Protective efficacy of mutant strains of Borrelia burgdorferi as potential reservoir host-targeted biologics against Lyme disease.

Lyme disease (LD), caused by Borrelia burgdorferi (Bb), is the most common vector-borne disease in the United States. Novel strategies to control transmission of Bb to humans via ticks are critical for the prevention of LD. One such strategy is to leverage non-infectious mutant strains of Bb for pathogen-derived biologics to block Bb transmission during the natural infectious cycle. Deletion of Borrelia host-adaptation Regulator (ΔbadR) and replacement of eight conserved residues with alanines in Carbon Storage Regulator A of Bb (8S) resulted in mutants with upregulation of RpoS and several immunogenic lipoproteins, that were incapable of colonization in C3H/HeN mice. Intradermal vaccination of mice with the live mutant strains resulted in significant anti-borrelial antibody responses and a reduction in Bb acquisition by naïve Ixodes scapularis larvae following needle challenge with Bb B31-A3. While vaccination with the ΔbadR mutant conferred a significant reduction in the percentage of infected mice, ML23 and 8S mutants conferred variable levels of protection. Comparative proteomic analysis of purified borrelial lipoproteins (PBLs) from parental and mutant strains revealed similar and unique antigenic components. Infection-derived mouse serum and serum from Lyme disease patients exhibited reactivity to lysates and PBLs from these mutants. Immunization with PBLs from B31-A3 and 8S strains conferred significant protection against challenge with Bb-infected nymphs, underscoring the utility of PBLs as protective formulations. Overall, non-infectious mutant strains, or their lipoproteins, can be exploited as biologics to block the acquisition of Bb by naïve larvae from reservoir hosts, thereby disrupting the enzootic transmission cycle of the agent of Lyme disease.