Degree Type

Dissertation

Date of Award

2016

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

Major

Chemical Engineering

First Advisor

Balaji Narasimhan

Abstract

Even though there are a large number and a wide variety of influenza vaccines manufactured for human use every year, the influenza virus continues to pose a significant public health problem. First, it has the ability to rapidly change its antigenic structure thereby avoiding the immune system, and secondly it has a large presence in animal reservoirs making zoonosis a constant threat. Current vaccines are limited, because they have different levels of efficacy across age groups and are notably weaker in the elderly. Additionally, the manufacturing process requires several months of lead time, putting significant strain on the ability to match the vaccine to circulating strains. A new generation of rationally designed influenza vaccines is necessary to combat these threats. In this regard, the use of nanovaccine technologies in influenza vaccine development shows great promise.

The overall goal of this research was to synthesize targeted nanoparticle-based vaccines against the influenza virus. Early on, in vitro studies were performed that focused on determining the role of the interactions between nanoparticle polymer chemistry, surface carbohydrate functionalization, and serum protein adsorption on dendritic cell activation. These studies identified nanoparticle formulations that are efficiently internalized by dendritic cells and that induced dendritic cell maturation. Later, the safety and biocompatibility of these carbohydrate-functionalized nanoparticles were evaluated by analyzing the histopathology of the liver, kidneys, and lungs of mice administered with these nanoparticle treatments. The cytokine and chemokine secretion in the bronchoalveolar lavage fluid as well as biomarkers in the blood and urine were analyzed for histopathological changes. In vivo, the ability of the carbohydrate-functionalized nanoparticles to induce potent cellular and humoral immune responses was evaluated using a model antigen, ovalbumin. These results were utilized to design efficacious nanoparticle-based formulations containing the influenza hemagglutinin antigen. Using these formulations, a live viral challenge was conducted in an animal model and the clinical response was evaluated.

Copyright Owner

Jonathan Tate Goodman

Language

en

File Format

application/pdf

File Size

277 pages