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• W3199116404 abstract "Vaccines are the most effective public health toolfor prevention of infectious disease, and have largely (orcompletely) reduced the burden of morbidity and mortality causedby viral pathogens such as measles, polio and smallpox. Despitethis remarkable track record of success, we presently lackeffective vaccines for several important viruses - including thehuman immunodeficiency virus type-1 (HIV-1), as well as novelstrains of the influenza A virus (IAV), that may have pandemicpotential. Infection by HIV-1 and IAV can be prevented byvirus-neutralizing antibodies, but vaccine delivery methods thatefficiently elicit such antibodies at the mucosal sites of virustransmission remain elusive. The goal of this thesis was thereforeto identify antigen delivery methods that might improve themagnitude and quality of virus-specific humoral immune responses,including responses at mucosal sites. To do this, I focused on theanalysis of humoral immune responses to representative viral (HIV,IAV) antigens that were either: (1) delivered in a dense, arrayedformat on the surface of nanoscale scaffolds, or (2) expresseddirectly at the sublingual mucosal surface, using a vectoredapproach. My first set of experiments tested whether dense,repetitive display of a viral antigen on the surface ofbacteriophage lambda capsids could elicit a superior humoralimmune response compared to a soluble version of the same protein.For this initial study, the IAV hemagglutinin (HA) was selected asa test antigen. HA was successfully displayed on the phageparticle, and shown to efficiently induce agglutination of redblood cells – much like wild-type influenza virus particles.However, immunization with phage particles displaying HA elicitedhumoral immune responses that were no greater in magnitude thanthose elicited by soluble HA. Similar results were obtained incomplementary studies conducted by another member of the Dewhurstlab, who displayed the HIV-1 envelope glycoprotein (Env) on thesurface of the phage capsid. These disappointing results wereattributed to the highly immunogenic nature of the bacteriophagecapsid itself. I next tested whether sublingual (SL) delivery ofan Env-expressing viral vector could elicit strong Env-specificmucosal antibody responses. This is important because the SLmucosa is a readily accessible mucosal surface that has beenunderexplored as a vaccine delivery route. Two recombinant viralvectors were constructed, each expressing the same HIV-1 Envantigen: (a) an adenovirus serotype-5 [Ad5] vector and (b) herpessimplex virus [HSV-1] vector. SL delivery of the Ad5 vectorelicited a strong Env-specific serum IgG response, high levels ofEnv-specific antibody-secreting cells (ASC), and strong serum andmucosal IgA responses. In contrast, SL delivery of the HSV-1 vectorresulted in poor Env-specific responses. Interestingly, the rAd5vector was efficiently trapped by saliva, unlike the HSV-1 vector– suggesting that mucoadhesion may be a prerequisite for…" @default.
• W3199116404 created "2021-09-27" @default.
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• W3199116404 date "2013-01-01" @default.
• W3199116404 modified "2023-09-23" @default.
• W3199116404 title "Optimizing Antigen Delivery Approaches for HIVImmunization" @default.
• W3199116404 hasPublicationYear "2013" @default.
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