Lyme disease is a bacterial infection that is transmitted through the bite of Ixodes ticks infected with Borrelia spirochetes. According to the Centers for Disease Control and Prevention, over 300,000 Americans are diagnosed with Lyme disease each year, yet there are currently no effective strategies available in the United States to prevent human Lyme disease. Direct administration of antibodies has been shown to be a safe and effective method to prevent other infections, such as respiratory syncytial virus infection in premature infants. A similar strategy could be used to prevent infections due to pathogens that cause Lyme disease. Serum concentrations of antibodies against outer surface protein A (OspA) of Borrelia have been shown to correlate with protection from infection with Borrelia. A bactericidal antibody against OspA of Borrelia may therefore be an effective therapeutic drug to prevent Lyme disease. Such a prophylactic antibody, administered in geographic areas where Lyme disease is endemic, could protect individuals from becoming infected with Borrelia during the 6-month peak risk period.

We have recently developed a panel of half-life extended OspA-specific human monoclonal antibodies (HuMabs) that, when administered to mice, are 100% effective in preventing tick transmission of Borrelia burgdorferi to the mice. The goal of this proposal is to demonstrate that this protection translates into a nonhuman primate model for Lyme disease as a preparation for clinical trials. We plan to test the modified anti-OspA antibodies in nonhuman primates to choose a lead antibody and then to determine the minimum serum concentration needed to provide effective protection for the entire ~6-month period of risk. We predict that the modified human monoclonal anti-OspA antibody will protect animals from Borrelia-infected tick challenge and maintain protective antibody serum concentrations in nonhuman primates. We will also investigate the potency of optimized OspA-specific HuMabs using human serum samples in tick feeding models and passive mouse transfer experiment, which could be developed into a surrogate marker as an efficacy endpoint for clinical trials.

This proposal addresses the Prevention Focus Area of the Program Announcement, as the resulting antibody could be administered in endemic areas prior to the tick season for long-term protection against Lyme disease, thereby fulfilling an unmet medical need for the American public. Furthermore, this novel antibody-based preventive drug for Lyme disease has several advantages over conventional vaccine-based immunization, including safety, immediate protection, and independence from age-dependent responses.

The experimental results and methods developed from this proposal will be directly applicable to subsequent clinical trials. Through our proposed research, we will establish the feasibility of using HuMabs for disease prevention, thereby providing a promising strategy to prevent human Lyme disease, as well as a proof-of-concept for other tick-borne illnesses.