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dc.contributor.authorKhan, Tilaen_US
dc.date.accessioned2017-04-06T15:43:01Z
dc.date.available2017-04-06T15:43:01Z
dc.date.issued2012-06-05en_US
dc.identifier.otheretd-07102012-204707en_US
dc.identifier.urihttp://hdl.handle.net/10919/77130
dc.description.abstractInfluenza epidemics and pandemics remain a significant burden to world health and economy. Low efficacy of current inactivated influenza vaccines in the elderly and immunocompromized and the inability to protect against antigenically drifted or shifted strains of influenza virus are the two major problems in influenza vaccine research. To overcome these hurdles, we have utilized an in vitro cell culture vaccine platform, which results in whole inactivated influenza vaccine (WIV) bearing bioactive membrane-anchored immunomodulatory proteins such as cytokines on the virion surface, collectively known as CYT-IVACs (Cytokine bearing-Inactivated Vaccine). In addition, we tested whether a multimeric M2e peptide presented on WIV can serve to enhance immunogenicity and augment protective efficacy of whole virus vaccines. Our panel of cytokines includes IL-2, IL-4, IL-12, IL-23, and Flt3L as well as the multimeric M2e peptide, all fused to the membrane anchoring regions of influenza virus hemagglutinin protein and constitutively expressed in virus permissive MDCK cell line. Subsequent infection with influenza virus results in incorporation of fusion constructs directly into budding progeny virions that are harvested, purified and inactivated to generate distinct CYT-IVAC formulations. Following validation of immunomodulator incorporation, vaccines were tested for in vivo efficacy in either "young adult" or "aged" female Balb/c mice. Our results demonstrate that our CYT-IVAC~IL-12/HA and CYT-IVAC~IL-23/HA serve as potent mucosal adjuvants in young adult mice elicited significantly high levels of mucosal IgA antibodies and afford superior protection against lethal virus challenge. Our Flt3L/HA formulation was the most effective stimulator of systemic anti-viral antibody levels. In "aged" mice a single dose formulation of IL-12 bearing CYTIVAC was superior at affording protection against lethal homotypic virus challenge. Finally, administration of multimeric M2e molecule co-presented on WIV elicited prolonged antibody responses in "young adult mice" and provided cross-protection from challenge with the heterologous influenza A pandemic strain 2009 H1N1. In conclusion, the CYT-IVAC approach represents a novel tailored advancement to current WIV approaches that has the potential to elicit both potent mucosal and systemic immune responses in young and old.
dc.language.isoen_USen_US
dc.publisherVirginia Techen_US
dc.rightsI hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Virginia Tech or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.en_US
dc.subjectvaccineen_US
dc.subjectM2een_US
dc.subjectcytokineen_US
dc.subjectvirusen_US
dc.subjectinfluenzaen_US
dc.subjectwhole inactivated vaccineen_US
dc.titleTailored influenza virus vaccines for both the young and old: Vaccine Efficacy of Whole Inactivated Vaccines bearing Immunomodulatory Adjuvants or Multimeric peptidesen_US
dc.typeDissertationen_US
dc.contributor.departmentVeterinary Medical Sciencesen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineVeterinary Medical Sciencesen_US
dc.contributor.committeechairRoberts, Paul Christopheren_US
dc.contributor.committeememberWitonsky, Sharon G.en_US
dc.contributor.committeememberMeng, Xiang-Jinen_US
dc.contributor.committeememberYuan, Lijuanen_US
dc.contributor.committeememberBassaganya-Riera, Josepen_US
dc.type.dcmitypeTexten_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-07102012-204707/en_US
dc.date.sdate2012-07-10en_US
dc.date.rdate2016-10-03
dc.date.adate2012-07-25en_US


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