University of Pittsburgh
Grant: $68,540 - National Institutes of Health - Sep. 17, 2009
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Award Description: Specific Aim to the supplement: To determine pathological and innate immune responses to various isolates of H1N1 variant viral challenges. We will establish the baseline innate immune response and pathology in ferrets to H1N1 influenza infection using recently isolated strains of H1N1. Our hypothesis is these viruses are more pathogenic in humans than seasonal H1N1 strains that can be determined in a ferret model. Currently, isolates of these H1N1 strains are spreading across the world. Small animal models (ferrets) are useful for studying influenza infection for pathology, immune responses, viral dissemination, transmission, and aerosol studies. These animal models are needed to assess correlates of protection for pandemic isolates and to assess candidate H1N1 variant influenza vaccines. We will use several H1N1 variant strains, particularly the Mexican isolates, to determine if there are differences in the pathogenicity by various H1N1 isolates. The current seasonal H1N1 strain, A/Brisbane/59/2007 will be used as a comparator. Ferrets will be infected (via different routes at different doses) with H1N1 viruses and then groups of ferrets will be sacrificed (days 0, 1, 3, 5, & 7 post-challenge for acute responses at day 21, to assess adaptive immune responses), analyzed for morbidity/clinical signs, mortality, pathology and viral spread from lung to other tissues, i.e. brain or gut. In addition, gene expression and innate responses will be assessed. These baseline infection studies will allow us to use the ferret model to assess transmission studies and protection against challenge of our VLPs in future studies.
Project Description: Our overall goal 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 will develop these novel VLP vaccines, to produce appropriate highly pathological influenza viruses representing H5N1 strains, and to assess the vaccine-induced immune responses and pathology induced by viral infection in a relevant primate model.The goals of this application are specifically targeted to meet the World Health Organization (WHO) recommendations for vaccine development set in 2006 in Geneva, which highlighted the need for establishment of relevant animal models and immune assessment for pandemic influenza vaccines. Our network of experienced and multidisciplinary researchers will develop these novel VLP vaccines, to produce a highly pathogenic H5N1 influenza virus for challenge studies, and to assess the vaccine efficacy and virus induced pathology in a relevant primate model. Results: We will test our VLP vaccines in cynomolgus macaques and analyze the elicited adaptive immune responses (humoral and cellular) to this vaccine. Monkeys will be vaccinated, either by intranasal or intramuscular routes at week 0 and 3, and peripheral blood mononuclear cells (PBMC) and serum will be collected during the acute vaccination regimen (week 5) and then the monkeys will be housed to week 12 to examine the longevity of the immune response. The VLP-elicited immune responses will be compared to the responses elicited by a recombinant HA control vaccine. Monkeys will be vaccinated and challenged with HPAI virus at peak immune response (week 5) or following the induction of memory responses (week 12). Both adaptive and innate immune responses, as well as pathological analysis will be determined. Deliverables: 1. An effective pandemic influenza VLP as a candidate vaccine. 2. Development of a primate model for H5N1 infections and vaccine assessment.
Infrastructure Description: N/A
Jobs Summary: Award recently received. At this time no jobs have been created/retained. (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 17, 2009. Help expand these official descriptions using the wiki below.
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