deletion of both the PhQ gene and the PhoP gene. There is no mention of a
S. cholerasuis
vaccine which can cross protect pigs against disease caused by heterologous Salmonella species.
Miller et al., 1989, Proc. Natl. Acad. Sci USA 86:5054 discloses
S. typhimurium
strains with mutations in the positive regulatory regulon phoP which are markedly attenuated in virulence for BALB C mice. The phoP regulon is composed of two genes present in an operon termed phoP and phoQ. The PhoP and the phoQ gene products are highly similar to other members of bacterial two-component transcriptional regulators that respond to environmental stimuli and control the expression of a large number of other genes. A mutation at one of these PhoP regulatory regions, regulates the pagC genes and produces a virulence defect. Strains with pagC, phoP and phoQ mutations afford partial protection to subsequent challenge by wild-type
S. typhimurium
. However, there is no description or claim made for
S. cholerasuis
vaccines which cross protect against diseases caused by heterologous Salmonella species.
U.S. Pat. No. 5,436,001 discloses methods of attenuating virulent Gram negative bacteria in order to produce avirulent vaccine strains. The method is described as serial passaging a gram negative organism through phagocytic cells a sufficient number of times until the bacteria are rendered avirulent to the animal host while still being immunogenic. A method to attenuate
S. cholerasuis
var, Kunzendorf strain 38 is described. Several pig vaccination/challenge studies were conducted. These studies demonstrated that a
S. cholerasuis
attenuated, and produced according to the methods of the patent, could protect against a homologous S. cholerasuis challenge. However, there was no description or claim of cross protection using a
S. cholerasuis
vaccine to protect against disease caused by a heterologous Salmonella such as
S. typhimurium.
Smith et al (Am J Vet Res, 1984, Vol 45, No. 11: 2231-2235) describes an aromatic-dependent avirulent
S. dublin
strain which was tested for safety as a parenteral vaccine for calves as well as for its capability to protect calves from challenge with homologous
S. dublin
or heterologous
S. typhimurium
. Indeed, the vaccine was shown to be safe and provided protection against disease in cattle caused by both
S. dublin
and
S. typhimurium
. However, the publication states that in a previous study, conducted in an identical manner, protection was not produced. Additionally, it is noted that this publication does not describe the use of
S. cholerasuis
vaccines to cross protect against disease caused by eterologous Salmonella of swine nor does it describe oral vaccination.
Alternately, Smith et al (Am J Vet Res, 1984, Vol 45, No 11: 858-1861) describe the production of an aromatic-dependent avirulent
S. typhimurium
which was tested for safety and efficacy in calves. Both the ability to protect against a homologous
S. typhimurium
challenge and a heterologous
S. dublin
challenge were evaluated. The parental vaccine was found to be relatively safe although some disease signs were noted post vaccination. Since 2 of 5 vaccinated calves had slight anorexia, 4 of 5 had diarrhea, and all had marked febrile response after challenge exposure, it was determined that the aromatic-dependent avirulent
S. typhimurium
vaccine did not protect calves against a different serotype (
S. dublin
) as well as it had against a homologous serotype (
S. typhimurium
). However, even against the homologous challenge, 3 of 7 vaccinated calves developed mild diarrhea and 1 of 7 calves had a positive blood culture. This publication actually teaches away from the present invention of a
S. cholerasuis
vaccine which cross protects against disease caused by a heterologous Salmonella species such as
S. typhimurium.
Fox et al (Am J Vet Res, 1997, Vol 58, No. 3, 265-271) describes an attempt to use an avirulent live
S. cholerasuis
vaccine to protect calves against disease caused by
S. dublin
infection. The vaccine, designated SC54, contains an avirulent live culture of
S. cholerasuis
normally used for intranasal or oral vaccination of swine to aid in the prevention of salmonellosis in swine caused by
S. cholerasuis
. The results indicate a varied response to vaccination of calves with different doses and routes of administration of SC54. Vaccination with SC54 did not prevent the fever and fecal shedding of
S. dublin
but did reduce
Abraham Albert Surendran
Charles Samuel D.
Trigo-Tavera Emilio
Blackstone William M.
Graser Jennifer E.
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