Controlled Release of NKT Cell Agonist and Nonreplicating Pathogen for Single-Dose Vaccination
Abstract
For Topic Areas: (1) Vaccine Development for Infectious Diseases and (2) Sustained-Release Drug Delivery Title: Controlled release of NKT cell agonist and non-replicating pathogen for single-dose vaccination Performance period 2019-2021. Many of the current vaccines are administered in multiple doses as a combination of the prime dose followed by one or more boost doses with variable duration of months to years in between. The boost dose is used because the immunity generated by the initial prime dose does not produce sufficient quantities of antibodies and/or immune cells to give long-term protection. The prime-boost approach significantly improves the efficacy of the vaccine, but it is not ideal for compliance, particularly for the military. Multiple doses may not be feasible for Soldiers on the battlefield and even for children of military personnel who may have issues with getting timely boosts if they move to a new location. For military operations, an ideal vaccine will provide extended protection after a single dose. The proposed work will develop two parallel, complementary approaches to replace the multi-dose vaccines with a single dose. In the first approach, addition of suitable immune-activating agents (adjuvants) can improve the immune response, resulting in a significantly higher amounts of antibodies and immune cells compared to just the vaccine, potentially eliminating the need for the boost dose. In the second approach, the initial dose is designed so as to provide both the prime and the boost with the same dose. For example, injecting particles that can release the vaccine as bursts at the specific durations when boosts are needed could eliminate the need for multiple doses while still achieving the benefits of prime-boost approach. Both of these approaches (adjuvants and controlled release of the vaccine) are complementary and thus could also be combined. In fact, the optimal approach could include a boost containing the vaccine and the adjuvant, followed by boosts that also contain both the vaccine and the adjuvants. The proposed research is based on the hypothesis that using controlled release to achieve burst releases of both adjuvant and vaccine will achieve the most efficacious and compliant vaccination. Specifically, we hypothesize that using adjuvants targeting immunoregulatory natural killer T (NKT) cells will significantly improve the longevity of single-dose non-replicating vaccines against a wide variety of microbial pathogens of concern for military operations. Further improvements in longevity will be achieved via particle-based systems that will release NKT-cell agonists (adjuvant) and the inactive entire virus (antigen) in a manner to simulate the prime and the boost. These studies will be conducted using a mouse model of influenza focusing on improving vaccine-mediated protection against the influenza virus. We will first test the improvements in immunity achieved via addition of the NKT-cell agonists as adjuvants, as evidenced by the amount of influenza virus-specific antibodies and immune cells generated. In parallel, we will develop poly(lactide co-glycolide) (PLGA) particles that can provide pulsatile release of antigen (entire virus) and the agonists. To test these particles, we will inject the controlled release immunization formulation and test improvements in efficacy based on antibody titers and influenza-specific immune cell numbers. Finally, we will compare the best formulations for their ability to protect mice against a dose of influenza virus that causes significant morbidity in mice receiving a single-dose of a non-adjuvanted vaccine.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910005
Entities
People
- John Driver
Organizations
- United States Army
- University of Florida