A dramatic rise in the incidence of invasive fungal disease in recent years, as well as the emergence of drug resistant and previously rare fungal species, has highlighted the need for broadly effective new therapeutic and prophylactic antifungal treatment strategies (3-5). The increased incidence of invasive fungal infection is partly attributable to an increase in the immunocompromised patient population, owing to the growing number of patients with disease associated acquired immunodeficiencies, those in critical care units, patients undergoing surgery or immunosuppressive treatment, and those receiving organ or cellular transplant therapies. Importantly, the risk factors that predispose individuals to invasive fungal disease do not preclude the possibility of mounting an effective immune response and responding favorably to immunotherapy (6, 7), giving promise to the development of effective vaccine or immunotherapy based approaches to meet this underserved medical need.
The two most prevalent pathogenic fungi affecting humans, Aspergillus and Candida spp., account for an estimated 8-10% of all health care acquired infections, with an attributable mortality of 30-40% (5, 8). Candida species are the fourth leading cause of nosocomial sepsis cases in the US and the rising incidence of invasive fungal disease from all pathogenic fungi represents a significant healthcare burden worldwide. Excess healthcare costs due to increased length of stay and treatment of hospital acquired fungal infections are in the range of US$1 thousand million annually in the US alone. Furthermore, comprehensive antifungal susceptibility testing of clinical isolates has made it evident that, despite advances in safe and effective antifungal drugs, all classes of currently available antifungal agents are subject to the emergence of resistant strains (5). Cryptococcal meningitis, an infection with the fungus Cryptococcus also known as cryptococcosis, is a very serious opportunistic infection among people with advanced HIV/AIDS. Cryptococcosis is not contagious, meaning it cannot spread from person-to-person. Cryptococcal meningitis specifically occurs after Cryptococcus has spread from the lungs to the brain. A global problem, worldwide, approximately 1 million new cases of cryptococcal meningitis occur each year, resulting in 625,000 deaths. Most cases are opportunistic infections that occur among people with HIV/AIDS. Although the widespread availability of antiretroviral therapy (ART) in developed countries has helped reduce cryptococcal infections in these areas, it is still a major problem in developing countries where access to healthcare is limited. Throughout much of sub-Saharan Africa, for example, Cryptococcus is now the most common cause of adult meningitis. Cryptococcal meningitis is one of the leading causes of death in HIV/AIDS patients; in sub-Saharan Africa, it may kill as many people each year as tuberculosis. (24).
These significant challenges of combating fungal disease point to the critical need for a highly effective pan-fungal vaccine as a valuable component of the anti-fungal arsenal. To date, two fungal cell wall carbohydrate components, β-mannan and β-glucan, have been explored as targets for anti-fungal vaccination. Conjugate vaccines composed of either linear β-(1→3)-glucan or β-(1→2)-mannotriose have been shown to confer protection against fungal disease, with efficacy in both active and passive immunization (9-11). In animal models of fungal disease, the β-glucan vaccine proved effective against C. albicans, A. fumigatus, and C. neoformans, validating the possibility of successful vaccination against multiple, disparate fungal pathogens (9, 12). Nevertheless, the production of effective vaccine responses requires careful consideration of the fine structure of the target antigens, as there is mounting evidence that one mechanism of immune evasion employed by fungal pathogens is the expression of immunodominant epitopes that induce non-protective or inhibitory antibody responses. These decoy epitopes ablate the efficacy of responses toward protective epitopes. For example, vaccines composed of linear β-(1→3)-glucan epitopes produce protective responses, while vaccines composed of β-(1→3)-glucans with β-(1→6)-glucan branches produce antibodies to both structures but do not confer protection against fungal disease (13, 14).
Moreover, the fundamental utility of the vaccine is dependent on the universality of target antigens. For example, the β-(1→2)-mannotriose epitope does not appear in all Candida species and the vaccine antigen employing this epitope relies on protective peptide epitopes to expand its utility (10). Considering the limited distribution of some cell wall carbohydrate epitopes and in view of the mechanisms employed by fungal pathogens to avoid productive immune responses to cell wall components, there is a need for a universally effective fungal vaccine. This invention is designed to target highly conserved fungal cell wall carbohydrate epitopes in order to provide a pan-fungal vaccine.
Chitin has not been examined as an antifungal vaccine target, largely for reasons related to its highly insoluble nature. Methods available in the art for degrading chitin into soluble fragments are not stoichiometrically controlled and it is thus difficult to modulate the degree of depolymerization.
USPTO Backgrounds
USPTO Backgrounds