Author ORCID Identifier

https://orcid.org/0000-0003-0644-6997

Semester

Summer

Date of Graduation

2026

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Mariette Barbier

Committee Member

Cory Robinson

Committee Member

Jennifer Franko

Committee Member

Paul Chantler

Committee Member

Nyles Charon

Abstract

Borrelia burgdorferi, the causative agent of Lyme disease (LD), is transmitted through the bite of infected Ixodes scapularis ticks as part of an enzootic cycle in which humans are incidental hosts. LD is a multi-system illness that impacts approximately 476,000 individuals annually in the U.S. and is often described as “The Great Imitator,” due to its highly variable, non-specific symptoms, ranging from flu-like to arthritic, cardiac, and neurologic manifestations. Once infected, immunity is not permanent and reinfection is possible upon additional tick bite(s). Current personal protective measures rely on individual behaviors, such as tick checks and avoiding tick-dense habitats, emphasizing the need for LD-directed prevention efforts, such as vaccines. LYMErix® was the only previously FDA-approved LD vaccine but was pulled from the market in 2002. While there are currently LD vaccines in clinical trials, to date, there is no FDA-approved LD vaccine available to the public. Vaccine development against B. burgdorferi is complex due to the lack of conventional vaccine targets and need to consider antigen expression at different stages of the enzootic cycle.  It is further limited by waning immunogenicity observed in recombinant protein-based platforms, such as LYMErix®. For these reasons, we sought to investigate immunogenicity and efficacy across a variety of vaccine platforms as well as a combination of antigens for the development of a multivalent vaccine against B. burgdorferi. We hypothesize that modification of the vaccine platform through which OspA is delivered can increase immunogenicity and efficacy of an OspA-based vaccine. Additionally, we propose that inclusion of additional antigens, upregulated in both the tick and mammalian host, is necessary to provide protection against LD transmission and disease progression. First, we developed a reliable B. burgdorferi murine challenge model to investigate correlates of infection, such as ankle swelling, that produced a clear, quantifiable disease phenotype to further evaluate vaccine-mediated protection. To determine the optimal platform for OspA delivery, immunogenicity and efficacy was compared among recombinant OspA genetically fused to a detoxified mutant of diphtheria toxin, a virus-like particle platform, and a selected mRNA-based vaccine construct. While all vaccine platforms were immunogenic, only rOspA and OspA-SpyVLP provided significant protection against B.  burgdorferi colonization. Furthermore, only rOspA, EcoCRM OspA, and OspA-SpyVLP elicited significant protection against B. burgdorferi-induced ankle swelling and OspA-SpyVLP-vaccinated mice produced the highest avidity and borreliacidal antibodies. Using the most promising platforms, recombinant protein and virus-like particles, we developed a quadrivalent vaccine formulation including OspA, OspC, Oms28, and P66. We demonstrated that both multivalent formulations were immunogenic and provided significant protection against B. burgdorferi colonization. B. burgdorferi-induced ankle swelling was mitigated by both multivalent formulations; however, the multivalent VLP-vaccinated mice demonstrated significantly lower ankle widths and higher borreliacidal activity compared to recombinant multivalent-vaccinated mice. Collectively, these data suggest vaccine platforms and antigen selection are critical considerations in LD vaccine development and require further optimization to enhance efficacy, assess immunological memory, and performance in a tick-challenge model.

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