A double-blinded, placebo-controlled field trial of an OspA-based oral reservoir targeted vaccine against Borrelia burgdorferi

Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes scapularis ticks, remains a significant vector-borne illness in the United States. Small mammal reservoirs, particularly Peromyscus leucopus, play a critical role in B. burgdorferi maintenance. Here, we conducted a five-year, randomized, double-blinded, placebo-controlled field trial deploying an oral OspA-based reservoir-targeted vaccine (RTV) across seven Maryland sites. Bayesian modeling provided estimates of vaccine impact on mouse anti-OspA antibody levels, nymphal tick infection prevalence (NIP), mouse infection rates, and seroconversion to B. burgdorferi in hunting dogs. RTV sites exhibited an estimated 10.5% proportional increase in protective murine anti-OspA antibody levels and a 15.4% reduction in NIP by year five. We also found a lower infection prevalence in mouse blood-fed nymphal ticks (9.8%). RTV sites exhibited modest decreases in mouse infection prevalence, and dog seroconversion rates were similar between groups. Our results indicate that anti-OspA antibody in vaccinated-infected/uninfected P. leucopus reduced B. burgdorferi summertime larval infection prevalence, measured as NIP reductions the following spring. This suggests that OspA-based oral RTV reduces B. burgdorferi transstadial transmission within tick populations. Our findings advance the development of reservoir-targeted solutions for Lyme disease prevention. Further evaluation of impacts on incidental hosts is needed.