Evaluation of OspC as a Vaccine Antigen for Lyme Disease

Abstract

Lyme disease (LD), caused by bacteria of the Borrelia burgdorferi sensu lato complex, is the most common vector-borne illness in North America. While effective antibiotic treatments are available for LD, 10-20% of patients will develop post-treatment Lyme disease syndrome, significantly reducing their quality of life and emphasizing the need for novel prophylactics. Notably, there is currently no commercially available vaccine for the prevention of LD in humans. Outer surface protein C (OspC), an immunogenic lipoprotein found on the surface of B. burgdorferi, is a promising antigen for LD vaccine development as it is highly expressed by the bacteria during early mammalian infection. However, the development of a broadly protective OspC-targeting vaccine is challenged by the vast antigenic variation of OspC, with over 20 different ospC major allele groups.

In this thesis, I evaluate the protective efficacy of LD vaccines targeting OspC using a variety of next-generation vaccine platforms in a C3H/HeN mouse model. I demonstrate that monovalent DNA and mRNA vaccines encoding OspC type A delivered by lipid nanoparticles (LNPs) elicit a functional OspC-specific antibody response that confers complete protection against homologous B. burgdorferi infection, dissemination, and pathologies. This work highlights the applicability of clinically approved LNP formulations for the delivery of pDNA vaccines in addition to conventional RNA payloads. Furthermore, I show that a modified vaccinia virus-vectored vaccine encoding OspC type A can confer complete protection against homologous B. burgdorferi infection comparable to a veterinary LD vaccine through the induction of potent OspC-specific antibody and CD4+ T cell responses.

Finally, this thesis demonstrates the protective efficacy of a polyvalent mRNA vaccine encoding five common OspC types. The optimal LNP formulation was first evaluated by comparing the potency, expression kinetics, biodistribution, and immunogenicity of different LNP formulations delivering either DNA or mRNA encoding firefly luciferase. Additionally, the infection profiles of the five corresponding B. burgdorferi strains were characterized to identify strain-specific differences before systematic challenge of the pentavalent OspC mRNA vaccine. The candidate mRNA vaccine afforded protection against multiple strains expressing different OspC types and reduced associated pathologies. This study is the first demonstration of multi-strain protection of an OspC vaccine in the absence of outer surface protein A. Overall, this thesis illustrates the efficacy and immune mechanisms of next-generation vaccines targeting OspC and provides a foundation for the rational design of future LD vaccines.