Morbidity and mortality from invasive fungal infections remain unacceptably high despite availability of new antifungal agents, underscoring the need for more effective preventative strategies. For example, hematogenously disseminated candidiasis is a life-threatening disease and remains the third most common bloodstream infection in hospitalized patients both in the United States and many European countries. Our strategy for disease management is prevention, rather than treatment, through immunization or administration of preformed antibodies. Novel fully synthetic peptide and glycopeptide vaccines against Candida albicans cell surface epitopes have been successfully used to combat disseminated candidiasis in mice in our lab. Strong evidences show that antibodies specific for the peptide Fba (derived from C. albicans cell surface protein fructose bisphosphate aldolase) and C. albicans cell surface ?-1, 2-mannotriose [?-(Man)3]) contribute to the protection. Most recently, we demonstrated that addition of tetanus toxoid to the synthetic glycopeptide conjugate vaccine induced antibody-dependent protective immunity without the need for adjuvant, which are a novel observation and a major step forward in a vaccine for human use. The overall goal of this research is to preserve the duality of vaccine protection, and broaden the range of the protection against Candida species of medical significance.
In Aim 1, we will investigate peptides that are universally expressed in a variety of Candida species, and test new glycopeptide vaccines for efficacy in protecting against disseminated candidiasis.
In Aim 2, we will determine whether immunity established in normal mice protects the animals during a neutropenic episode. Neutropenia is one of the most common risk factor for the development of hematogenously disseminated candidiasis in humans. This study will address the fundamental question concerning vaccine induced immunity in high-risk populations.
Hematogenously disseminated candidiasis in humans has become the third leading cause of hospital-acquired blood stream infections and despite antifungal therapy at least 40% of affected individuals will die of this disease. Given their increasing frequency and unacceptably high morbidity and mortality rates, prevention of the disease has become of paramount importance. Our approach is disease prevention through active vaccination and/or passive immunization with antibodies. Our key finding is that a synthetic glycopeptides-TT conjugate vaccine induces antibody-dependent protection without the need for adjuvant. Thus, our new vaccine construct is novel and should be more amenable to widespread human use. This project seeks to maintain the dual protection of the vaccine efficacy, and broaden the range of induced protection against disseminated candidiasis caused by most medically important Candida spp. Fundamental questions will also be addressed as to whether an established antibody immunity against disseminated candidiasis will be sufficient to protect the host upon an immunocompromised event later. The work may well have far-reaching implications on vaccines and antibodies against infectious agents in general.