R01AI152209

Heritable Immunization of the White-Footed Mouse Reservoir of Lyme Disease - Project Summary

RFA-AI-19-037

The rising incidence of Lyme disease demands new strategies for prevention. Existing methods such as acaricides, deer reduction, landscaping, and personal protective clothing are inherently short-term and must be regularly re-applied, maintained, and worn. The Mice Against Ticks project seeks to develop a durable one-time intervention to disrupt the ecological cycle of Lyme disease transmission for many decades.

The causative agent of Lyme disease, B. burgdorferi, is passed back and forth between ticks and their small animal hosts, which serve as zoonotic reservoirs of the disease. The white-footed mouse, P. leucopus, is widely considered to be the most important reservoir because it is both ubiquitous and extremely efficient at acquiring and transmitting pathogens via ticks.

Our overarching goal for this proposed project is to heritably immunize white-footed mice against Lyme by encoding protective P. leucopus antibodies targeting B. burgdorferi outer surface protein A (OSPA) in the mouse germline. According to our calculations, combining at least four such antibodies should prevent evolutionary escape by B. burgdorferi because too many simultaneous OSPA mutations would be needed.

Crucially, even if these mice are less important in some areas than currently thought, immunization will reduce the number of infected ticks, which in turn will infect fewer secondary reservoirs, ultimately leading to a reduction in the local burden of Lyme disease. We have already successfully isolated anti-OSPA antibodies from OSPA-immunized P. leucopus, derived putative P. leucopus embryonic stem cells, and shown that the albumin locus appears suitable for antibody secretion from the liver.

We now seek to:

1. Identify antibodies that bind to at least four different OSPA epitopes.
2. Establish a stable embryonic stem cell line and perform germline editing.
3. Generate heritably resistant mice that express antibodies from a cisgenic cassette linked to a reciprocal chromosomal translocation, a naturally occurring form of high-threshold gene drive that would enable the reversible and tightly localized engineering of wild P. leucopus populations.

Our open and community-guided approach has met with apparent enthusiasm by residents of Nantucket and Martha's Vineyard, indicating that local communities suffering from tick-borne diseases throughout the Northeast and Upper Midwest may wish to immunize their own wild mouse populations in order to help prevent Lyme disease for many decades.

Massachusetts Institute Of Technology

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Cambridge, Massachusetts 021394301 United States

Single Zip Code

Targeted Prevention for Tickborne Diseases (R01 Clinical Trial Not Allowed) (RFA-AI-19-037)

Amendment Since initial award the total obligations have increased 300% from $957,529 to $3,832,530.