Mold Vaccine Research Article

[Guest guest]

Here is the beginning of the article. The complete article is much too long to

post, so I will put a link to it, at the end of this post.

Joe

....................................................................

A novel glyco-conjugate vaccine against fungal pathogens

Antonella Torosantucci1, Carla Bromuro1, Paola Chiani1, Flavia De Bernardis1,

Francesco Berti2, Chiara Galli2, Francesco Norelli2, Cinzia Bellucci2, Luciano

Polonelli3, Paolo Costantino2, Rino Rappuoli2, and Cassone1

1 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto

Superiore di Sanità, 00186 Rome, Italy

2 Chiron Vaccines, 53100 Siena, Italy

3 Microbiology Section, Department of Pathology and Laboratory Medicine,

University of Parma, 43100 Parma, Italy

CORRESPONDENCE Cassone: cassone@...

To generate a vaccine to protect against a variety of human pathogenic fungi,

we conjugated laminarin (Lam), a well-characterized but poorly immunogenic

ß-glucan preparation from the brown alga Laminaria digitata, with the diphtheria

toxoid CRM197, a carrier protein used in some glyco-conjugate bacterial

vaccines. This Lam-CRM conjugate proved to be immunogenic and protective as

immunoprophylactic vaccine against both systemic and mucosal (vaginal)

infections by Candida albicans. Protection probably was mediated by

anti-ß-glucan antibodies as demonstrated by passive transfer of protection to

naive mice by the whole immune serum, the immune vaginal fluid, and the

affinity-purified anti-ß-glucan IgG fractions, as well as by administration of a

ß-glucan–directed IgG2b mAb. Passive protection was prevented by adsorption of

antibodies on Candida cells or ß-glucan particles before transfer. Anti-ß-glucan

antibodies bound to C. albicans hyphae and inhibited their growth in vitro

in the absence of immune-effector cells. Remarkably, Lam-CRM–vaccinated mice

also were protected from a lethal challenge with conidia of Aspergillus

fumigatus, and their serum also bound to and markedly inhibited the growth of A.

fumigatus hyphae. Thus, this novel conjugate vaccine can efficiently immunize

and protect against two major fungal pathogens by mechanisms that may include

direct antifungal properties of anti-ß-glucan antibodies.

--------------------------------------------------------------------------------

Abbreviations used: CT, cholera toxin; GG, glucan ghosts; Lam, laminarin; NMR,

nuclear magnetic resonance; ppm, parts per million; Zym, zymoliase.

Fungal diseases are a major infectious threat that demands increasing medical

attention. A few invasive mycoses (e.g., histoplasmosis and coccidiomycosis) are

geographically limited, but of special concern are the worldwide infections

caused by opportunistic fungal agents in immunocompromised hosts. In particular,

candidiasis and aspergillosis are common in hospitalized patients and carry a

high mortality toll even in the presence of effective therapy (1). Early and

accurate diagnosis of these systemic infections is often difficult because of

the nonspecificity of clinical symptoms and lack of standardized diagnostic

tools. Moreover, antifungal therapy may be frustrated by toxicity and emergence

of resistance (2).

A prophylactic and/or therapeutic vaccine would be the safest and most

effective means to meet this pressing medical need. Thus, different approaches

to antifungal vaccination are being developed that, in analogy with bacterial

and viral vaccines, are based on the use of one or more antigens, including

whole inactivated cells, specific for each particular fungus (3, 4). However, no

such vaccine is currently available. In none of the vaccine formulations under

study has ß-glucan, a polysaccharide that is critical for fungal viability and

is present in all human pathogenic fungi, been considered as vaccine component.

Previous circumstantial evidence indicates that intact cells of Candida

albicans (5) and Saccharomyces cerevisiae (unpublished data) treated to expose

glucan rather than mannoprotein on the cell surface confer a substantial degree

of anti-Candida protection. Therefore we have considered that a vaccine composed

of ß-glucan would best fit the medical need, possibly allowing simultaneous

immunization against more than one fungal infection. To test the strength of

this novel approach and to avoid any likely contamination with other fungal

antigens, a ß-glucan of nonfungal source, i.e., laminarin (Lam), a rather

well-characterized ß(1, 3) glucan preparation from the brown alga Laminaria

digitata (6), was selected as the immunizing antigen. Because laminarin, like

most free polysaccharides, is a poor immunogen, it was conjugated with the

diphtheria toxoid CRM197, a protein carrier safely used in other human vaccines

(7, 8). This novel glyco-conjugate has been tested extensively

as an immunoprophylactic vaccine against experimental systemic and mucosal

infections by C. albicans, a fungal pathogen of particular medical relevance.

Initial investigations with Aspergillus fumigatus support the concept that our

conjugate vaccine may prove indeed effective against multiple agents of

opportunistic fungal infections.

click this link for complete article:

http://tinyurl.com/65jnfc