Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-07-09
2003-10-14
Minnifield, Nita (Department: 1645)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S069100, C435S320100, C435S325000, C435S252300, C435S252330, C435S071100, C435S071300, C536S023100, C536S023500, C536S023700
Reexamination Certificate
active
06632640
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to vaccines for bacterial toxins from
Staphylococcus aureus.
INTRODUCTION
The most common cases of food poisoning are caused by the bacteria
Staphylococcus aureus
. Exotoxins produced by the organism cause gastrointestinal distress, to include diarrhea and vomiting, and can also cause toxic shock syndrome which may lead to death. These exotoxins also called enterotoxins since they typically exert their effects on the gastrointestinal tract, cause disease by binding to the major histocompatibility complex (MHC) on T-cells which results in the release of large amounts of various cytokines. This cytokine release has been postulated to mediate the many toxic effects of the
S. aureus
exotoxins. There are at least eight antigenically distinct exotoxins (labeled SEA, SEB, SEC1, SEC2, SEC3, SED, SEE, and SEG) produced by
S. aureus
. Presently, there is no approved/licensed SEA or SEB vaccine. Treatment for
Staphylococcus aureus
infections is becoming more difficult since the organism has become resistant to most antibiotics.
Therefore, there is a need for an efficacious vaccine protective against
Staphylococcus aureus
intoxication.
SUMMARY OF THE INVENTION
The present invention satisfies the need discussed above. The present invention relates to a method and composition for use in inducing an immune response which is protective against intoxication with
Staphylococcus aureus.
In this application is described a vaccine strategy where a gene coding for a protein of interest is cloned in a VEE virus vector in place of the VEE virus structural genes; the result is a self-replicating RNA molecule, a replicon, that encodes its own replicase and transcriptase functions, and in addition makes abundant quantities of mRNA encoding the foreign protein. When replicon RNA is transfected into eukaryotic cells along with two helper RNAs that express the VEE structural proteins (glycoproteins and nucleocapsid), the replicon RNA is packaged into VEE virus-like particles by the VEE virus structural proteins, which are provided in trans. Since the helper RNAs lack packaging signals neccessary for further propagation, the resulting VEE replicon particles (VRPs) which are produced are infectious for one cycle but are defective thereafter. Upon infection of an individual cell with a VRP, an abortive infection occurs in which the infected cell produces the protein of interest in abundance, is ultimately killed by the infection, but does not produce any viral progeny (Pushko et al., 1997,
Virology
239, 389-401).
Genes encoding a mutant SEA (mSEA) exotoxin and a mutant SEB (mSEB) exotoxin were each inserted into the VEE replicon vaccine vector (FIG.
1
). The mutant gene product is unable to bind to the MHC on T-cells (Bavari, et al., 1996
, Vaccines
96, 135-141). Evaluation of the mSEA-replicon and mSEB-replicon in vitro have shown high level expression of both bacterial proteins. Balb/c mice immunized with the mSEB-replicon produced high specific antibody titers and were protected when challenged intraperitoneally with wild type SEB.
Therefore, it is one object of the present invention to provide a VEE virus replicon vector comprising a VEE virus replicon and a DNA fragment encoding a mutant SEA exotoxin or a mutant SEB exotoxin.
It is another object of the present invention to provide a self replicating RNA comprising the VEE virus replicon and any of the SEA or SEB fragments described above.
It is another object of the present invention to provide infectious VEE virus replicon particles produced from the VEE virus replicon RNA described above.
It is further an object of the invention to provide an immunological composition for the protection of mammals against
Staphylococcus aureus
intoxication comprising VEE virus replicon particles containing any of the
Staphylococcus aureus
fragments described above or a combination of different VEE virus replicons each having a different
Staphylococcus aureus
fragment.
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Lee John S.
Pushko Peter
Smith Jonathan F.
Ulrich Robert G.
Arwine Elizabeth
Harris Charles H.
Minnifield Nita
The United States of America as represented by the Secretary of
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