DNA-Nanoparticles (DNA-NP) for Antigen Presentation and Vaccine Design for Aerosolized Pathogens
Abstract
Venezuelan equine encephalitis virus (VEEV) is an arbovirus primarily transmitted by mosquito bites in various part of the world and responsible for recurring natural outbreaks of human and animal disease. While the vast majority of cases of natural mosquito-borne infection by VEEV result in very mild outcomes such as flu-like symptoms, in rare cases the virus can cause encephalitis and even lead to the death of the patient. However, if the infection occurs though the aerosol route, the outcomes for the patient become more serious with a higher chance of encephalitis and long-term neurological sequelae including seizures and paralysis. The virus is highly infectious and stable as an aerosol and reaches the brain through the olfactory nerve. The neuroinflammation of the brain tissue is exacerbated by the rapid rate of replication of the virus, which tends to worsen the neurological conditions of the infected person. This clearly represents a serious threat for the Warfighter and the civilian population in case of use of weaponized VEEV. VEEV is also one of several such acutely infectious agents that the Warfighter may be exposed to for which no Food and Drug Administration (FDA)-approved countermeasures are currently available. One important unmet need in countermeasure, specifically vaccine development, is the lack of an effective tool that can fine-tune the prioritization process for candidates (by enabling high-throughput screening similar to those available for small molecules), while also improving immunogenic potential. Vaccines are possibly the most effective strategy to protect the Warfighter and also sustainable long term. Traditional vaccine development methods for high priority pathogens including VEEV rely on low-throughput methods that greatly limit the potential to explore candidate libraries as in the case of therapeutics. This also significantly extends the timeline for vaccine/product development, making quick responses to outbreaks a major challenge. To address this unmet need for a robust tool that can enable candidate prioritization, assessment of product developability and capable of eliciting an immune response, we propose a novel and unique antigen delivery platform as a tool in which the platform is made of a DNA nanoparticle (DNA-NPs) of accurate and prescribed shape and size, the surface of which can be modified with immunogenic antigens. As a model, we will use the two envelope glycoproteins E1 and E2 from VEEV and display them in specific 3D organization and stoichiometry on the DNA-NPs to present them to antigen presenting cells (APCs) and induce a strong immune response against the virus. This tool will be used to determine the impact of antigen nanoscale organization on particle uptake in vitro and immune responses in vivo. Moreover, by using biocompatible DNA-NPs as the delivery platform, we are reducing the risk associated with the use of live attenuated vaccine candidates. The platform will be tested first in vitro with model APCs in order to determine the most efficient organization of E1 and E2 on the surface of the DNA-NPs (candidate prioritization) before testing them in a mouse model in the context of an aerosol challenge with the virulent Trinidad Donkey (TrD) virus. Pending demonstration of success, we will pursue additional efforts to improve the formulation and the stability of our DNA-NP-based vaccine platform to support large animal model studies with aerosolized virus. The results obtained in this study will be foundational to our long-term efforts to acquire FDA approval for VEEV-DNA-NP as a vaccine candidate for VEEV. Moreover, this DNA-NPs presenting VEEV antigens will serve as proof of principle for the application of this novel and versatile tool to create DNA-origami based antigen delivery strategies for many other aerosolized pathogens that pose a threat to the Warfighter.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010054
Entities
People
- Aarthi Narayanan
Organizations
- George Mason University
- United States Army