Date of Award

8-2024

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Biosciences

First Advisor

Wei Zhang

Second Advisor

Linda Huang

Third Advisor

Daniel Dowling, Juliet Girard, David Dowling

Abstract

Efficient and effective vaccine formulation requires prioritizing adjuvant discovery, design, and optimization. The emergence of recent epidemics and pandemics has underscored the pressing need for novel adjuvants. These agents serve as immunomodulators capable of eliciting and sustaining effective immune responses, thereby reducing the dosage and dose frequency of antigen-specific immunizations. Creating a library of adjuvants that trigger specific immunoreceptors will enable the development of customized vaccines that elicit a targeted immune response. Small molecule adjuvants (SMAs) have been instrumental in advancing our understanding of immune-response receptors' structure and signaling mechanisms. Although there are many types of SMAs available, including inorganic aluminum salts, monophosphorylated lipids, oligodeoxynucleotides, natural products, and synthesized drug-like molecules, only a few have been approved for use in humans. Nevertheless, SMAs continue to offer great potential for the development of novel and effective therapies for a wide range of diseases. Advanced medicinal chemistry tools, including structure-activity relationship (SAR) and pharmacokinetic analyses, integrated with computational molecular modeling and green chemistry principles, are utilized to define, optimize, and synthesize, in collaboration with Boston Children’s Hospital part of the Precision Vaccine Program (PVP), the toll-like receptor 3 (TLR3) dependent PVP-057 and the stimulator of interferon genes (STING) dependent PVP-098 into ‘Lead' adjuvant candidates. We established well-defined workflows to develop effective strategies for identifying promising candidates. These workflows provide a structured framework for evaluating and prioritizing different compounds based on specific criteria, such as their adjuvanticity effect, synthetic efficiency, and mechanism of action. By following these workflows, we minimize the risk of overlooking important candidates and ensure we make informed decisions based on the available data. Moreover, we focus on designing a green synthetic route to cut down on production costs and waste. This involves the use of readily available materials and schematic designs that are not only cost-effective but also have a reduced environmental impact. With this approach, we developed novel, effective, and efficient ‘Hit’ PVP-057 and -098 into ‘Lead’ candidate SMAs. These adjuvants show potential in Varicella zoster virus (VZV) and Sars-CoV-2 (Covid-19) vaccine formulations, respectively. By continuing to push the boundaries of SMA discovery, we safeguard the health of communities around the world and make a positive impact on the future of public health.

Comments

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