Advances in combating fungal diseases: vaccines on the threshold

Abstract

The dramatic increase in fungal diseases in recent years can be attributed to the increased aggressiveness of medical therapy and other human activities. Immunosuppressed patients are at risk of contracting fungal diseases in healthcare settings and from natural environments. Increased prescribing of antifungals has led to the emergence of resistant fungi, resulting in treatment challenges. These concerns, together with the elucidation of the mechanisms of protective immunity against fungal diseases, have renewed interest in the development of vaccines against the mycoses. Most research has used murine models of human disease and, as we review in this article, the knowledge gained from these studies has advanced to the point where the development of vaccines targeting human fungal pathogens is now a realistic and achievable goal.For many years, the concept of developing vaccines against fungal diseases attracted little interest, but this has changed in the past fifteen years (reviewed in REFS 1-6 ) because of the dramatic increase in the incidence rates of fungal diseases worldwide. Carbohydrate and, especially, protein antigens that exert protective immunity against various fungal diseases have now been identified. Fungal carbohydrates can induce the production of antibodies that enhance host resistance in many ways and, fuelled by advances in cellular and molecular biology, numerous fungal proteins that trigger T-cell-mediated immunity and that are immunogenic in murine models of fungal disease have been identified (TABLE 1). A vaccine based on one or more of these candidate antigens could prevent disease by inducing protective antibodies, T-cell-mediated immunity or a combination of both of these aspects of the host immune response. In this Review, we will assess the state of fungal vaccine development, both prophylactic and therapeutic. Overview of the immune response to fungiSuccessful resolution of the diseases caused by pathogenic fungi is crucially dependent on the coordinated interactions of many constituents of the host immune response. The host response to these organisms varies, as would be expected for such a heterogeneous group of pathogens, which differ morphologically, genetically and biochemically. Therefore, the effector molecules and cells that are important for combating opportunistic fungi such as Candida and Aspergillus spp. are less important for primary pathogens such as Coccidioides spp. and Histoplasma capsulatum (BOX 1). The innate response to fungiAs with all pathogens, the innate immune system is a crucial determinant in the antifungal response (FIG. 1) The non-cellular effectors of innate immunity comprise collectins, complement and natural antibodies. These molecules mediate opsonization and therefore promote the ingestion of fungi by phagocytes. One member of the collectin family, pentraxin 3, is necessary for the response to Aspergillus spp. 23 , and the pulmonary collectins surfactant proteins A and D not only cause aggregation of fungi but also have fungicidal activity ...

Synthetic glycopeptide vaccines combining β-mannan and peptide epitopes induce protection against candidiasis

“…T he rising incidence of life-threatening fungal diseases and associated high treatment failure rate are providing impetus for development of antifungal vaccines as a preventive strategy (1). Whereas some vaccines are constructed to induce cell mediated immunity, others favor protective antibody responses.…”

“…The role of antibody immunity against fungal disease has been controversial (1,2), which is likely because of a lack of appreciation for critical parameters such as antibody specificity, isotypes and titers and the relationship between humoral and cell mediated immunity (3). The less understood phenomenon of immunoglobulins that may cause tissue damage provides additional complexity.…”

Fungal Vaccines and Immunotherapeutics

“…The chemical identity of the amorphous polysaccharides differs among species, although it generally includes mannans of varying lengths and linkages (Latge 2010). Although fungi evade lysis by the complement system, deposition of complement components, such as C3b and iC3b on its surface, leads to its opsonization, enabling phagocyte recognition of fungal particles (Cutler et al 2007).…”

“…This region is determined by a B cell's activation status and the signals it receives from CD4 þ T cells. After binding an antigen recognized by a surfacebound IgD or monomeric IgM, B cells become activated and start producing pentameric IgM (Cutler et al 2007). As CD4 þ T cells also become activated, they start producing cytokines, such as interleukin-4 (IL-4) or interferon-g (IFN-g), and up-regulate the expression of CD40 ligand on their surface.…”

Problems of Vaccinal Prevention of Deep Mycoses

“…Основные трудности в их разработке были связаны со сложностью их кли-нических испытаний [5,6]. Это объяснялось тем, что при высоком уровне инфицированности насе-ления различными грибами клинические формы с тяжелым течением были относительно редки.…”