Date of Award

Summer 8-18-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Joseph A. Vetro

Abstract

Since the early attempts of Benjamin Jesty at inducing immunity against smallpox and the pioneering work of Edward Jenner, vaccination has been, and continues to remain, the principal method of protection from diseases. However, most of the successful vaccines have been against pathogens that do not have major mechanisms to evade the immune system. So far, many life-threatening diseases like hepatitis C, HIV infection, malaria etc., have been resistant to existing vaccination strategies. Thus, there is an urgent need to develop new vaccination strategies that can generate long-lived protective immunity against such pathogens.

The purpose of this thesis is to investigate the effect of targeting PLGA nanoparticles to antigen-presenting cells using a novel immunostimulatory peptide EP67 as the targeting moiety on the immune responses generated against the encapsulating model antigen. In this study, we have shown that surface modification of PLGA nanoparticles with EP67 simultaneously targets and activates BMDCs, which results in enhanced antigen presentation to T-cells. Furthermore, we demonstrated that respiratory immunization with EP67 surface-modified OVA-encapsulated PLGA nanoparticles (i) increased protection against respiratory infection with LM-OVA by significantly reducing bacteria (ii) increased magnitudes of OVA-specific CD4+/CD8+ T-cells in lungs and spleen, (iii) increased proportions of short-lived effector cells (SLECs), double positive effector cells (DPECs), and memory precursor effector cells (MPECs) in lungs, (iv) increased effector memory MPECs and central memory MPECs without affecting SLECs in spleen, and (v) affected the cytokine secretion profile of splenocytes responsive to MHC-II epitope of OVA. Overall, this work demonstrates the proof-of-concept that surface modification of PLGA nanoparticles with EP67 can increase the efficacy of immune responses generated against the encapsulated antigen.

Available for download on Friday, June 21, 2019

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