Mycosis vaccines

Details Mycosis vaccines Mycosis vaccines

1999-05-05

2001-09-18

Stucker, Jeffrey (Department: 1648)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Fungus

C424S093510, C424S274100, C435S007310, C435S254100, C435S254200, C435S254220, C435S255100, C435S255700

Reexamination Certificate

active

06290950

ABSTRACT:

The present invention is in the field of mycology and pertains to vaccines comprising homogenised inactivated dermatophyte microconidia and inactivated homogenised yeast blastospores or antigenic material of said spores, methods for their production and their use for the prophylaxis and/or treatment of mycoses in mammals, preferably humans. The vaccines according to the present invention are especially useful for the prophylaxis and/or treatment of skin mycoses, preferably Dermatomycosis and/or Candidosis and/or Onychomycosis.
Recently, the percentage of fungal infections (mycoses) has increased dramatically. Specifically, the percentage of fungal infections of the skin (skin mycoses) has increased to 4-8% of all skin diseases in humans. This percentage is increased up to 15-20% under tropical conditions. The most common pathogens associated with skin mycoses are dermatophytes of the genus Trichophyton, like
Trichophyton rubrum, Trichophyton mentagrophytes
and/or
Trichophyton verrucosum
. Other fungal pathogens associated with skin mycoses are yeasts, for example the genus Candida, i.e.
Candida albicans.
A typical example for skin mycosis is Onychomycosis, i.e.
Tinea unguium
. Onychomycosis afflicts about 2-8% of the human population. Major pathogens associated with Onychomycosis in European countries are dermatophytes of the species
Trichophyton rubrum
and
Trichophyton mentagrophytes
as well as yeasts of the species
Candida albicans. Candida albicans
is found much more frequently in infected finger nails than toe nails. Unlike other skin mycoses, Onychomycoses never heal spontaneously and always lead in the terminal state to Onychodystrophy, if left untreated.
Skin mycoses are normally treated using a topical therapy with antimycotic chemical substances. However, these chemical substances have considerable side effects (e.g. hepatotoxicity, potential teratogenicity, gastrointestinal and central nervous system irritations as well as allergic reactions) and/or reach the target site only insufficiently, like in case of Onychomycosis, where the infected site is covered by the nail. Especially in chronic infections, where hair roots or nails are infected, these chemical therapies are lengthy and frustrating, for both the physician and the patient. Further, the rate of recurrence of infection is extremely high.
Skin mycoses can develop into systemic fungal infections (systemic mycosis), i.e. in immune compromised individuals. Systemic infections usually need to be treated with chemical agents for weeks or months. Treatment sometimes can last up to one year. Compliance of the patients often suffers when side-effects appear, and the benefit-risk-relation has become a special issue.
According to current knowledge, chronic fungal infections occur in otherwise healthy individuals, i.e. non immune deficient individuals, because in these individuals only an antibody response is triggered against the fungus, i.e. IgE mediated immunological response, but no cell-mediated immune response. However, the antibody-mediated immunological response alone is not sufficient to fight the fungus infection successfully. Chronic mycosis is the result (Sorensen, G. W., Arch. Dermatol. 112, 1976, 4042; Hay, R. J., Shennan, G., Br. J. Dermatol. 106, 1982, 191-198; Dahl, M. V., Adv. Dermatol. 2, 1987, 305-320).
Vaccines comprising live dermatophytes are well known for their ability to elicit both responses, however, as with all live vaccine preparations, infection of healthy individuals by freshly vaccinated individuals is a permanent risk. Inactivated vaccines often fail to elicit a sufficient cell mediated response and accordingly are not as efficient as live vaccines.
Approaches concerning the use of inactivated dermatophytes as Dermatomycosis vaccines are known from prior art. For example Wharton, M. et al. (1950, J. Invest. Derm. 14, 291-303) teach active immunisation against
Trichophyton purpureum
infection in rabbits with an inactivated suspension of
Trichophyton rubrum
hyphae. EP 393371 and WO 9307894 teach inactivated Dermatomycosis vaccines comprising dermatophytes of the genus Trichophyton and/or Microsporum. To our knowledge, no mycoses vaccines are known from prior art, that comprise homogenised inactivated dermatophyte microconidia and inactivated homogenised yeast blastospores.
It was now surprisingly found, that vaccines comprising homogenised inactivated dermatophyte microconidia and inactivated homogenised yeast blastospores confer good resistance against fungal infections.
The present invention now provides vaccines comprising homogenised inactivated dermatophyte microconidia and inactivated homogenised yeast blastospores or antigenic material of said spores, methods for their production and their use for the prophylaxis and/or treatment of mycosis in mammals, preferably humans. The vaccines according to the present invention are especially useful for the prophylaxis and/or treatment of skin mycoses, preferably Dermatomycosis and/or Candidosis and/or Onychomycosis.
The vaccines of the present invention have excellent immunogenic-properties in the absence of adverse side effects. In particular, the vaccines of the present invention do not provoke allergic reactions.
In one embodiment, the vaccines of the present invention comprise inactivated yeast blastospores and/or yeast blastospores that are in a swollen condition and/or have germ tubes and/or dermatophyte microconidia and/or dermatophyte microconidia that are in a swollen condition and/or have germ tubes, or antigenic material of said spores. Preferably, the yeast blastospores belong to the genus Candida, more preferably the species
Candida albicans
and/or the dermatophyte microconidia belong to the genus Trichophyton and/or Microsporum, i.e. the species
Trichophyton rubrum
and/or
Trichophyton mentagrophytes
and/or
Microsporum canis
. Highly preferred are the strains
Candida albicans
DSM-9456, and/or
Candida albicans
DSM-9457 and/or
Candida albicans
DSM-9458 and/or
Candida albicans
DSM-9459 and/or
Trichophyton rubrum
DSM-9469 and/or
Trichophyton rubrum
DSM-9470 and/or
Trichophyton rubrum
DSM-9471 and/or
Trichophyton rubrum
DSM-9472 and/or
Trichophyton mentagrophytes
DSM-7279 and/or
Microsporum canis
DSM-7281. Highly preferred are combinations of strains according to the examples. Preferably, 50% of the yeast blastospores and/or the dermatophyte microconidia are in swollen condition and/or have germ tubes. Preferably, the concentration of the spores is 40 to 90 million per ml, highly preferred is a concentration of about 60 million spores per ml. For inactivation of the spores, preferably thiomersal, formaldehyde or 2-propiolactone are used.
In another embodiment of the present invention, the yeast blastospores and/or dermatophyte microconidia are modified by chemical treatment, preferably by treatment with H
2
O
2
and/or sodium permanganate and/or potassium permanganate.
The vaccines of the present invention can modulate the immune system, i.e. they have immunostimulatory properties and can be administered in the absence of additional immunostimmulatory substances. Therefore, in one embodiment, the vaccines of the present invention do not comprise adjuvants or other immunomodulatory or immunostimulatory substances.
To further increase their immunogenic properties, in another embodiment, the vaccines of the present invention further comprise at least one substance with immunomodulatory activity, preferably an adjuvant, preferably selected from the group of vitamin-E acetate, o/w-emulsion, aluminium phosphate, aluminium oxide, aluminium hydroxide/methyl cellulose gel, an oil-emulsion, muramil-dipeptides, Freund's adjuvants and saponins and/or at least one cytokine, preferably selected from the group of IL 2, IL 12, INF-Gamma.
In one embodiment, the vaccines of the present invention are used for the treatment and/or prophylaxis of mycoses, preferably skin mycosis, preferably Dermatomycosis and/or Candidosis and/or Onychomycosis in mammals, preferably humans.
In another embodiment, the vacc

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