Candida is the most common cause of invasive fungal infections in the United States and in other countries with advanced medical care with $ billions/year in cost to the healthcare of the United States and mortality rates ranging between 30%-40%. Likewise, the significant public health impact of methicillin resistant Staphylococcus aureus (MRSA) infections has evolved extensively in recent years. Although often thought of as an infection confined to immunocompromised hosts, the majority of those who develop potentially life-threatening disseminated candidiasis are not immunosuppressed. Thus, the use of a targeted vaccine to prevent candidiasis is feasible and facilitated by the fact that clinical isk factors for developing candidiasis are well-defined. These risk groups are common to both S. aureus and Candida. We have made the discovery that C. albicans cell surface Als3p, which functions as an adhesin/invasin, is a viable vaccine candidate against infections caused by Candida spp. Importantly, this vaccine (which is composed of a recombinantly produced N-terminus of Als3p [rAls3p-N]) shares 3D structural homology with cell surface proteins of S. aureus. Indeed the rAls3p-N vaccine is protective in murine models of hematogenously disseminated staphylococcemia and SSSI. We formed NovaDigm Therapeutics Inc. to advance the candidate vaccine into clinical trials. Recently, we have successfully completed two Phase I clinical trials and have initiated a national Phase 1b/2a trial in recurrent vulvo-vaginal candidiasis, which includes efficacy analysis. Our preliminary data from serum and PBMCs samples collected during the two Phase 1 clinical trials, show that anti-Als3p antibodies generated by the vaccine are functional with enhanced opsonophagocytosis killing (OPK) of C. albicans and S. aureus. Further, these antibodies reduced C. albicans virulence functions including: adherence, invasion, subsequent damage to host cells, and reduced C. albicans adherence to plastic. Finally, the PBMCs collected from vaccinees had elevated production of interferon-? and IL-17 vs. PBMCs from placebo. We propose to build on these exciting data to further define the basic mechanisms of action of this vaccine in humans, by correlating in vitro functions of antibodies and PBMCs collected from patients vaccinated with rAls3p-N with the efficacy outcome from Phase 1b/2a trial. We will also characterize the antigens on S. aureus that cross react to human sera collected from individuals vaccinated by rAls3p-N. Our goal is to develop and maximize the efficacy of novel active and passive immunization strategies for Candida, and S. aureus infections.
These aims will leverage our unique resources from Phase I clinical trials showing that rAls3p-N vaccine was safe and immunogenic, and will further define the potential mechanisms of action of rAls3p-N for the first time in humans, using samples collected from Phase 1b/2a trial. They will create the foundation for development of additional immunotherapeutic modalities targeting Candida and S. aureus infections.
Current treatment options for Candida and Staphylococcus aureus infections are inadequate and frequently fail with cost estimated to be in the $ billions/ year in the United States alone. We have developed a vaccine (rAls3p-N) that targets both diseases have recently successfully completed two Phase I clinical trials and initiated a national Phase 1b/2a trial. Samples obtained from patients during the Phase 1b/2a trial will be used to study the mechanism of protection elicited by the vaccine in humans which will aid in further development of the vaccine.
|Uppuluri, Priya; Lin, Lin; Alqarihi, Abdullah et al. (2018) The Hyr1 protein from the fungus Candida albicans is a cross kingdom immunotherapeutic target for Acinetobacter bacterial infection. PLoS Pathog 14:e1007056|
|Uppuluri, Priya; Singh, Shakti; Alqarihi, Abdullah et al. (2018) Human Anti-Als3p Antibodies Are Surrogate Markers of NDV-3A Vaccine Efficacy Against Recurrent Vulvovaginal Candidiasis. Front Immunol 9:1349|
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|Ibrahim, Ashraf S; Luo, Guanpingsheng; Gebremariam, Teclegiorgis et al. (2013) NDV-3 protects mice from vulvovaginal candidiasis through T- and B-cell immune response. Vaccine 31:5549-56|
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