Graduation Date

Summer 8-12-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Joseph Vetro

Abstract

Encapsulation in biodegradable microparticles (MPs) is a promising approach to increase the efficacy of intranasally administered protein vaccines. The generation of long-lived adaptive immune responses against encapsulated protein vaccines, however, requires the incorporation of a suitable mucosal adjuvant. CPDI-02—a complement peptide-derived immunostimulant that selectively activates dendritic cells and macrophages over neutrophils while minimizing the inflammatory side effects of parent C5a—has previously been incorporated into both systemic and mucosal vaccine formulations via direct conjugation to chemical moieties, peptides, proteins, inactivated pathogens, and the surface of biodegradable particles, to enhance Th1-biased cellular immune responses. The effect of CPDI-02 surface conjugation to MPs encapsulating protein vaccine on short- and long-term mucosal and systemic humoral immune responses, however, has not previously been assessed. Further, alternative strategies for incorporating CPDI-02 into PLGA particles encapsulating protein vaccine (such as co-encapsulation of CPDI-02 with protein vaccine; or separately encapsulating protein vaccine and CPDI-02 and co-administering) have not been explored. In this dissertation, we report that respiratory immunization of naive mice with the model antigen ovalbumin (OVA) encapsulated in PLGA MP surface-conjugated with CPDI-02 generated: (i) increased numbers of OVA-specific IgA, IgM, and IgG antibody secreting cells (ASCs) in the lungs and spleen, (ii) increased short- and long-lived mucosal IgA and IgG antibody titers, and (iii) increased short- and long-lived OVA-specific serum titers of IgG subclasses relative to encapsulation in particles modified with scrambled, inactivated CPDI-02 and PBS vehicle control. We further report that co-administration of CPDI-02 and OVA separately encapsulated in PLGA MPs via the intranasal route increases the generation of: (i) short-term OVA-specific IgA ASCs in the lungs, (ii) mucosal IgA and IgG antibody titers, (iii) OVA-specific IgG ASCs in the spleen, (iv) OVA-specific serum titers of IgG subclasses, and (v) OVA-specific CD4+ and CD8+ T cells in the spleen, compared to other strategies for incorporating CPDI-02 into MPs encapsulating protein vaccine. Thus, the strategy by which CPDI-02 is incorporated into MPs affects the generation of mucosal and systemic cellular and humoral immune responses by encapsulated protein vaccines after respiratory immunization.

Comments

2022 Copyright, the authors

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