Safety and Immunogenicity of novel, live-attenuated V4020 vaccine for Venezuelan Equine Encephalitis (VEE) in healthy adults

ABSTRACT Venezuelan Equine Encephalitis virus (VEEV) is a life-threatening, NIH/NIAID category B human pathogen and a potential bioterrorism threat. Outbreaks of VEEV occur in Central America and have previously spread into the United States. The potentially devastating effects of VEEV reemergence in the U.S. demand an effective vaccine to protect immunologically naïve population. Currently, live attenuated TC-83 vaccine is used under IND protocol for vaccination of medical personnel at risk. The vaccine causes adverse effects, and efforts to develop an improved VEEV vaccine are underway. However, because vaccine development is a lengthy process and the supply of TC-83 vaccine is limited, the U.S. may soon experience a shortage of the VEEV vaccine. This can leave the U.S. population and at-risk personnel unprotected. Furthermore, in the absence of a vaccine, VEEV may fit the CDC definition of a BSL4 Select Agent. During previous NIH-supported research, Medigen evaluated a new platform technology for the development of vaccines against VEEV and, potentially, other viral diseases. The proposed V4020 vaccine includes attenuating rearrangement of the capsid and glycoprotein genes within the full-length genomic RNA. The attenuating rearrangement effectively prevents reversion because many independent mutations would be needed to revert to the pathogenic genotype. In addition, vaccine is made from a DNA copy of the rearranged RNA genome placed in the iDNA® infectious clone downstream from the CMV promoter. The key feature of iDNA infectious clone (and the difference from standard cDNA clone) is that live attenuated virus is launched from the plasmid, without the need for in vitro transcription. The use of genetically stable iDNA improves vaccine safety. In preliminary research, the V4020 virus containing rearranged genomic RNA and prepared from iDNA clone showed safety advantages and protection against VEEV challenges in BALB/c mice and in a cynomolgus macaque non-human primate (NHP) model. Specific Aim 1. Safety of V4020 live-attenuated VEEV vaccine in human subjects. Medigen in collaboration with U.S. Army Medical Research Institute for Infectious diseases (USAMRIID), to conduct Phase 1a, first-in- human study evaluating safety of V4020 VEEV vaccine in healthy adults. We propose a double blinded, placebo controlled, single-dose escalation study in 39 healthy adults, 18-50 years of age. Medigen will manufacture cGMP lot of V4020 vaccine and communicate with the FDA regarding clinical trial design. Groups of volunteers (13 subjects/group) will receive a single 104, 105, or 106 PFU dose of V4020 vaccine (10/group), with 3 subjects from each group randomized to receive placebo. The low dose will be administered first, and there will be at least 14 days delay before another group will start receiving the higher dose of vaccine. The study is designed to assess the safety of V4020 vaccine administered by subcutaneous (SC) administration. Specific Aim 2. Evaluate immune responses from human subjects vaccinated with V4020. In this aim, we will evaluate clinical samples (plasma, saliva, urine) to be collected during the clinical study to identify a dosing regimen that provides a multi-faceted immune response (neutralizing antibody, T-cell response, cytokines, etc). Putative early signatures will be identified that could be used to predict later immunogenicity and obtain insight into mechanisms of V4020 immunogenicity in human subjects. Our preliminary data suggest that the rational design, attenuating rearrangement, and iDNA technology can provide a safe and effective solution for V4020 VEEV vaccine by improving safety, genetic stability, and immunogenicity. Furthermore, the attenuating rearrangement can be easily adapted for the development of other vaccines including preparation of live attenuated vaccines for WEEV, EEEV, other alphaviruses, and other RNA viruses. If successful, this technology can potentially transform the field of live attenuated vaccines for many viral diseases.