Cure Lab has discovered a novel approach to vaccine design that provides broad spectrum immunity against influenza infection, influenza regularly affects the world population and imposes a considerable health care and economic burden. Annually, 5-15% of the world's population contracts influenza, resulting in 3-5 million cases of severe illness, and an estimated 250,000 to 500,000 deaths from influenza-associated complications. The purpose of this grant is to develop and bring to market a new generation influenza vaccine. In this phase I grant, we will establish proof of principle for our approach in an animal model and develop a product prototype. We will modify conserved internal NP and M1 proteins of influenza virus in such a way that they will generate enhanced T-cell response upon immunization. This will be accomplished by changing the conformation of said proteins in such a way that the ubiquitin-proteasome system degrades them more efficiently and thus produces more MHC class l-presented peptides, inducing a more effective and long-term T-cell response. First, we will construct both a plasmid and a recombinant vaccinia virus expressing a modified NP gene of influenza A and test protective efficacy and immunogenicity in the mouse model. Second, we will test proteasome-dependent degradation of additional conserved internal proteins of influenza viruses A and B, modify identified target proteins according to Cure Lab algorithm and analyze their intracellular degradation, thus preparing them for use as a part of our vaccine regimen. Third, we will construct multiple vaccine vectors expressing destabilized conserved influenza proteins and test their immunogenicity and protective efficacy in vivo, establishing along the way the immune correlates of protection, as well as the best immunization routes and schedules. The overall aim of this project is to demonstrate better protective effect or/and enhanced immune response using modified influenza proteins as immunogens compared to wild-type viral proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI063634-01
Application #
6880674
Study Section
Special Emphasis Panel (ZRG1-IMM-G (12))
Program Officer
Lacourciere, Karen A
Project Start
2005-07-05
Project End
2007-06-30
Budget Start
2005-07-05
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$526,994
Indirect Cost
Name
Curelab, Inc.
Department
Type
DUNS #
145084237
City
Canton
State
MA
Country
United States
Zip Code
02021
DiFrancesco, Robin; Rosenkranz, Susan; Mukherjee, A Lisa et al. (2010) Quality assessment for therapeutic drug monitoring in AIDS Clinical Trials Group (ACTG 5146): a multicenter clinical trial. Ther Drug Monit 32:458-66
Ilyinskii, Petr O; Meriin, Anatoli B; Gabai, Vladimir L et al. (2008) The proteosomal degradation of fusion proteins cannot be predicted from the proteosome susceptibility of their individual components. Protein Sci 17:1077-85
Ilyinskii, P O; Meriin, A B; Gabai, V L et al. (2008) Prime-boost vaccination with a combination of proteosome-degradable and wild-type forms of two influenza proteins leads to augmented CTL response. Vaccine 26:2177-85
Zhirnov, Oleg P; Isaeva, Elena I; Konakova, Tatyana E et al. (2007) Protection against mouse and avian influenza A strains via vaccination with a combination of conserved proteins NP, M1 and NS1. Influenza Other Respi Viruses 1:71-9
Ilyinskii, Petr O; Gabai, Vladimir L; Sunyaev, Shamil R et al. (2007) Toxicity of influenza A virus matrix protein 2 for mammalian cells is associated with its intrinsic proton-channeling activity. Cell Cycle 6:2043-7