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Cytokine-bearing Influenza Vaccine: Adjuvant Potential of Membrane-bound Immunomodulators

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dc.contributor.authorHerbert, Andrew S.en
dc.contributor.committeechairRoberts, Paul C.en
dc.contributor.committeememberMyles, Kevin M.en
dc.contributor.committeememberWitonsky, Sharon G.en
dc.contributor.committeememberMeng, Xiang-Jinen
dc.contributor.departmentBiomedical and Veterinary Sciencesen
dc.date.accessioned2014-03-14T20:11:53Zen
dc.date.adate2009-06-01en
dc.date.available2014-03-14T20:11:53Zen
dc.date.issued2009-04-27en
dc.date.rdate2009-06-01en
dc.date.sdate2009-05-11en
dc.description.abstractInfluenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts. This, along with the ominous threat of an avian influenza pandemic (H5N1), demonstrates the need for a much improved, more sophisticated influenza vaccine. Our group has developed an in vitro model system for producing a membrane-bound Cytokine-bearing Influenza Vaccine (CYT-IVAC). Numerous cytokines are involved in directing both innate and adaptive immunity and it is our goal to utilize the properties of individual cytokines and other immunomodulatory proteins to create a more immunogenic vaccine. Here we report methodologies for the construction of membrane-bound cytokine fusion constructs in which our cytokine of interest (mouse GM-CSF, mouse IL-2, mouse IL-4) was fused to the membrane anchoring regions of viral Hemagglutinin (HA). Progeny virions, produced from influenza infected MDCK cells expressing membrane-bound cytokines, readily incorporated membrane-bound cytokines during budding and these cytokines on the virus particles retained bioactivity following viral inactivation. In vivo vaccination studies in mice showed enhanced antibody titers and improved protection following lethal challenge in those mice vaccinated with IL-2 and IL-4-bearing CYT-IVAC's compared to the conventional wild-type vaccine without membrane-bound cytokines. In addition, the immune response induced by IL-2 and IL-4-bearing CYT-IVACs was skewed toward Th1 (cellular) mediated immunity compared to the Th2 (humoral) dominated response induced with wild-type vaccination. Cellular mediated immunity afforded by IL-2 and IL-4 CYT-IVACs was manifested as enhanced influenza specific T cell proliferation and activation. In conclusion, we have developed a novel methodology to introduce bioactive membrane-bound cytokines directly into virus particles in order to augment the immunogenicity of inactivated, whole virus influenza vaccines.en
dc.description.degreePh. D.en
dc.identifier.otheretd-05112009-180421en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-05112009-180421/en
dc.identifier.urihttp://hdl.handle.net/10919/27660en
dc.publisherVirginia Techen
dc.relation.haspartAndrewHerbertDissertation.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectinfluenzaen
dc.subjectviral vaccineen
dc.subjectmembrane-bound cytokinesen
dc.subjectvaccine adjuvanten
dc.subjectimmunomodulatory proteinen
dc.titleCytokine-bearing Influenza Vaccine: Adjuvant Potential of Membrane-bound Immunomodulatorsen
dc.typeDissertationen
thesis.degree.disciplineBiomedical and Veterinary Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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