MOLECULAR SWITCH VACCINES FOR BIODEFENSE, CANCER, AND INFECTIOUS DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This study will evaluate a novel vaccine platform based on an attenuate strain of Listeria in rhesus macaques. Dr. Lanford is the SNPRC investigator with Dr Gauduin as a collaborator, and Dr.Dirk Brockstedt is the PI from Aduro. The program will conduct safety and immunogenicity studies in 20 adult rhesus macaques, with live-attenuated and photochemically inactivated (known as Killed But Metabolically Active or KBMA) Listeria vaccine engineered to expressed designated HCV consensus sequence antigens and HIV gag. The study will divide the animals into 5 groups of 4 based on dose and route of administration. Blood and lymph node biopsies will be taken during the course of the study and examined for T cell responses to HCV and HIV by ELISPOT and Flow. The HIV antigen is included for comparison of potency with HCV, since a large volume of data is available for the response to gag in macaques. The live-attenuated strain of Listeria (known as CRS-100 or ANZ-100) has deletions in two genes encoding virulence determinants ActA and InternalinB resulting in 1,000-fold attenuation compared to wild-type Lm. In the proposed studies, the Listeria vectors will be given at doses up to 1E+9 by intravenous infusion (shown to be well-tolerated in GLP studies conducted in cynomolgus monkeys), or 1E+10 by intramuscular injection. The animals will be monitored for CBC, blood chemistries, cytokine-chemokine induction, and vaccine-induced HCV/HIV-specific cellular immunity. We hypothesize that the combination of HCV antigens based on the consensus sequence together with a vaccine platform that naturally targets the innate and acquired immune response to the virus reservoir in the liver will result in the Lm-based vaccines being an effective therapy for individuals with chronic HCV infection. This platform can be used to simultaneously deliver the antigens from multiple pathogens.