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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AI077771-02S2
Application #
7922884
Study Section
Special Emphasis Panel (ZAI1-TP-M (J1))
Program Officer
Cassels, Frederick J
Project Start
2009-09-17
Project End
2010-08-31
Budget Start
2009-09-17
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$68,540
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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