Candida species are opportunistic fungal pathogens that are among the most common causes of nosocomial infections. Candida is the third most common organism recovered from the blood of hospitalized patients. Even with modern antifungal therapy, disseminated candidiasis has an unacceptable mortality of 40%-50% and resistance to conventional antifungal therapies is rising. Thus, a vaccine to prevent life threatening Candida infections in patients who are acutely at risk is particularly attractive. Scientists at NovaDigm have isolated two proteins, Als1p and Als3p, that are strong adhesins for Candida albicans to human cells. When combined with complete Freund's adjuvant (CFA), these vaccines result in significant protection against disseminated and mucosal candidiasis in animal models. The mechanism of protection is vaccine-mediated induction of Type 1 (high IFN-?), T-cell-mediated immunity. Additionally, based on homology studies of Als tertiary structure to surface adhesins expressed on Staphylococcus aureus, we demonstrated that Als vaccination also improves survival in a murine model of disseminated staphylococcemia. Our group is focused on development of novel vaccine technologies and adjuvants which enhance Als vaccine efficacy, are less toxic than CFA, and are suitable for direct translation to clinical trials. Here we propose the use of a live, immunostimulatory bacterium as an adjuvant-antigen delivery vehicle to induce cell-mediated immune responses against Candida. Listeria monocytogenes is an intracellular bacterium that triggers potent host innate and adaptive immune responses that are required for clearance of the organism. Bacterial motifs recognized by both external toll-like receptors (TLRs) and intracellular receptors, NODs, activate innate immune cells and induce a robust Type 1 immune response. These features make it an ideal vaccine delivery vector. Our group has previously capitalized on these properties to successfully develop this bacterium as a vaccine against specific viral, protozoan, and neoplastic targets. Additionally, attenuated recombinant Listeria (rLM) strains that can not replicate have been created that have substantially decreased virulence while maintaining vaccine immunogenicity. Thus, rLM vaccines expressing heterologous antigens are currently a realistic approach to immunization against various infectious agents and cancer and are currently in Phase I studies under the direction of our collaborators. We hypothesize that delivery of the Candida adhesion protein Als3p by Listeria monocytogenes will result in specific cell-mediated immune responses against Als3p that will ultimately protect mice against candidiasis or staphylococcemia. To test this hypothesis, we will provide proof of concept by engineering rLM strains expressing the Als3p antigen. We will define initial characteristics of the vaccine strains, including the antigen-specific cellular responses in mice and will perform pilot studies to determine the effectiveness of these vaccines in mice to protect against Candida challenge. Successful completion of these studies will lead directly to Phase II STTR studies to determine protective efficacy in candidiasis and staphylococcemia animal models.
Public Health Relevance: Candidiasis is an opportunistic fungal infection that is among the most common infections in hospitalized patients - mortality from candidiasis is near 50% and no effective vaccine is available. NovaDigm has developed a highly promising vaccine for Candida based on the Candida Als3p protein. We have previously expressed proteins in the bacterium Listeria in order to boost their immune stimulation to serve as vaccines against infections and cancers. We propose to engineer recombinant Listeria expressing the Candida protein Als3p and to test this live bacterial vaccine for its ability to stimulate an immune response against Als3p and to protect against Candida infection in mice. Successful completion of these studies will enable development of the vaccine in a future Phase II proposal.
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