These two grant requests present a disturbing picture of a virus that could turn the AIDS epidemic paradigm upside down.
DESCRIPTION (provided by applicant): Kaposi's sarcoma herpes virus (KSHV) also known as human herpes virus 8 (HHV-8) causes several cancers including Kaposi's sarcoma, primarily in immune-compromised patients. HHV-8 has been shown to be transmitted sexually, through saliva, and through infected blood and organs to recipients. While a number of serological assays have been devised in the research setting to detect HHV-8 infection, there are no FDA-approved assays. Furthermore, there is no gold standard diagnostic assay for HHV-8 infection and none are of adequate sensitivity and specificity to be used commercially for diagnostic or blood screening purposes. Nevertheless, these assays have revealed that as much as 3 to 5% of US blood donors have been infected with HHV-8, and some high-risk populations such as homosexual men, the HHV-8 prevalence is as high as 65%. Thus, there is a need for a commercial diagnostic to identify HHV-8 infected individuals to prevent further transmission of this virus within thegeneral population and immune-compromised individuals as well as into the general blood supply. The overall goal of this project is to develop a sensitive and specific serological multi-antigen assay for the detection of HHV-8 antibodies that can be usedcommercially to diagnose at-risk patients and identify blood/tissue donors with HHV-8 infection. Epiphany's first-generation HHV-8 enzyme- linked immunosorbent assay diagnostic (ELISA), composed of a single antigen assay and a dual antigen assay, provide gt80% sensitivity and 96% specificity in identifying HHV-8 infected individuals and thus one of the more sensitive diagnostics. However, to be a commercial success, the sensitivity and specificity needs to be improved which we propose by improving the quality and number of capture antigens. In our Phase I grant, we demonstrated the feasibility of our approach by identifying an improved K8.1 capture antigen expressed in a eukaryotic system. To further optimize the assay for commercial use, we will in Aim 1 expand our search for both improved and new capture antigens, then in Aim 2 we will develop a multi-antigen assay. In Aim 3 we will conduct pilot-scale production and beta testing of the diagnostic assay to determine the specificity and sensitivity of the assay by retrospective testing of clinical blood samples. Achieving the goals in this project would generate a commercial HHV-8 diagnostic test which will identify infected patients and donors to reduce transmission risk and to make the blood supply safer.PUBLIC HEALTH RELEVANCE: Infection with the herpes virus HHV-8, only discovered in 1994, may cause several cancers including Kaposi's sarcoma, especially in patients with weak immune systems such as those with HIV. HHV-8 can be transmitted sexually, through saliva, and via blood and organ donations and approximately up to 5% of blood donors in the US have been infected with HHV-8. The project proposes to develop for commercialization a blood test to identify HHV-8 infected individuals thereby providing a diagnosis for infected individuals to understand their risk and modify their behavior as well as make the blood supply much safer for high-risk individuals and blood recipients in general.
Project Summary Abstract
Kaposi's sarcoma herpes virus KSHV is an oncovirus that causes several cancers including Kaposi's sarcoma KS It is estimated that to of U S blood donors have been infected with KSHV yet in some high risk populations such as homosexual men prevalence is as high as In spite of HAART KS remains the second most common AIDS associated malignancy A third of AIDS KS cases now arise in individuals with relatively high CD cell counts and low HIV viral load A recent study has observed a continuing high prevalence and increased acquisition of KSHV in HIV infected persons on HAART The data clearly indicate that KS is still occurring in HIV infected individuals even in the context of successful HAART In immunosuppressed populations approximately in transplant patients will develop KS The prevalence of KSHV is responsible for the continuing incidence of KS and its associated reduction in life expectancy of HIV individuals Despite its strong disease association particularly in the HIV and immunosuppressed populations there is no FDA approved clinical diagnostic test for KSHV and consequently a significant unmet need remains for a simple cost effective commercially viable KSHV diagnostic kit that would be an essential component of any effort to control virus transmission and monitor serostatus of those already infected The ability to gauge the KSHV serostatus of an HIV individual would help clinicians make appropriate interventional choices to prevent KS onset The overall goal of this project is to develop a serological multi antigen assay for the detection of KSHV antibodies that can be used commercially to diagnose at risk patients and identify blood tissue donors with KSHV infection In prior SBIR Phase I and II work Epiphany developed a single well multi antigenic KSHV enzyme linked immunosorbent assay ELISA called Combo In screening a sera panel containing both KSHV true positives and normal low risk blood donors Combo was the only assay out of other independent ELISAs to detect all consensus KSHV samples with excellent specificity and sensitivity estimated andgt respectively For the next stage of the kit development it is critical to examine Comboandapos s performance against large sera banks of epidemiologically validated KSHV positive and negative controls with relevant confirmatory assays to establish the true effectiveness of the assay A collaborative consortium that merges Epiphany with the biomedical and clinical research capabilities of the University of Miami UofM Miller School of Medicine the Miami Center for AIDS Research CFAR and the labs of Dr Enrique A Mesri CFAR has been created Together Epiphany and Miami CFAR are uniquely equipped to achieve the following Aims In Aim synthetic manufacturing and analytical process development will be implemented followed by pilot production of a set of Combo diagnostic ELISA kits In Aim these kits will be assessed and optimized by screening retrospective clinical blood samples and serologically characterized plasma PMBCs and validated by western blot In Aim large scale kit production will commence Assay stability and validation studies will be performed A larger panel of HIV sera and tissues available to UofM CFAR its cores and transplant centers and national repositories will be massively screened to establish sensitivity and specificity Achieving the goals of this project will establish the clinical and commercial value of Combo ultimately resulting in the first FDA approved clinical diagnostic assay for KSHV Project Narrative Kaposiandapos s sarcoma herpes virus KSHV is an oncovirus that causes several cancers including Kaposiandapos s sarcoma KS especially in patients with weakened immune systems such as those infected with HIV Even in the age of HIV antiretroviral therapy KSHV co infection remains a serious health issue for the HIV positive population and is still the second most common cause of malignancies among AIDS patients Despite its strong disease association particularly in the HIV positive and immunosuppressed populations there is no FDA approved clinical diagnostic test for KSHV and consequently this project seeks to develop a simple cost effective commercially viable KSHV diagnostic assay kit that would be an essential component of any effort to control virus transmission and monitor serostatus of those already infected in order to help clinicians make appropriate interventional choices to prevent KSHV related disease
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