Advances in combating fungal diseases: vaccines on the threshold

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Abstract
Fungal diseases have been dramatically increasing over the past several decades. Antifungal drugs have been the mainstay of prevention and treatment of the mycoses, but in this review the authors provide strong rationale for vaccines as a preventive measure. The article considers an array of carbohydrate and protein fungal antigens against which immune responses are protective in animal models of human disease. Protection can occur as a result of vaccine formulations comprising single or multiple purified or synthetic antigens, or as a result of whole-cell vaccines. Support is provided for pursuing vaccines that induce both antibody and cell-mediated immune responses against the candidate antigens. The mechanisms of vaccine-mediated protection vary, depending in large part on the nature of the fungal agent in question. The authors discuss the fact that antibodies against carbohydrate antigens, as in the case of host defence against candidiasis, protect by opsonization or by promoting rapid ingestion of the fungal cells by host phagocytes. Antibodies against carbohydrates from the causative agent of cryptococcosis function by modulating host inflammatory responses and enhancing cell-mediated immunity. In response to protein antigens, a subset of CD4+ T cells and T cell cytokines, such as interferon γ and IL-12, are discussed as being central to host defence against fungi, most notably those that cause histoplasmosis, blastomycosis and coccidioidomycosis. Indeed, an absence of key T-cell subsets can compromise the vigor of an immunological response to a given vaccine. For optimal anti-fungal immunity, the authors suggest that it might be desirable to stimulate broader immune responses than can be elicited simply with a single protein antigen or clone of T cells. This could be done by using a complex immunogen that contains multiple antigens, an antigen together with a new and more potent adjuvant, or even a genetically engineered live attenuated fungus. Alternatively, new formulations or delivery methods of vaccines, including in the form of nucleic acids, might prove fruitful for this purpose. Recent findings indicate that immunity to fungi might include elements of the immune system not traditionally considered to be important, especially under circumstances in which the immune system is impaired. Therefore, the loss of select cytokines or subsets of T cells can sometimes be compensated by other cytokines or T cells. This finding raises the possibility that vaccines can be developed that recruit residual elements of immunity in compromised hosts who are otherwise at high risk of fungal infections. The review concludes with considering the possibility of the development of universal vaccine approaches. This idea was promoted by reports on cross-generic protection induced by a β-glucan vaccine, but the authors suggest that a universal vaccine would be one that advantages both antibody and cell-mediated immune responses.