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.
|Gebremariam, Teclegiorgis; Lin, Lin; Liu, Mingfu et al. (2016) Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest 126:2280-94|
|Uppuluri, Priya; Lopez-Ribot, Jose L (2016) Go Forth and Colonize: Dispersal from Clinically Important Microbial Biofilms. PLoS Pathog 12:e1005397|
|Chan, Liana C; Chaili, Siyang; Filler, Scott G et al. (2015) Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus. Infect Immun 83:4427-37|
|Yeaman, Michael R; Filler, Scott G; Schmidt, Clint S et al. (2014) Applying Convergent Immunity to Innovative Vaccines Targeting Staphylococcus aureus. Front Immunol 5:463|
|Yeaman, Michael R; Filler, Scott G; Chaili, Siyang et al. (2014) Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection. Proc Natl Acad Sci U S A 111:E5555-63|
|Fu, Yue; Phan, Quynh T; Luo, Guanpingsheng et al. (2013) Investigation of the function of Candida albicans Als3 by heterologous expression in Candida glabrata. Infect Immun 81:2528-35|
|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|
|Schmidt, Clint S; White, C Jo; Ibrahim, Ashraf S et al. (2012) NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine 30:7594-600|
|Edwards Jr, John E (2012) Fungal cell wall vaccines: an update. J Med Microbiol 61:895-903|
|Luo, Guanpingsheng; Ibrahim, Ashraf S; French, Samuel W et al. (2011) Active and passive immunization with rHyr1p-N protects mice against hematogenously disseminated candidiasis. PLoS One 6:e25909|
Showing the most recent 10 out of 22 publications