Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Fungus
Reexamination Certificate
2000-04-17
2001-06-19
Wortman, Donna C. (Department: 1645)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Fungus
C424S184100, C424S274100, C424S093100, C424S093200, C424S093210, C435S471000, C435S254100, C435S911000
Reexamination Certificate
active
06248322
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to attenuated variants of the fungus
B. dermatitidis
, and methods of using them to vaccinate against the wild type fungus.
Blastomycosis is a disease caused by infection with the fungus
Blastomyces dermatitidis
. Humans and other animals (particularly dogs) can be infected by inhaling aerosolized fungal spores from, for example, soil where the organism dwells. At body temperature, these spores convert to yeast forms. Acute primary pulmonary infection caused by the yeast can produce an influenza or pneumonia syndrome. Progressive forms of the disease can cause serious damage to the lungs, skin, bones, joints, or prostate gland.
It is therefore desirable to develop a vaccine against this disease. In U.S. Pat. No. 5,093,118 (the disclosure of this patent and all other publications referred to herein being incorporated by reference as if fully set forth herein) we described the isolation of a cell wall protein of the fungus
B. dermatitidis
that we named WI-1. It was suggested that this protein be used in a vaccine for Blastomycosis.
In U.S. Pat. No. 5,302,530 we described the coding DNA for this protein. While WI-1 has been of some value in raising antigenic responses, its impact on long-term survival of hosts challenged with certain strains of the wild type fungus has not been sufficient. Thus, efforts have continued to try to find more widely effective vaccines against this disease.
In unrelated work, fluorescence staining of the fungal surface and extractions of cell wall proteins have shown that WI-1 can be expressed to a lower extent in genetically related strains having higher virulence. B. Klein et al., 62 Infect. Immun. 3536-3542 (1994). If anything, this would have taught away from trying to delete WI-1 expression as a means of attenuating a fungus.
It should also be noted that we recently published techniques for genetically manipulating
B. dermatitidlis
by using DNA mediated gene transfer. See L. Hogan et al., 186 Gene 219-226 (1997).
To date we are unaware of anyone having successfully obtained an attenuated replication competent
B. dermatitidis
fungal vaccine, or any other vaccine against this fungus (e.g. protein based, DNA based, or otherwise) which meets the needs in this art. Thus, a need exists for an improved vaccine against
B. dermatitidis.
BRIEF SUMMARY OF THE INVENTION
In one aspect the invention provides a recombinant, replication competent,
B. dermatitidis
fungus that is incapable of expressing WI-1 protein. Preferably the fungus does not contain any portion of the WI-1 coding gene.
In another aspect the invention provides a method for causing a mammal to resist lung infection by
B. derrmatitidis
. One administers to the mammal the above recombinant fungus. Preferably, the mammal is canine or human, and the administration is by subcutaneous injection on multiple days.
Strains of
B. dermatitidis
have been modified to render them incapable of expressing a WI-1 protein. They are otherwise intact. Particularly with respect to subcutaneous injection on multiple days, hosts exposed to our attenuated fungus develop infection resistance against the wild type fungus.
Particularly surprising is that dosages can be provided which are high enough to provide infection resistance and increased long-term survival, but low enough so that the attenuated fungus does not reside throughout the body on a long-term basis. This is highly desirable.
These and other advantages of the present invention will become apparent after study of the following specification and claims.
REFERENCES:
patent: 5093118 (1992-03-01), Klein et al.
patent: 5302530 (1994-04-01), Klein et al.
patent: 5948413 (2000-09-01), Mendoza
Reiss et al. Dermatologica 152=16-22, 1976.*
T. Brandhorst et al., Targeted Gene Disruption Reveals An Adhesin Indispensable For Pathogenicity ofBlastomyces Dermatitidis, 189 J. Exp. Med. 1207-1216 (Apr. 19, 1999—not prior art).
B. Klein et al. Altered Expression Of The Surface Protein WI-1 In Genetically Related Strains OfBlastomyces DermatitidisThat Differ In Virulence Regulates Recognition Of Yeasts By Human Macrophages, 62 Infect. Immun. 3536-3542 (1994).
L. Hogan et al., Transforming DNA Integrates At Multiple Sites In The Dimorphic Fungal PathogenBlastomyces Dermatitidis, 186 Gene 219-226 (1997).
L. Hogan et al., Genomic Cloning, Characterization, And Functional Analysis Of The Major Surface Adhesin WI-1 OnBlastomyces DermatitidisYeasts, 270 J. Biol. Chem. 30725-30732 (1995).
P. Worsham et al., Quantitative Plating Of Histoplasma Capsulatum Without Addition Of Conditioned Medium Or Siderophores, 26 J. Vet. Med. Mycol. 137-143 (1988).
S. Lyons et al., An Immunological Method For Detecting Gene Expression In Yeast Colonies, 81 PNAS USA 7426-7430 (1984).
B. Klein et al., Purification And Characterization Of the Major Antigen WI-1 FromBlastomyces DermatitidisYeasts, And Immunological Comparison With A Antigen, 62 Infect. Immun. 3890-3900 (1994).
S. Newman et al., The WI-1 Antigen OnBlastomyces DermatitidisYeasts Mediates Binding To Human Macrophase CD18 and CD14 Receptors, 154 J. Immunol. 753-761 (1995).
J. Chan et al., Killing Of Virulent Mycobacterium Tuberculosis By Reactive Introgen Intermediates Prodced By Activated Murine Macrophages, 175 J. Exp. Med. 1111-1122 (1992).
J. Mukherjee et al., Therapeutic Efficacy Of Monoclonal Antibodies To Cryptococcus Neoformans Glucuronoxylomnnan Alone And In Combination With Amphotericin B., 38 Antimicrob. Agents Chemother. 580-587 (1994).
S. Zebedee et al., Mouse-Human Immunoglobulin G1 Chimeric Antibodies With Activities Against Cryptococcus Neoformans, 38 Antimicrob. Agents Chemother. 1507-1514 (1994).
J. Mukherjee et al., Antibodies To Crytococcus Neoformans Glucuronoxylomannan Enhance Antifungal Activity Of Murine Macrophages, 63 Infect. Immune. 573-579 (1995).
M. Riesselman et al., Improvements And Important Considerations Of An Ex Vivo Assay To Study Candida Albicans-Splenic Tissue Interactions, 145 J. Immunol. Meth. 153-160 (1991).
M. Wüthrich et al., Immunogenicity And Protective Efficacy Of The WI-1 Adhesin OfBlastomyces Dermatitidis, 66 Infect. Immun. 5443-5449 (1998).
Gudding et al., Vaccination Of Cattle Against Ringworm Caused ByTrichophyton Verrucosum, 47 Am. J. Vet. Res., 2415-2417 (1986).
L. Romani et al., Course Of Primary Candidiasis In T Cell-Depleted Mice Infected With Attenuated Variant Cells, 166 J. Infect. Dis. 1384-1392 (1992).
Brandhorst Theodore T.
Klein Bruce S.
Wüthrich Marcel
Quarles & Brady LLP
Wisconsin Alumni Research Foundation
Wortman Donna C.
Zeman Robert A.
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