This proposal draws on the collaborative efforts of researchers at the University of Pittsburgh and our corporate partner, Novavax, Inc., to develop a new generation of pandemic influenza vaccines based upon the currently circulating strains of highly pathogenic avian influenza (HPAI) H5N1 isolates. This strategy involves the development of virus-like particles (VLPs) for the elicitation of immune responses in the respiratory mucosa of non-human primates. In addition, we propose to challenge vaccinated monkeys with HPAI H5N1 (A/lndoneisa/05/2005, clade 2) in the University of Pittsburgh's newly constructed ABSL-3 Regional Biocontainment Laboratories (RBL) for non-human primates. These VLPs are comprised of viral structural proteins that assemble spontaneously cells. Morphologically, VLPs resemble live influenza virus, are immunogenic, and represent an alternative to inactivated or subunit vaccines with the advantage that viral structural antigens are presented in a non-infectious form in the absence of a viral genome, while maintaining the integrity of conformationally-dependent antigenic epitopes. Our working hypothesis is that influenza VLP vaccines will provide a broader protection for the general population, which will be correlated with enhanced innate, humoral, and cellular host immune responses. We have assembled a network of experienced researchers to develop these novel VLP vaccines, to produce appropriate highly pathological influenza viruses representing H5N1 strains (HPAI), and to assess the vaccine-induced immune responses and pathology induced by viral infection in a relevant primate model. This application is designed to examine the immunogenicity of our H5N1 pandemic influenza VLP vaccines, in a non-human primate model, and compare to a single HA protein immunogen. These VLP vaccines are highly efficacious in small animals, however, we have determined that traditional immunological assays for analyzing the effectiveness of an influenza vaccine (HAI and mVN assays) are not predictive of protection against HPAI. Therefore, in order to examine protective immunity elicited by these VLP vaccines, we have assembled an interactive team to address the following Specific Aims:
Aim 1 : To compare the induced immune responses by clade 2 VLP and rHA vaccines in non-human primates.
Aim 2 : To determine pathological and innate immune responses to clade 2 viral challenge.
Aim 3 : To determine the protective efficacy and immunological correlates of protection of the clade 2 VLP vaccine against HPAI H5N1 influenza challenge in monkeys.
|Crevar, Corey J; Carter, Donald M; Lee, Kevin Y J et al. (2015) Cocktail of H5N1 COBRA HA vaccines elicit protective antibodies against H5N1 viruses from multiple clades. Hum Vaccin Immunother 11:572-83|
|Soloff, Adam C; Bissel, Stephanie J; Junecko, Beth Fallert et al. (2014) Massive mobilization of dendritic cells during influenza A virus subtype H5N1 infection of nonhuman primates. J Infect Dis 209:2012-6|
|Carter, Donald M; Bloom, Chalise E; Nascimento, Eduardo J M et al. (2013) Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus. J Virol 87:1400-10|
|Verma, Swati; Dimitrova, Milena; Munjal, Ashok et al. (2012) Oligomeric recombinant H5 HA1 vaccine produced in bacteria protects ferrets from homologous and heterologous wild-type H5N1 influenza challenge and controls viral loads better than subunit H5N1 vaccine by eliciting high-affinity antibodies. J Virol 86:12283-93|
|Giles, Brendan M; Crevar, Corey J; Carter, Donald M et al. (2012) A computationally optimized hemagglutinin virus-like particle vaccine elicits broadly reactive antibodies that protect nonhuman primates from H5N1 infection. J Infect Dis 205:1562-70|
|Giles, Brendan M; Bissel, Stephanie J; Dealmeida, Dilhari R et al. (2012) Antibody breadth and protective efficacy are increased by vaccination with computationally optimized hemagglutinin but not with polyvalent hemagglutinin-based H5N1 virus-like particle vaccines. Clin Vaccine Immunol 19:128-39|
|Giles, Brendan M; Bissel, Stephanie J; Craigo, Jodi K et al. (2012) Elicitation of anti-1918 influenza virus immunity early in life prevents morbidity and lower levels of lung infection by 2009 pandemic H1N1 influenza virus in aged mice. J Virol 86:1500-13|
|Soloff, Adam C; Weirback, Heather K; Ross, Ted M et al. (2012) Plasmacytoid dendritic cell depletion leads to an enhanced mononuclear phagocyte response in lungs of mice with lethal influenza virus infection. Comp Immunol Microbiol Infect Dis 35:309-17|
|Bissel, Stephanie J; Giles, Brendan M; Wang, Guoji et al. (2012) Acute murine H5N1 influenza A encephalitis. Brain Pathol 22:150-8|
|Petrovsky, Nikolai; Ross, Ted M (2011) Challenges in improving influenza vaccine protection in the elderly. Expert Rev Vaccines 10:7-11|
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