Our long-term goal is sustainable reduction of the incidence of Lyme borreliosis (LB). We propose to achieve this safely and inexpensively by targeting vaccines to the reservoir hosts of the agent Borrelia burgdorferi. Building upon our proof-of-concept studies and extending the work's scope to include further definition of the key reservoir species, we will develop live attenuated vaccines for oral delivery in the field and initiate controlled vaccine trials at field sites. The field studies will also inform implementation of a reservoir-targeted plague vaccine (Project 7.3). This is a multidisciplinary, multi-institution translational research project.
Specific aim 1 is further development of a vaccine that uses the vaccinia virus backbone of the commercial rabies vaccine to express OspA of B. burgdorferi and to (a) administer this to a major reservoir, the white-footed mouse, Peromyscus leucopus, and (b) evaluate different methods of field delivery of the vaccine. These studies will be carried out in collaboration with industrial partners Merial for the vaccine construct and with Foodsource Lures Corp for the bait. The primary endpoint for will be the prevalence of B. burgdorferi in nymphs of Ixodes scapularis after they fed on infected P. leucopus as larvae. This will be assessed by quantitative PCR of host-seeking nymphs in the spring of the year after vaccination. In years 3-5 these studies will be extended to include second generation poxvirus-based constructs (Project 7.2) or, as an alternative, Salmonella-based oral vaccines (Project 7.4).
Specific aim 2 is assessment of the effectiveness of the oral vaccines from Aim 1 in controlled field trials on an island site off New England. The vaccine will first be directly administered to captured P. leucopus and then in a second trial by distributed bait with vaccine. In subsequent years vaccine targeting of P. leucopus will continue and will be extended to other reservoir species, as indicated by Aim 3, and on a mainland site.
Specific aim 3 is determination of which vertebrate species besides P. leucopus are major source of infection for larval ticks and, as such, would be additional targets for vaccination for effecting reduction in nymphal infection. For this, we will individual nymphal ticks for B. burgdorferi and for identity of the species that was the source of the blood meal for the larval stage of the tick. The source of residual blood proteins and/or mitochondria! DNA will be identified by mass spectrometry of peptide digests and/or by PCR.

Public Health Relevance

Lyme borreliosis, a high-priority emerging disease, is the most common vector-borne infection in the U.S. and Europe. Interventions with repellents, deer culls, pesticides, and landscape management have benefit but the effects are limited. As a novel disease prevention strategy, we will target anti-B. burgdorferi vaccines not to humans but instead to the animal reservoirs of the pathogen in nature. This is analogous to the successful strategy of preventing rabies in humans by immunizing wildlife reservoirs with a vaccine in bait.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-09
Application #
8462557
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$121,917
Indirect Cost
$12,197
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Waggoner, Jesse J; Gresh, Lionel; Mohamed-Hadley, Alisha et al. (2016) Single-Reaction Multiplex Reverse Transcription PCR for Detection of Zika, Chikungunya, and Dengue Viruses. Emerg Infect Dis 22:1295-7
Ziegler, Christopher M; Eisenhauer, Philip; Bruce, Emily A et al. (2016) The Lymphocytic Choriomeningitis Virus Matrix Protein PPXY Late Domain Drives the Production of Defective Interfering Particles. PLoS Pathog 12:e1005501
Barbour, Alan G (2016) Infection resistance and tolerance in Peromyscus spp., natural reservoirs of microbes that are virulent for humans. Semin Cell Dev Biol :
Park, Arnold; Yun, Tatyana; Hill, Terence E et al. (2016) Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality. J Gen Virol 97:839-43
Levin, Mattias; King, Jasmine J; Glanville, Jacob et al. (2016) Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy. J Allergy Clin Immunol 137:1535-44
Chomel, Bruno B; Molia, Sophie; Kasten, Rickie W et al. (2016) Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. PLoS One 11:e0148299
Kern, Aurelie; Zhou, Chensheng W; Jia, Feng et al. (2016) Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release. Vaccine 34:4507-13
Zeltina, Antra; Bowden, Thomas A; Lee, Benhur (2016) Emerging Paramyxoviruses: Receptor Tropism and Zoonotic Potential. PLoS Pathog 12:e1005390
Waggoner, Jesse J; Ballesteros, Gabriela; Gresh, Lionel et al. (2016) Clinical evaluation of a single-reaction real-time RT-PCR for pan-dengue and chikungunya virus detection. J Clin Virol 78:57-61
Sanman, Laura E; Qian, Yu; Eisele, Nicholas A et al. (2016) Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife 5:e13663

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