Vaccines for Prevention of RG3 and RG4 Emerging Tickborne Viral Diseases

PROJECT SUMMARY Tickborne illnesses continue to be a significant public health concern in the US and worldwide, as environmental and climate changes have allowed the dramatic expansion of ticks, tick habitats, and their mammalian hosts. In the New England region alone, Lone Star ticks were first reported in 2017, followed by the establishment of exotic Asian longhorned ticks in 2018. A recent CDC report indicates that tickborne diseases in the US have more than doubled from 2004 to 2016, accounting for 77% of all reported vector-borne diseases. The report also indicates that the US is not fully prepared to prevent and control these threats. A number of tickborne viruses that cause encephalitis and hemorrhagic fever in humans are of particular concern in the US, such as the re-emerging Powassan virus (POWV), as well as the recently discovered Heartland virus (HRTV). Another emerging tickborne virus in Asia is severe fever with thrombocytopenia syndrome virus (SFTSV), closely related to HRTV, which is transmitted by the Asian longhorned tick that is spreading rapidly and is now present in 12 US states. A number of additional exotic tickborne viral agents are of concern to the US, including tickborne encephalitis virus (TBEV), Omsk hemorrhagic fever virus (OHFV), and Crimean-Congo hemorrhagic fever virus (CCHFV). To better prepare for these emerging threats, we assembled a team of experts in (1) vaccine development at the University of Connecticut, (2) tickborne viruses at the Connecticut Agricultural Experiment Station, and (3) animal models in maximum biocontainment at the National Emerging Infectious Diseases Laboratories and propose the development and testing of vaccines for four Risk Group 3 (RG3) and RG4 tickborne encephalitis and hemorrhagic fever viruses classified as NIAID Category A or C Priority Pathogens, and prioritized by the WHO under its most recent 2018 Blueprint list of priority diseases in need of accelerated research and development. We developed a rapid method to generate vaccinia virus (VACV) vectors that will allow us to quickly test a number of tickborne viral genes to ensure robust expression of protective antigens and secretion of virus-like particles (VLPs). This platform is based on a gold-standard viral vector (VACV) that induces high levels of humoral and cell-mediated immune responses. These VACV vectors are replication-defective when administered as a vaccine, yet easy to propagate in standard cell culture at high titers, unlike other replication-defective poxvirus vectors such as MVA. We will also generate DNA- based vaccines and purified VLPs (as a subunit vaccine), so that three different classes of vaccine candidates can be tested for immunogenicity, either alone or in prime-boost regimens. Finally, we will test the efficacy of the vaccines using tick-transmission animal models to recapitulate the enhancement of transmission and dissemination that has been documented by tick feeding.