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. My lab has successfully used novel fully synthetic peptide and glycopeptide vaccines against Candida albicans cell surface epitopes combat disseminated candidiasis in mice. 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. Therefore, this glycopeptide vaccine [ -(Man)3-Fba] is able to provide dual immune recognition to help ensure protective immunity against C. albicans. We also demonstrated that addition of tetanus toxoid to the synthetic glycopeptide conjugate vaccine ( -(Man)3-Fba-TT) induced antibody-dependent protective immunity without the need for adjuvant, which are a major step forward in a vaccine for human use. Most recently, we have identified a panel of novel peptide mimotopes, which structurally mimics protective epitope -(Man)3, as surrogate immunogens that substitute glycan part of glycopeptide vaccine. Strikingly, three of the peptide mimotopes were able to induce robust antibody responses and antibody-mediated protection in mice. The overall goal of this research is to design a new mimotope-peptide-TT vaccine feasible for human use, and further test the vaccine efficacy in a new mouse model that closely simulates humans by having protracted GI tract colonization with C. albicans.
In Aim 1, we will modify the glycopeptide conjugate -(Man)3-Fba by taking place of glycan part with newly identified peptide-mimotopes, and then the new mimotope-Fba conjugate vaccines will be tested for protective efficacy in mice.
Aim 2, mice will be modified to have protracted GI tract colonization with C. albicans, and vaccine efficacy will be tested under host conditions that more closely simulate those of humans.
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 protective antibodies. Our key finding is that a synthetic glycopeptides-TT conjugate vaccine induces dual antibody-dependent protection without the need for adjuvant. This project seeks to further improve the composition of the glycopeptide-TT vaccine by inducing a peptide mimotope to take the place of glycan part of the vaccine. This new strategy can lead to the new generation of double peptide conjugate vaccines; as well as making mass vaccination programmers; a reality for resource- limited developing countries where the burden of infectious disease is greatest. We will also utilize a new mouse model that more closely simulates humans to test vaccine efficacy; and address fundamental questions about vaccine and antibody protection in host colonized with C. albicans.
| Xin, Hong (2016) Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis. Vaccine 34:245-251 |
