Heritable immunization of mice against Lyme disease enables ecological disease prevention.

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.