Date of Award

January 2012

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Michael Cappello

Second Advisor

Nancy Ruddle

Abstract

Most pathogens invade their human host or establish infection at mucosal surfaces. In contrast to parenteral vaccines, mucosal immunization has the potential to induce a robust immune response at mucosal surfaces capable of blocking the entry and establishment of many pathogens. Despite these advantages, very few mucosal vaccines are licensed for human use, largely because antigens administered by the mucosal route are either poorly or non-immunogenic. A strategy to overcome this problem is co-administering vaccine antigens with a mucosal adjuvant. Recently, bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) was identified as a potential mucosal adjuvant. To evaluate c-di-AMP as a mucosal adjuvant two studies were conducted: The first characterized the immune responses elicited by c-di-AMP when used as a sublingual and intranasal adjuvant; and the second tested the protective efficacy of c-di-AMP in a vaccine model of hookworm pathogenesis. From our studies, c-di-AMP stimulates strong humoral and cellular immune responses, and induces a predominately Th1/Th17 T cell response pattern, as shown by elevated expression of IgG2a and enhanced secretion of IFN-gamma, IL-17, and IL-22. Despite these successes, when tested in a hookworm vaccine model c-di-AMP failed to significantly enhance the protective efficacy of hookworm excretory-secretory (ES) antigens. However, we did discover that ES antigens alone, given intranasally, confer a 73.8% reduction in adult worm burden, and appear to modulate the severity of hookworm-associated anemia and weight loss. We hypothesize that part of this success is due to inherent adjuvant properties of ES, which boost the immunogenicity of vaccine relevant antigens.

Comments

This is an Open Access Thesis.

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