Abstract
Heritable immunization is a promising approach to controlling infectious diseases by embedding immunity directly into the genomes of wild species that spread human pathogens. Here, we report the genetic engineering of Mus musculus to genomically encode a single-chain antibody against Borrelia burgdorferi, the causative agent of Lyme disease. After optimization of the antibody format, engineered mice stably produce a LA-2 scFv-albumin fusion protein targeting the Borrelia outer surface protein A (OspA) across multiple generations, demonstrating robust heritability and stability of gene expression. Following sequential challenges with infected and uninfected ticks, heterozygous mice exhibit strong resistance to infection, effectively interrupting the Borrelia burgdorferi disease transmission cycle. Having recently established protocols to genetically engineer the white-footed mouse Peromyscus leucopus, a key reservoir of Lyme disease, these findings demonstrate the feasibility of heritable immunization as a potential strategy for mitigating Lyme disease transmission in the environment. Engineered reservoir immunity may offer a promising approach to controlling vector-borne and zoonotic disease.
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Acknowledgements
This work was supported by a Tick-Borne Disease Research Program Award from the Department of Defense’s Congressionally Directed Medical Research Program (Award # TB160101 W81XWH-17-1-0669 to KME), the National Institutes of Health (Award # R01 AI 152209 supporting all authors), the National Science Foundation (CAREER Award # 1943141 to KME), the Rainwater Charitable Foundation (to KME), The Michael R. Paine Conservation Trust (to KME) and Mice Against Ticks, Inc. (to KME). Additionally, this work was supported by Esvelt lab funding sources, including the MIT Media Lab (to KME), an Alfred P. Sloan Research Fellowship (to KME), gifts from the Open Philanthropy Project and the Aphorism Foundation (to KME), and the National Institute of Digestive and Kidney Diseases (R00 DK102669-01 to KME). JB was supported by the MIT Media Lab. EJC was partially supported by a Ruth L. Kirschstein NRSA fellowship from the National Cancer Institute (F32 CA247274-01).
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The Massachusetts Institute of Technology has submitted an international patent application to the USPTO on behalf of inventors JB and KME pertaining to the heritable immunization methods for disease control described in this work (application number PCT/US2025/059924). Additionally, JB serves as a director of the Mice Against Ticks nonprofit, and EJC serves as a consultant. The remaining authors declare no competing interests.
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Buchthal, J., Chory, E.J., Hill, Z. et al. Heritable immunization of mice against Lyme disease enables ecological disease prevention. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71757-6
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DOI: https://doi.org/10.1038/s41467-026-71757-6
