Lyme disease is caused by a bacterium which is transmitted to humans by ticks. Following a tick bite, bacteria are able to spread via the bloodstream, causing severe inflammation in the heart, joints, and nervous system. This disease is the most common vector-borne disease in North America and Eurasia. Alarmingly, a 2018 Centers for Disease Control and Prevention study found that tick-borne disease cases in the United States doubled from 2004 to 2016, with Lyme disease accounting for 82% of all reports. Military Service members, due to their substantial outdoor training activities in or near wooded or grassy areas, are at a higher risk of Lyme infection than the general population. The increase in cases among military Service members is approximately 300% since 2001. While a Lyme disease vaccine was once available, its low efficacy rate, complicated vaccination regime, lack of safety and efficacy data for young children, and unknown length of vaccine-induced immunity proved to be substantial weaknesses. Consequently, this product has been withdrawn from the market, and no other human vaccine against Lyme Disease is currently available. Thus, developing human vaccines for Lyme disease prevention is urgently needed. A consortium of academic and government institutes including Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine, New York State Department of Health and Cornell University propose to develop an innovative Lyme disease vaccine targeting the Lyme disease bacteria protein, CspZ. This protein protects against the infection from all the Lyme disease-causing bacteria strains that were isolated from humans with severe this disease-associated manifestation in North America and Eurasia. The previous work and the recent preliminary experiments performed at the New York State Department of Health indicates that a genetically modified CspZ protein (CspZ-YA) protects mice from Lyme disease infection. However, the production process and the immunostimulant formulation of this version of CspZ-YA are not suitable for large-scale production and human use. The rationale of this proposal is that CspZ-YA has been shown to elicit both robust bactericidal antibody titers as well as a balanced cytokine response, and thus has great potential for use as an efficacious LD vaccine.

Scientific Objective

The objective of the project is to develop a production process and identify a suitable immunostimulant formulation and boost frequency for the CspZ-YA vaccine that will trigger the most robust and safe immune response to efficiently eliminate bacteria and prevent Lyme disease-associated manifestations.

Aims

Aim 1: Develop a high-yielding reproducible process to manufacture tag-free CspZ-YA.

Aim 2: Define the host immune responses triggered by CspZ-YA under different boost frequency, dose, and adjuvants.

Aim 3: Identify the regimens of CspZ-YA that most efficiently prevent bacterial colonization and LD-associated manifestation.

The proposal is focused on the development of a safe, effective, and innovative vaccine against Lyme disease. This application addresses the following Fiscal Year 2019 (FY19) Tick-Borne Disease Research Program’s (TBDRP’s) Focus Area: Safe and effective human vaccines for tick-borne diseases.

Over a period of 3 years, we propose to develop a process for the production of CspZ-YA, and to conduct immunogenicity and efficacy studies in a mouse model. For vaccine product development to be technically and economically feasible, we aim to establish a simple, scalable, and reproducible process that produces sufficient quantities of highly purified and immunogenic recombinant protein antigen and is ready for later industrial-scale manufacture and future clinical trials. For the preclinical testing, we aim to determine the optimal immunostimulant formulation, dose and injection route for this vaccine against Lyme disease. Ultimately, the development and delivery of a vaccine could represent one of the most cost-effective means of controlling or eliminating Lyme disease. Ideally, this effective vaccine against Lyme disease will prevent the Lyme disease pathogen colonization and manifestations, which will significantly reduce the burdens of Lyme disease to strengthen the health and welfare of military Service members and the American public.