Development of a vaccination platform for emerging flavivirus infections

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Project Summary: The Flavivirus genus (referred to as flaviviruses) consists of numerous emerging and re-emerging global pathogens of critical human significance. Endemic and emerging flaviviruses like dengue virus (DENV), Powassan virus (POWV), Zika virus (ZIKV), West Nile virus, Japanese Encephalitis virus and Yellow fever virus continue to spread and cause significant human disease. We have used RNA structural data from a conserved 3’ untranslated region (UTR) pseudoknot called xrRNA1 to develop an attenuation approach in a highly conserved structural region of the flavivirus 3’UTR for vaccine development. This approach allows us to 1) swap out flavivirus structural genes in our clone to rapidly develop chimeric, attenuated flavivirus vaccines for mosquito-borne flaviviruses and 2) provides a conserved site for attenuation for tick-borne flaviviruses like POWV. Based on our preliminary data, we hypothesize that xrRNA1-mutant, attenuated flavivirus vaccines will be safe, immunogenic, and provide protection from challenge in murine models of flavivirus disease. The objective of the proposed studies is to complete pre-clinical development of the attenuated flavivirus vaccine approaches. We will complete our proposed work in three aims that will evaluate immunologic and virologic outcomes following virus challenge after vaccination with candidate ZIKV vaccine (Aim 1), DENV vaccine (Aim 2), and POWV vaccine (Aim 3). We have recently published our data showing attenuation and immunogenicity of mutant xrRNA1 ZIKV (X1) in pregnant and non-pregnant mice. In this proposal, we will first evaluate the efficacy of ZIKV X1 vaccine in pregnant and non-pregnant mice challenged with ZIKV and DENV. These studies will allow us to evaluate ZIKV vaccine efficacy during pregnancy and evaluate the role of ZIKV vaccination in DENV disease enhancement. Next, we will use the attenuated, ZIKV vaccine platform developed in our laboratory using xrRNA1 structural data, insert chimeric pre-membrane and envelope structural genes from DENV1-4 and evaluate the attenuation, immunogenicity and efficacy of monovalent and quadrivalent DENV1-4 vaccine candidates. Given the complexity of DENV infection, we will evaluate disease enhancement and immunodominance in our quadrivalent vaccines along with efficacy. Third, we will expand our attenuation strategy in the X1 structure to tick-borne flaviviruses by utilizing our recently defined secondary structure of the POWV 3’UTR. Using POWV mutant vaccine candidates with targeted mutations in the X1 structure, we will characterize attenuation, immunogenicity, and efficacy of a POWV vaccine approach in a murine model of disease. The proposed studies will begin to translate our structural understanding of xrRNAs in the flavivirus 3’UTR into potential vaccine candidates. Moreover, this project will initiate studies focused on developing a platform for vaccine development for emerging flavivirus infections.