Exploring Dose and Schedule Variations of a Novel Dengue Antiviral Prophylaxis Intervention to Support US Military Operational Requirements

Overarching Challenge: The U.S. Service Member requires safe and efficacious dengue countermeasures (such as antivirals, immunotherapeutics, and vaccines) to eliminate or significantly mitigate the risk of dengue virus (DENV) infections and support readiness. There are an estimated 396 million DENV infections each year with 96 million causing clinical symptoms such as fever, headache, and bone pain. Dengue occurs locally in over 125 countries and more than 40% of the world's population lives at daily risk of infection. There is no licensed drug to prevent infection or treat someone who has already been infected and is experiencing symptoms. There is one U.S. FDA licensed dengue vaccine, but it is not indicated for the U.S. Service Member. Background: The DENVs are flaviviruses and once infected, a person may experience no clinical symptoms, a non-specific mild febrile illness, classic dengue fever, severe dengue with plasma leakage and/or hemorrhagic manifestations, and potentially death. In areas with less experience treating dengue, the mortality rate for severe dengue can be as high as 20%-30%. The seroprevalence rate of past DENV infection in a subgroup of U.S. Service Members was measured between 5% and 13% and the seroconversion rate during first time deployments was approximately 1.5%. Therefore, a large proportion of U.S. Service Members are at risk for DENV infection and some are at risk for second infections and severe disease associated with the same. Relevance to Topic Area: Our proposal directly responds to the topic area, "emerging infectious diseases." Hypothesis: We hypothesize that the pathophysiology of dengue disease is derived from DENV replication, infection of target cells, and the resulting pro-inflammatory immune cascade; as such, an antiviral compound that can prevent or substantially reduce DENV replication has the potential to prevent or significantly attenuate dengue disease. Therefore, we will demonstrate that the highest dose of an experimental Janssen Dengue Drug is superior to placebo with respect to its antiviral activity in healthy adult participants inoculated with Dengue 1 Live Virus Human Challenge (DENV-1-LVHC), as measured by area under the DENV-1 RNA VL concentration-time curves from immediately before inoculation (baseline on Day 1) until Day 29 (AUCD1-D29 [VL]). Specific Aims: We intend to compare RNAemia in recipients of the experimental Janssen Dengue Drug compared to placebo recipients who are then both experimentally infected with an attenuated live DENV-1 virus strain. We will assess the Area Under the RNAemia Curve as well as peak and mean RNAemia over time. Viremia will also be assessed in the same manner. Humoral and cellular immune responses following infection in the two groups will be explored as well as the difference in signs, symptoms, and lab abnormalities across the two groups. Genome sequences of potential breakthrough DENVs will also be analyzed as well as transcriptome profiles. Study Design: We intend to advance the development of the experimental Janssen Dengue Drug by testing different doses in a pre-exposure prophylaxis (PrEP) administration scenario and assessing its ability to prevent or substantially reduce dengue RNAemia caused by experimental infection with an attenuated live DENV-1 virus strain. Volunteers in a first cohort will be randomized to receive either the experimental Janssen Dengue Drug or placebo, after which all volunteers are experimentally infected with an attenuated, live DENV-1 virus strain known to cause mild to moderate and temporary dengue-like symptoms, lab abnormalities, RNAemia/viremia, and immune responses. Based on the results of the first cohort, doses of the experimental Janssen Dengue Drug candidate will be selected for testing in a second cohort with a focus on defining optimal pK/pD and dosing schedules. Data from cohort 2 will define the optimal target product profile for an operational military population. The team is requesting CDMRP resources to support only cohort 2. If the experimental Janssen Dengue Drug is able to prevent or reduce the expected outcomes of experimental infection, it will demonstrate potential for having clinical benefit with naturally acquired wild-type DENV infections. Military Relevance: There are very few places the U.S. military deploys where dengue in not endemic. The existing high operational tempo and frequent deployment and redeployment places Service Members at increased risk for infection, re-infection, and the potential for severe disease. Without effective dengue countermeasures, the mission is at risk. Our proposal is directly responsive to the DOD's requirements to develop effective countermeasures by using a novel research tool (experimental dengue infection) to advance the development of a potential anti-DENV prophylactic. Success would advance the development of the experimental Janssen Dengue Drug with the hopes of fielding an antiviral against DENV that could be used for prophylaxis as well as for treatment of dengue infections. In light of the challenges associated with developing dengue vaccines, parallel pursuit of alternative countermeasures (an antiviral against DENV) is required. Less