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-8999352-B2
Publication Date
2015-04-07
Expiration Date
2025-06-01
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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 having a diminished ability to antagonize the cellular interferon (IFN) response, specifically via mutations in the swine NS1 gene that reduce or eliminate the NS1 protein's ability to inhibit the cellular IFN response. These genetically engineered viruses replicate in vivo but display decreased replication and virulence, making them highly attenuated and suitable as live virus vaccines and pharmaceutical formulations. The viruses induce a robust interferon response that can generate immunity without causing illness or only mild symptoms.
The problem addressed by the invention arises from the pathogenicity and antigenic variability of swine influenza viruses in pigs, which complicates the development of effective vaccines. Prior methods for attenuation involved chance isolation of mutants with host range or temperature sensitivity, which are unpredictable and may be poorly immunogenic. The swine influenza virus's NS1 protein antagonizes the IFN response, enabling viral replication and pathogenesis; thus, viruses with impaired NS1 function are attenuated. However, the specific genetic alterations for attenuation were not known or predictable. The invention provides rationally designed attenuated viruses by introducing specific NS1 mutations that impair IFN antagonism, overcoming limitations of conventional vaccines and providing a platform for safer, effective live vaccines suitable for swine influenza virus prevention and other IFN-treatable diseases.
Claims Coverage
The patent includes one independent claim directed to a genetically engineered swine influenza virus with a specific NS1 gene mutation and its modified phenotypes and formulations.
Genetically engineered swine influenza virus with specific NS1 protein truncation
A swine influenza virus genetically engineered to have a mutation in the NS1 gene resulting in an NS1 protein truncated to amino acid residues 1-126, conferring an impaired interferon antagonist phenotype.
Virus as reassortant or chimeric expressing heterologous sequences
The genetically engineered virus can be a reassortant or a chimeric virus that expresses heterologous sequences or epitopes from foreign pathogens or tumor antigens, or at least one genomic segment derived from a different influenza virus strain listed explicitly.
Formulations with genetically engineered attenuated virus
Immunogenic and pharmaceutical formulations comprising the genetically engineered attenuated swine influenza virus and a physiologically acceptable excipient or carrier, including defined viral concentration ranges.
Infected cells and eggs containing the genetically engineered virus
Isolated cells, particularly pig cells or pig cell lines (including defined cell lines), or embryonated chicken eggs (including interferon-deficient ones) containing the genetically engineered attenuated swine influenza virus.
Method for inducing immune response and vaccine production
Methods for inducing an immune response in pigs by administration of the genetically engineered attenuated virus, and methods for producing pharmaceutical formulations by propagation in substrates and recovery of progeny virus.
The claims focus on a genetically engineered swine influenza virus with a defined NS1 truncation leading to impaired interferon antagonist activity and cover its reassortants, chimeric forms, related immunogenic and pharmaceutical formulations, methods of use for immunization, propagation in cells or eggs, and the inclusion of heterologous sequences. This establishes comprehensive coverage over the design, production, and application of specific attenuated swine influenza viruses.
Stated Advantages
The attenuated swine influenza viruses demonstrate decreased virulence, allowing for safe use in live virus vaccines.
These viruses induce a robust cellular interferon response, enhancing immune protection.
Live vaccines using these viruses provide longer-lasting immunity and potential cross-protection against diverse strains compared to inactivated vaccines.
Vaccines are suitable for intranasal administration, avoiding side effects associated with injections and inducing mucosal immunity.
The engineered viruses can be used as vectors to express foreign pathogenic or tumor epitopes, expanding their utility.
The viruses can be propagated in various substrates, including interferon-deficient cells and embryonated eggs, facilitating vaccine production.
Documented Applications
Use of attenuated swine influenza viruses in live virus vaccine formulations to protect pigs from swine influenza infections.
Use of the viruses in immunogenic formulations to induce immune responses against swine influenza virus or heterologous antigens, including tumor antigens.
Use of attenuated viruses pharmaceutically to prevent, manage, or treat other infections or interferon-treatable diseases such as cancer in subject animals.
Recombinant expression of heterologous sequences or epitopes in the attenuated virus for vaccination against other pathogens or neoplastic conditions.
Methods of vaccinating pigs and other animals by administration of effective amounts of these attenuated viruses to induce immunity.
Use of genetically engineered attenuated viruses propagated in cells, cell lines or embryonated chicken eggs for vaccine manufacture.
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