Thomas Pho

BioE PhD Proposal Presentation

Time and Date: 1 PM, Wednesday, November 30th, 2022

Location: UA Whitaker Biomedical Engr 1214 Classroom BME

                Virtual Link: https://gatech.zoom.us/j/92291588905

Advisor: Julie Champion, Ph.D. (Chemical and Biomolecular Engineering)

Committee Members:

Ravi S. Kane, Ph.D. (Chemical and Biomolecular Engineering)

James E. Dahlman, Ph.D. (Biomedical Engineering)

Jennifer E. Curtis,, Ph.D. (Physics)

Mark Prausnitz, Ph.D. (Chemical and Biomolecular Engineering) 

Surface Engineering of Protein Nanoparticles for Intranasal Vaccination

                Intranasal delivery offers a promising alternative approach to invasive intramuscular injection, with additional benefits such as the induction of induce mucosal antibodies and cellular responses to neutralize pathogens before entering systemic circulation. Activation of mucosal immunity is a key milestone for next-generation vaccine development. However, nasal secretions and mucosa are biological barriers that have been shown to inhibit the delivery of antigens and nanoparticles to nasal-associated lymphoid tissue (NALT). Protein based nanocarriers, are composed of therapeutic proteins at high mass to carrier ratio, while allowing for biocompatibility and tunable physiochemical properties. The surfaces of these carriers can be decorated with coatings and chemical conjugation modifications, which can alter transport and immune responses due to their interaction with biological barriers and cells. While the transport behavior and cellular response is known using in vitro models, little is known on the vaccination efficacy using subunit vaccines and in vivo localization when administrated intranasally.  The objective of this research is to evaluate intranasal localization of coated nanoparticles and their immune response during vaccination. The selection of these nanoparticles’ coatings will optimize the formulation of dual influenza antigen subunit nanoparticle upon intranasal vaccination. Understanding the principles behind modifying nanoparticle surface formulations will assist in improving accessibility to the NALT and delivery of protein based nanocarriers for intranasal delivery. In aim 1, coated nanoparticle using polyethylene glycol (PEG), layer-by-layer formulation using polycationic and anionic adjuvates, and unmodified protein nanoparticles will be delivered intranasally in murine models. The localization and biodistribution will be observed using non-invasive in vivo imaging system for regional localization and tissues will be further analyzed for colocalization in the nasal-associated lymphoid tissue (NALT) using flow cytometry and immunohistochemistry. The effect of spatially localization by modifying surface chemistry will be determined through these imaging processes allowing for detection of nanoparticles in specific cellular region and circulation time. In aim 2, surface coated nanoparticles will used for intranasal vaccination in murine model and employ mucosal specific response and systemic humoral and cellular response. Off target response from surface modification will be evaluate for safety profile of these constructs. In aim 3, the incorporation of dual influenza antigens will be used to construct a subunit vaccination with surface structure control. The nanoparticle construct will be evaluated for activation of both antigen-specific B cells and T cell upon intranasal or intramuscular vaccination using the best surface formulation found in aim 2. In addition, memory and challenge studies will be conducted to compare both delivery routes for protection against influenza.