Biomedical Sciences ETDs

Author

Sarah Vaughan

Publication Date

7-1-2013

Abstract

Highly pathogenic avian influenza (HPAI) H5N1 is an emerging infectious virus with a 60% fatality rate in humans. In the United States, a vaccine for H5N1 has been developed and stockpiled using FDA approved methods for seasonal vaccines; however, the H5N1 vaccine was shown to be less immunogenic than seasonal vaccines when evaluated in clinical trials. Adjuvants can be used to enhance the immune response to antigens. For the studies described herein, a lethal mouse model of H5N1 infection was utilized to examine the immune response to the H5N1 vaccine with and without the addition of an alum adjuvant, and these responses were compared to those induced by a seasonal influenza vaccine. Mice that received the adjuvanted vaccine displayed significantly reduced weight loss and increased survival following infection with H5N1 compared to mice that received the non-adjuvanted vaccine. Increased levels of antibodies were detected in mice that received either the adjuvanted H5N1 vaccine or the seasonal vaccine compared to mice that received the non-adjuvanted H5N1 vaccine. In vitro, both the seasonal and adjuvanted H5N1 vaccines more efficiently activated dendritic cells (DCs) when compared to the non-adjuvanted H5N1 vaccine, as seen by enhanced levels of cytokine production following treatment with the seasonal vaccine and an increase in co-stimulatory molecule expression following treatment with adjuvanted H5N1 vaccine. When treated with the adjuvanted H5N1 vaccine, DCs demonstrated increased antigen uptake and intracellular processing compared to cells treated with the non-adjuvanted vaccine. Pre-treatment with mannan or mannose diminished cytokine production by DCs in a dose dependent manner following seasonal, but not H5N1, vaccine treatment implicating C-type lectin receptor activation as the mechanism by which the seasonal vaccine elicits protection. These findings provide an explanation for attenuated DC function following H5N1 vaccination, and while an alum adjuvant is able to rescue H5N1 vaccine immunogenicity it does so via a different mechanism than that utilized by seasonal influenza vaccines. Furthermore, these studies provide insight into the development of more immunogenic vaccines targeting HPAI.

Keywords

Influenza, Highly Pathogenic Avian Influenza, H5N1, Influenza Vaccine, Immune Response to Vaccination, C-type Lectin Receptors, BALB/c Mice, Bone Marrow Derived Dendritic Cells, Adjuvant, Alum, H5N1 Vaccine

Sponsors

The Lovelace Respiratory Research Institute

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Harrod, Kevin

First Committee Member (Chair)

Wilson, Bridget

Second Committee Member

Chackerian, Bryce

Third Committee Member

Mold, Carolyn

Fourth Committee Member

Ozbun, Michelle

Fifth Committee Member

Wilder, Julie

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