Powassan virus is an emerging virus that is transmitted to people when they are bitten by a tick carrying the virus. Recently, the number of cases has been increasing, with cases reported in the Great Lakes and northeast areas of the United States, Canada, and Russia. Although infection with Powassan virus sometimes causes no symptoms, it can result in symptoms ranging from mild illness with fever and headache, to infection of the brain and spinal cord, causing severe neurological symptoms including vomiting, weakness, incoordination, seizures, speech difficulties, and even death. For survivors of the severe disease symptoms, up to 50% are left with long-term symptoms, including memory loss and weakness. There is no vaccine or specific treatment available to counteract the virus and its associated symptoms. This project directly addresses the Fiscal Year 2018 Tick-Borne Disease Research Program (TBDRP) Focus Area of Prevention, since the goal is the development of a human vaccine for a tick-borne disease. The studies will also add to our knowledge about whether prior infection or vaccination with Powassan virus can lead to protective immunity and thus impacts the Focus Area of Pathogenesis and the understanding of mechanisms of immune protection.

Troops and civilians are potentially exposed to Powassan virus when they encounter ticks in grassy and wooded areas. Transmission can occur as rapidly as within 15 minutes of tick attachment. Prevention of Powassan infection presently consists of avoiding tick bites through the use of insecticide treated clothing and DEET-containing insect repellents and the use of insecticide treated netting for sleeping. However, given the potentially severe disease that can occur and the lack of any effective treatment, the development of treatments and additional preventative measures is a high priority. Here, two different approaches will be taken to develop possible vaccine candidate strains of Powassan virus. The first will utilize the highly effective live-attenuated yellow fever vaccine and modify it to express Powassan virus proteins so that immunity to Powassan virus will develop upon vaccination. The second will modify the Powassan virus genome sequences to make it more susceptible to the body's immune responses and thus weaken its ability to replicate and cause disease symptoms. Candidate strains will then be tested in a mouse model, in which the wildtype Powassan virus causes severe symptoms and death, to determine if the disease symptoms are reduced and if vaccination with the weakened strains can protect against challenge with the virulent wildtype virus.

The central critical problem is that Service members and civilians are at risk for Powassan virus disease, for which there is no treatment and the outcome can be deadly. This work, which is preclinical in nature, will develop and test in a mouse model possible vaccine strains that can be further developed in future studies for eventual use as a preventative vaccine to protect our troops and civilians from Powassan. Thus, the long-term impact will be to alter clinical outcomes after Powassan virus infection through the prevention of this potentially deadly disease, thus alleviating illness and suffering. At this time, we are unable to project the time needed to achieve a patient-related outcome. Interim outcomes that this project will provide are live-attenuated vaccine candidates with demonstrated efficacy in a murine model. The work will advance the field of tick-borne diseases research by providing candidate vaccine strains that can be used to study viral and host factors important for causing disease or providing protection from Powassan virus disease, which is currently poorly understood. This could ultimately lead to additional treatment or preventative measures. The work will also provide preclinical candidate vaccine strains that can be further characterized and directly developed for use in humans.