Genetically engineered swine influenza virus and uses thereof
Inventors
Palese, Peter • Garcia-Sastre, Adolfo • Webby, Richard J. • Richt, Juergen A. • Webster, Robert G. • Lager, Kelly M.
Assignees
St Jude Childrens Research Hospital • Icahn School of Medicine at Mount Sinai • US Department of Agriculture USDA
Publication Number
US-8124101-B2
Publication Date
2012-02-28
Expiration Date
2025-06-01
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention relates, in general, to attenuated swine influenza viruses having an impaired ability to antagonize the cellular interferon (IFN) response, and the use of such attenuated viruses in vaccine and pharmaceutical formulations. In particular, the invention relates to attenuated swine influenza viruses having modifications to a swine NS1 gene that diminish or eliminate the ability of the NS1 gene product to antagonize the cellular IFN response. These viruses replicate in vivo, but demonstrate decreased replication, virulence and increased attenuation, and therefore are well suited for use in live virus vaccines, and pharmaceutical formulations.
Core Innovation
The invention provides attenuated swine influenza viruses with an impaired ability to antagonize the cellular interferon (IFN) response. In particular, this involves modifications to the swine NS1 gene that diminish or eliminate the ability of the NS1 gene product to antagonize the IFN response. These viruses replicate in vivo but demonstrate decreased replication, virulence, and increased attenuation, making them suitable for use in live virus vaccines and pharmaceutical formulations.
The problem being addressed arises from the limitations of existing swine influenza virus vaccines. Conventional methods of producing attenuated viruses rely on chance isolation of host range mutants, which are difficult to propagate, may not induce sufficiently robust immune responses, and do not provide long-lasting immunity. Additionally, prior technologies based on recombinant DNA had limited predictability and utility for negative strand RNA viruses like influenza. Thus, there is a need for new and more effective vaccines and immunogenic formulations for preventing swine influenza virus infections, particularly those generated by deliberate genetic modifications.
Claims Coverage
The patent contains independent claims directed to vaccine formulations and methods of inducing immune responses using genetically engineered attenuated swine influenza viruses. The main inventive features relate to specific mutations in the NS1 gene of swine influenza virus resulting in attenuated phenotypes with altered interferon antagonist activity.
Use of NS1 gene mutations to achieve attenuation
A vaccine formulation comprising a genetically engineered attenuated swine influenza virus having a mutation in the swine NS1 gene that results in deletion of all amino acid residues of NS1 except amino acid residues 1-126. This mutation diminishes the ability of the NS1 gene product to antagonize the cellular interferon response.
Chimeric virus expressing heterologous sequences
The genetically engineered attenuated swine influenza virus can be a chimeric virus that expresses a heterologous sequence, such as a tumor antigen or an epitope of a foreign pathogen, to generate specific immune responses.
Method of inducing immune response in pigs
Methods of inducing an immune response in a pig by administering an effective amount of the vaccine formulations comprising a genetically engineered attenuated swine influenza virus with the stated NS1 gene mutation or as a chimeric virus expressing heterologous sequences.
The independent claims focus on genetically engineered swine influenza viruses with NS1 gene deletions that impair interferon antagonist activity, providing attenuated viruses that serve as live vaccines and vectors. These inventions include chimeric viruses expressing foreign epitopes and methods of immunization of pigs, representing innovations in vaccine formulations and immunological methods.
Stated Advantages
The attenuated swine influenza viruses induce a robust cellular interferon response while showing decreased virulence and replication relative to wild-type viruses.
Live virus vaccines based on these attenuated viruses provide longer lasting immunity and improved cross-reactive cell-mediated cytotoxicity compared to inactivated vaccines.
The attenuated viruses can be used pharmaceutically for prevention or treatment of infections and IFN-treatable diseases such as cancer, including inducing antitumor responses.
Use of reverse genetics enables deliberate engineering of specific mutations for attenuation, improving vaccine safety and efficacy.
These viruses can be propagated in conventional and IFN-deficient substrates facilitating vaccine production.
Documented Applications
Use of attenuated swine influenza viruses as live virus vaccines to prevent swine influenza virus infection and associated symptoms in pigs.
Use of attenuated swine influenza viruses as vectors to express epitopes of foreign pathogens or tumor antigens for immunization against other infectious agents or tumors.
Use of attenuated swine influenza viruses in pharmaceutical formulations for prophylaxis or treatment of infections other than swine influenza virus infection and for IFN-treatable diseases such as cancer.
Methods for vaccinating pigs by administering vaccine formulations comprising attenuated swine influenza viruses with NS1 gene mutations.
Methods for propagating attenuated swine influenza viruses in various substrates including pig cells, embryonated eggs, and IFN-deficient systems for vaccine and pharmaceutical production.
Interested in licensing this patent?