Tesfahuneygn and Gebreegziabher. Int J Trop Dis 2018, 1:005 Volume 1 | Issue 1 Open Access International Journal of Tropical Diseases REVIEW ARTICLE Development of Vaccination against Fungal Disease: A Review Article Gebrehiwet Tesfahuneygn* and Gebremichael Gebreegziabher Check for updates Tigray Health Research Institute, Ethiopia *Corresponding author: Gebrehiwet Tesfahuneygn, Tigray Health Research Institute, PO Box: 07, Ethiopia, Tel: +25134- 2-414330 vaccines has been a major barrier for other infectious Abstract agents including fungi, partly due to of our lack of Vaccines have been hailed as one of the greatest achieve- knowledge about the mechanisms that underpin pro- ments in the public health during the past century. So far, the development of safe and efficacious vaccines has been tective immunity. a major barrier for other infectious agents including fungi, Fungal diseases are epidemiological hallmarks of partly due to of our lack of knowledge about the mecha- nisms that underpin protective immunity. Although fungi are distinct settings of at risk patients; not only in terms of responsible for pulmonary manifestations and cutaneous their underlying condition but in the spectrum of dis- lesions in apparently immunocompetent individuals, their eases they develop [1,2]. Although fungi are responsible impact is most relevant in patients with severe immunocom- for pulmonary manifestations and cutaneous lesions in promised, in which they can cause severe, life-threatening forms of infection. As an increasing number of immunocom- apparently immunocompetent individuals, their impact promised individuals resulting from intensive chemotherapy is most relevant in patients with severe immune com- regimens, bone marrow or solid organ transplantation, and promised, in which they can cause severe, life-threat- autoimmune diseases have been witnessed in the last de- ening forms of infection. As an increasing number of im- cades, so has the incidence of fungal diseases. munocompromised individuals resulting from intensive Vaccine development is a priority for several fungal patho- chemotherapy regimens, bone marrow or solid organ gens, including C. albicans, C. neoformans, A. fumigatus, transplantation, and autoimmune diseases have been and dimorphic fungi. Many challenges confront vaccine de- velopment for fungi, including different host risk factors and witnessed in the last decades, so has the incidence of modes of fungal pathogenesis. No single antigen can be fungal diseases [1,2]. Regardless of hundreds of thou- expected to be used in a “pan-fungal” vaccine; rather, spe- sands of fungal species, only a few cause disease in cific tailored vaccines will be required for the major fungal humans. The most common fungi that infect humans pathogens. are Candida spp., Aspergillus fumigatus, Cryptococcus Immunotherapy can be evaluated as preventive or as ad- neoformans, Pneumocystis jiroveci (carinii) and the junctive therapy. Prevention should be targeted to patients thermally dimorphic fungi e.g. Histoplasma capsulatum, at significant risk for the infection of interest and should fo- cus on infections with significant morbidity or mortality that Blastomyces dermatitidis, Coccidioides posadasii, Pen- are inadequately covered by standard therapies. One chal- icillium marneffei and Paracoccidioides brasiliensis [3]. lenge relates to accrual of adequate numbers of patients in trials involving uncommon infections. Despite recent additions to our antifungal drug ar- mamentarium, success rates for many mycoses remain Introduction unacceptably low and antifungal drug therapy is often limited by toxicity, resistance and high cost. To circum- Vaccines have been hailed as one of the greatest vent these difficulties, alternative approaches to pre- achievements in the public health during the past cen- vention and treatment are being developed, including tury. So far, the development of safe and efficacious vaccines and passive immunotherapy. Citation: Tesfahuneygn G, Gebreegziabher G (2018) Development of Vaccination against Fungal Dis- ease: A Review Article. Int J Trop Dis 1:005. Accepted: August 23, 2018; Published: August 25, 2018 Copyright: © 2018 Tesfahuneygn G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Tesfahuneygn and Gebreegziabher. Int J Trop Dis 2018, 1:005 • Page 1 of 8 • Here, we review the progress of current research in that stimulated antibody titers (e.g., pneumococcus) or this field, discuss some of the potential obstacles to de- in the case of the bacillus Calmette-Guerin vaccine, de- veloping and marketing a protective antifungal vaccine. layed-type hypersensitivity responses. More recently, Vaccines against the fungi the concept of adjuvants has been expanded to include soluble mediators and antigenic carriers (e.g., endotox- In recent years, several studies in the field of medi- in, Flt3 ligand, and heat-shock protein) that activate an- cal mycology have been focused on the development of tigen-presenting cells and stimulate innate and cellular new vaccines against fungal pathogens. Many pertinent immunity [14]. Heat-shock proteins are an example of reviews and papers have been published with both new naturally produced proteins that have been exploited as strategies and challenges to the development of anti- vaccine adjuvants in cancer and infectious diseases [14- fungal vaccines due to the rise of dangerous systemic 20]. Heat-shock proteins exhibit powerful immunostim- fungal infections, especially related to immunocom- ulatory effects on dendritic cells in a TLR2- and TLR4-de- promised patients, premature infants, cancer patients pendent fashion [21,22] and induce antibody and type I and those with invasive treatments for long periods in cellular immunity that may be promising in fungal vac- hospital settings, which are known as high-risk groups cine development [23]. Fungi also produce heat shock [4-6]. High-risk groups in the past decades have been proteins that may be targets for vaccine development. expanding in number owing to advances in the medical Long, et al. [24] identified heat-shock protein 60 as the field, where new treatments to critical diseases, such as ligand on H. capsulatum that mediates binding to CD18 cancer, have arisen [7]. These treatments improve pa- receptors on human macrophages. Immunization with tient’s survival rates, but can also affect natural barriers recombinant heat shock protein 60 from H. capsulatum of the body or even significantly impact the competence conferred protection from a subsequent challenge in of the immune system of the individual, contributing to mice [25]. Paradoxically, vaccination may be useful to an increased vulnerability to infections caused by fungi attenuate pathological inflammatory responses or in- [8]. duce tolerance. Allergic bronchopulmonary aspergillo- sis develops from sensitization to airway A. fumigatus Vaccine development is a priority for several fun- antigens, leading to a Th2 CD4+ cell response charac- gal pathogens, including C. albicans [9], C. neoformans terized by secretion of IL-4, IL-5, and IL-13 [26]. T cells [10], A. fumigatus [6], and dimorphic fungi [11]. Many are the key components mediating allergic responses to challenges confront vaccine development for fungi, in- A. fumigatus antigens in mouse models of allergic bron- cluding different host risk factors and modes of fungal chopulmonary aspergillosis [27]. There is significant pathogenesis. No single antigen can be expected to be interest in immunotherapy for allergic bronchopulmo- used in a “pan-fungal” vaccine; rather, specific tailored nary aspergillosis, including the use of CpG sequences vaccines will be required for the major fungal pathogens [28], recombinant allergens, and peptides to induce [12]. tolerance, as well as antigenic and DNA-based vaccines One impediment to fungal vaccine development is aimed at controlling the Th2-mediated responses in al- that the patients who are most susceptible to oppor- lergic bronchopulmonary aspergillosis [29]. tunistic fungal infections are those least able to mount protective responses [13] showed that CD4+ T cells Challenges in Designing Mycological Immuno- were dispensable in vaccine immunity against pulmo- therapy Trials nary blastomycosis (an extracellular pathogen) and his- Immunotherapy can be evaluated as preventive or toplasmosis (a facultative intracellular pathogen) in im- as adjunctive therapy. Prevention should be targeted to munocompromised mice. CD8+ T cells, in the absence patients at significant risk for the infection of interest of CD4+ T cells, mediated vaccine-induced protection and should focus on infections with significant morbid- against these fungi, and protection by Blastomyces-im- ity or mortality that are inadequately covered by stan- mune CD8+ T cells could be adoptively transferred. dard therapies. These results contradict the dogma that induction of CD8+ T cell responses against exogenously processed One challenge relates to accrual of adequate num- antigens requires CD4+ T cells, and they provide en- bers of patients in trials involving uncommon infections. couragement for vaccine development for patients with Assuming a vaccine with 80% efficacy in preventing in- impaired CD4+ T cell immunity (e.g., patients with ad- vasive aspergillosis and a 5% frequency of invasive as- vanced AIDS). pergillosis in