Title page for ETD etd-07102012-204707


Type of Document Dissertation
Author KHAN, TILA
Author's Email Address tilakhan@vt.edu
URN etd-07102012-204707
Title Tailored influenza virus vaccines for both the young and old: Vaccine Efficacy of Whole Inactivated Vaccines bearing Immunomodulatory Adjuvants or Multimeric peptides
Degree PhD
Department Veterinary Medical Sciences
Advisory Committee
Advisor Name Title
Roberts, Paul Christopher Committee Chair
Bassaganya-Riera, Josep Committee Member
Meng, Xiang-Jin Committee Member
Witonsky, Sharon G. Committee Member
Yuan, Lijuan Committee Member
Keywords
  • vaccine
  • M2e
  • cytokine
  • virus
  • influenza
  • whole inactivated vaccine
Date of Defense 2012-06-05
Availability unrestricted
Abstract
Influenza 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.

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