Degree Type

Thesis

Date of Award

2020

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

Major

Chemical Engineering

First Advisor

Balaji Narasimhan

Abstract

Respiratory viral infections (RVIs) are amongst the most significant causes of morbidity and mortality worldwide causing more than three million deaths annually. These highly contagious illnesses affect both humans and animals. In humans, they affect a wide range of the population, including children under five years of age (14.1% of deaths in children annually are caused by RVIs worldwide) and older adults (individuals >65 years of age have the highest RVI-related morbidity and mortality rates in the United States).A significant global health burden is attributed to RVIs caused by the influenza virus. In United States, infections caused by the influenza virus result in 250,000-500,000 deaths and an annual health burden of about $71 billion. The influenza virus can cause both seasonal infections and periodic, unpredictable pandemics. Influenza outbreaks have been reported since the 14th century, though some records exist from 412 BC with reports of influenza-like symptoms. The influenza virus is notorious for undergoing antigenic shifts and drifts, causing pandemics, most notably the 1918 Spanish flu pandemic and the 2009 swine influenza pandemic. Amongst the different classes of the influenza virus, Influenza A, Influenza B, and Influenza C, the only one capable of undergoing re-assortments of the virus and antigenic shift is Influenza A virus8. Hence, in order to prevent mortalities due to potential pandemic threats, there is an urgent need for new approaches focused on combating the influenza A virus. Some of these approaches include the use of antivirals such as Tamiflu (oseltamivir®) within the first 48 hours of infection to reduce symptoms. Even though it has been proven to be safe and efficacious for patients, studies have shown some influenza A virus strains resistant to this medication. Vaccines have been used as another effective countermeasure to prevent infections caused by influenza since 1945. The first influenza vaccine discovered by Thomas Francis and Jonas Salk for use in the US military was a whole inactivated influenza A and B virus. Since then, the approach towards designing flu vaccines has not changed much, except for the recent approval of an adjuvanted flu vaccine. The licensed influenza vaccine is still either a live attenuated influenza virus (LAIV; FluMist) or an inactivated virus (IIV; Flu shot). Another inactivated virus vaccine adjuvanted with MF59 (Fluad) is also approved by the U.S. Food and Drug Administration (FDA). Various adjuvants are being studied are used in subunit vaccines, which use only a part of the pathogen, greatly improving the safety profile of the vaccine. However, not many adjuvants have been approved by the FDA for human use. Current flu vaccines still suffer from multiple shortcomings, including reliance on 70+ year-old egg-based production technology, inability to provide cross-protection against different virus strains, and high variability in the immune responses induced in individuals of different ages, to mention a few. The overall goal of the research described in this thesis is to outline approaches to address some these shortcomings by rational design of vaccines and moving away from choosing an off-the-shelf vaccine adjuvant for everything. The specific focus of this work is on developing a broadly-protective influenza vaccine for older adults. This was achieved by analyzing the effects of different adjuvants, including two nanoadjuvants (polyanhydride nanoparticles and pentablock copolymer micelles) and cyclic dinucleotides (CDN) on aged immune cells and understanding what each of these adjuvants contribute to induction of a robust immune response in older adults. In addition, the potential mechanism of action of these adjuvants was explored with the motivation of further optimizing the vaccine formulation. Polyanhydride nanoparticles have been demonstrated to provide low inflammatory dendritic cell activation, which leads to increased CD8+ T cell memory responses. Pentablock copolymer micelles provide a scaffold to facilitate the crosslinking of B cell receptors to provide T-independent B cell activation leading to rapid humoral immune responses. They also enhance the cytosolic delivery of antigen, MHC I presentation, and CD8+ T cell activation. Cyclic dinucleotides enhance B cell activating factor and humoral responses in aged mice without the production of nitric oxide. A vaccine formulation consisting of a combination of these adjuvants with influenza antigens (the combination nanovaccine) was tested in this work to assess the humoral and cellular immune responses generated in both young and aged animals.

DOI

https://doi.org/10.31274/etd-20210114-134

Copyright Owner

Sujata Senapati

Language

en

File Format

application/pdf

File Size

244 pages

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