Platform to Develop Live Attenuated Multivalent Vaccines Against Tick-Borne Pathogens
Abstract
Rationale, Scientific Objectives, Aims: The spread of diseases transmitted by insects and ticks (arthropods) is favored by global change such as a warming climate in North America that allows arthropods to be active for longer periods during the year, causing enhanced exposure of humans. Because of this, the number of patients with tick-borne diseases such as Lyme disease and human anaplasmosis has seen a steep increase since the turn of the century. Vaccines are an invaluable tool for prevention of infectious diseases, including those caused by agents carried by insects and ticks. The yellow fever vaccine is one of the oldest and most effective vaccines still in use today and is composed of a live virus grown under laboratory conditions that spontaneously mutated to lose its ability to cause inflammation of the brain in mice. It confers lifelong protection in humans. Although recent vaccines more commonly use synthetic proteins, because they are considered to be safe, live vaccines that only briefly infect without causing illness are the subject of renewed interest due to their superior efficacy and duration of protection. A modern example is the live typhoid vaccine. Important tick-borne diseases in the U.S. and the world are caused by bacteria that require a host cell for survival, much like a virus. Bacteria that cause deadly diseases like Rocky Mountain spotted fever, found in the U.S. mid-atlantic and south central states, and even in Minnesota, fall into this group. They also include the human anaplasmosis agent, Anaplasma phagocytophilum (Ap), which causes the second most common tick-borne disease in the U.S., an acute, potentially life-threatening illness sickening at least 2,000 persons a year, most likely an underestimate. Objective: We plan to create a vaccine against tick-borne diseases using a mild bacterium from this intracellular group, Rickettsia parkeri (Rp), that naturally protects against the much more dangerous disease agent causing Rocky Mountain spotted fever (RMSF) and related agents in Africa and Asia, causing spotted fevers and tick typhus. We will intentionally weaken Rp to only abortively infect laboratory mice, but for long enough to induce solid immunity. We further propose to engineer these bacteria to contain proteins of Ap so that the immunity induced would protect against RMSF and anaplasmosis. This will be accomplished using a flexible vaccine platform that could be adapted to other vaccine targets, e.g., human ehrlichiosis or tick-borne Powassan encephalitis, and other deadly viruses infecting people in Russia, Africa, and large parts of Asia. Specific Aims: (1) Produce weakened Rp with a consistent safety profile; (2) Transform Rp to contain and present immunity-stimulating portions of Ap proteins, generate stable vaccine candidates of safe Rp; and (3) Test the protective ability of weakened, Ap-protein supplemented Rp vaccine strains in mice exposed to spotted fever and Ap. Relevance: This project is relevant to and directly addresses the focus area "Vaccines and Prevention of Tick-borne Diseases" solicited by the TBDRP program. We propose to develop a live vaccine to protect against RMSF and other spotted fevers, as well as human anaplasmosis. The vaccine design is meant to allow a flexible design to add future protection against multiple arthropod-borne diseases, such as ehrlichiosis, scrub typhus, and tick-borne encephalitis. Impact on reducing health burden, improve welfare of military Service members and the American public: Vaccines are proven effective tools for prevention of diseases transmitted by insects and ticks, e.g., yellow fever and European tick-borne encephalitis. There are currently no vaccines against any tick-borne illnesses in the U.S. A weakened, safe, live vaccine that could be changed and expanded to provide protection against multiple diseases transmitted by arthropods in North and South America, Africa, and Asia would be very valuable. It would protect
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810319
Entities
People
- Ulrike Munderloh
Organizations
- United States Army
- University of Minnesota