Introduction

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Vaccines have been hailed as one of the greatest achievements in the public health during the past century. So far, the development of safe and efficacious vaccines has been a major barrier for other infectious agents including fungi, partly due to of our lack of knowledge about the mechanisms that underpin protective immunity.

Fungal diseases are epidemiological hallmarks of distinct settings of at risk patients; not only in terms of their underlying condition but in the spectrum of diseases they develop [1,2]. Although fungi are responsible for pulmonary manifestations and cutaneous lesions in apparently immunocompetent individuals, their impact is most relevant in patients with severe immune compromised, in which they can cause severe, life-threatening forms of infection. As an increasing number of immunocompromised individuals resulting from intensive chemotherapy regimens, bone marrow or solid organ transplantation, and autoimmune diseases have been witnessed in the last decades, so has the incidence of fungal diseases [1,2]. Regardless of hundreds of thousands of fungal species, only a few cause disease in humans. The most common fungi that infect humans are Candida spp., Aspergillus fumigatus, Cryptococcus neoformans, Pneumocystis jiroveci (carinii) and the thermally dimorphic fungi e.g. Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides posadasii, Penicillium marneffei and Paracoccidioides brasiliensis [3].

Despite recent additions to our antifungal drug armamentarium, success rates for many mycoses remain unacceptably low and antifungal drug therapy is often limited by toxicity, resistance and high cost. To circumvent these difficulties, alternative approaches to prevention and treatment are being developed, including vaccines and passive immunotherapy.

Here, we review the progress of current research in this field, discuss some of the potential obstacles to developing and marketing a protective antifungal vaccine

Vaccines against the fungi

In recent years, several studies in the field of medical mycology have been focused on the development of new vaccines against fungal pathogens. Many pertinent reviews and papers have been published with both new strategies and challenges to the development of antifungal vaccines due to the rise of dangerous systemic fungal infections, especially related to immunocompromised patients, premature infants, cancer patients and those with invasive treatments for long periods in hospital settings, which are known as high-risk groups [4-6]. High-risk groups in the past decades have been expanding in number owing to advances in the medical field, where new treatments to critical diseases, such as cancer, have arisen [7]. These treatments improve patient's survival rates, but can also affect natural barriers of the body or even significantly impact the competence of the immune system of the individual, contributing to an increased vulnerability to infections caused by fungi [8].

Vaccine development is a priority for several fungal pathogens, including C. albicans [9], C. neoformans [10], A. fumigatus [6], and dimorphic fungi [11]. Many challenges confront vaccine development for fungi, including different host risk factors and modes of fungal pathogenesis. No single antigen can be expected to be used in a "pan-fungal" vaccine; rather, specific tailored vaccines will be required for the major fungal pathogens [12].

One impediment to fungal vaccine development is that the patients who are most susceptible to opportunistic fungal infections are those least able to mount protective responses [13] showed that CD4+ T cells were dispensable in vaccine immunity against pulmonary blastomycosis (an extracellular pathogen) and histoplasmosis (a facultative intracellular pathogen) in immunocompromised mice. CD8+ T cells, in the absence of CD4+ T cells, mediated vaccine-induced protection against these fungi, and protection by Blastomyces-immune CD8+ T cells could be adoptively transferred. These results contradict the dogma that induction of CD8+ T cell responses against exogenously processed antigens requires CD4+ T cells, and they provide encouragement for vaccine development for patients with impaired CD4+ T cell immunity (e.g., patients with advanced AIDS).

Another impediment relates to the limited number of licensed vaccine adjuvants. Candidate adjuvants that act on multiple innate and antigen-specific host defense pathways are likely to be the most effective in protecting against opportunistic fungal infections. The definition of adjuvants has mostly been restricted to those that stimulated antibody titers (e.g., pneumococcus) or in the case of the bacillus Calmette-Guerin vaccine, delayed-type hypersensitivity responses. More recently, the concept of adjuvants has been expanded to include soluble mediators and antigenic carriers (e.g., endotoxin, Flt3 ligand, and heat-shock protein) that activate antigen-presenting cells and stimulate innate and cellular immunity [14]. Heat-shock proteins are an example of naturally produced proteins that have been exploited as vaccine adjuvants in cancer and infectious diseases [14-20]. Heat-shock proteins exhibit powerful immunostimulatory effects on dendritic cells in a TLR2- and TLR4-dependent fashion [21,22] and induce antibody and type I cellular immunity that may be promising in fungal vaccine development [23]. Fungi also produce heat shock proteins that may be targets for vaccine development. Long, et al. [24] identified heat-shock protein 60 as the ligand on H. capsulatum that mediates binding to CD18 receptors on human macrophages. Immunization with recombinant heat shock protein 60 from H. capsulatum conferred protection from a subsequent challenge in mice [25]. Paradoxically, vaccination may be useful to attenuate pathological inflammatory responses or induce tolerance. Allergic bronchopulmonary aspergillosis develops from sensitization to airway A. fumigatus antigens, leading to a Th2 CD4+ cell response characterized by secretion of IL-4, IL-5, and IL-13 [26]. T cells are the key components mediating allergic responses to A. fumigatus antigens in mouse models of allergic bronchopulmonary aspergillosis [27]. There is significant interest in immunotherapy for allergic bronchopulmonary aspergillosis, including the use of CpG sequences [28], recombinant allergens, and peptides to induce tolerance, as well as antigenic and DNA-based vaccines aimed at controlling the Th2-mediated responses in allergic bronchopulmonary aspergillosis [29].

Challenges in Designing Mycological Immunotherapy Trials

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Immunotherapy can be evaluated as preventive or as adjunctive therapy. Prevention should be targeted to patients at significant risk for the infection of interest and should focus on infections with significant morbidity or mortality that are inadequately covered by standard therapies.

One challenge relates to accrual of adequate numbers of patients in trials involving uncommon infections. Assuming a vaccine with 80% efficacy in preventing invasive aspergillosis and a 5% frequency of invasive aspergillosis in a population of interest (e.g., allogeneic hematopoietic stem cell transplant recipients), subjects receiving the vaccine would be expected to have a 1% rate of invasive aspergillosis. Assuming a power of 0.8, a ! .05, and a 1-sided analysis designed to show superiority of vaccination, a sample size of 544 patients would be required. This number is, in fact, an underestimate, because it does not consider false-positive diagnoses or differences in antifungal prophylaxis and diagnostic evaluation between centers, which would reduce the ability of the analysis to detect a protective effect of vaccination. Selecting a patient population with a higher risk of invasive aspergillosis (e.g., T cell-depleted allogeneic hematopoietic stem cell transplant recipients) would reduce the required sample size. The paradigm for clinical trial design aimed at preventing infection with dimorphic fungi (e.g., by vaccination) will be different, because these pathogens affect both immunocompetent and immunocompromised persons and are geographically restricted. In the 1980s, a randomized placebo-controlled study involving 2867 subjects from regions of endemicity showed no benefit of the formalin-killed spherule vaccine in preventing coccidioidomycosis [30]. The frequency of definite coccidioidomycosis was ∼1%, emphasizing the need for large numbers of subjects to demonstrate vaccine efficacy. Additional candidate vaccines for coccidioidomycosis are being developed [31]. Studies of adjunctive immunotherapy for established infection should target specific well-defined patient groups to maximize the likelihood of detecting a treatment effect. Kullberg, et al. [32] reasonably suggest that phase I and II studies of immunotherapies should focus on laboratory surrogates that are likely to predict efficacy (e.g., augmenting Th1 responses), which would pave the way to larger studies that evaluate clinically relevant end points (e.g., survival and resolution of infection). Funding for clinical trials of novel antifungal therapeutics may be the most important hurdle. Vaccines targeted to pathogens that affect a broad segment of the general population have more attractive marketing potential than do vaccines for opportunistic fungal pathogens that affect only those individuals with severe defects in the immune system. Bringing promising, novel antifungal immunotherapeutic to clinical trials and to market will likely require creative partnerships between academia, industry, and government.

Immune response against fungal infections

For all pathogens discussed in this review an interconnected innate and adaptive immune response is necessary for the resolution of the infection [6].

Innate response-The innate response against fungi is designed to be as efficient as possible and also stimulates several responses mediated by the adaptive immune system [33]. The first lines of defense are physical barriers, like the skin and mucosal epithelial surfaces in the sites of the body that are constantly being exposed to environmental organisms, including sites such as the mouth, the upper airways and the gastrointestinal and genitourinary tract [34]. The epithelium also has an important role by actively discriminating commensal fungi, such as C. albicans, which occurs in a nonpathogenic and pathogenic form [35].

Adaptive response-After stimulation of the innate immune system, it is essential that T-cells are activated for a successful elimination and development of protective immunity against fungi [36]. Hence, the majority of invasive fungal infections occur in condition of T-cell deficiency. The specific cytokines expressed by APCs cells like DCs and macrophages are crucial for the differentiation of CD4+ T-cells (T-helper cells) [37-39].

Since the kingdom Fungi besets a heterogeneous group of organisms, it is expected that each one will elicit a different immunological response (Table 1).

Competing Interests

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The authors declare that they have no competing interests.

Authors' Contribution

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GT, GG wrote and edited the manuscript. All authors read and approved the final manuscript.

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