Compositions and methods for dengue virus chimeric constructions in vaccines
Inventors
Stinchcomb, Dan T. • Kinney, Claire • Kinney, Richard M. • Livengood, Jill A.
Assignees
Takeda Vaccines Inc • US Department of Health and Human Services
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Publication Number
US-11931399-B2
Publication Date
2024-03-19
Expiration Date
2034-03-13
Abstract
Embodiments herein report compositions, uses and manufacturing of dengue virus constructs and live attenuated dengue viruses. Some embodiments concern a composition that includes, but is not limited to, a tetravalent dengue virus composition. In certain embodiments, compositions can include constructs of one or more serotypes of dengue virus, such as dengue-1 (DEN-1) virus, dengue-2 (DEN-2) virus, dengue-3 (DEN-3) or dengue-4 (DEN-4) virus constructs. In other embodiments, constructs disclosed herein can be combined in a composition to generate a vaccine against more one or more dengue virus constructs that may or may not be subsequently passaged in mammalian cells.
Core Innovation
Embodiments herein report compositions, methods, uses and manufacturing procedures for dengue virus constructs and vaccine compositions thereof. Some embodiments concern a composition that includes, but is not limited to, chimeric flavivirus virus constructs that alone or in combination with other constructs can be used in a vaccine composition. In certain embodiments, compositions can include constructs of more than one serotypes of dengue virus, such as dengue-1 (DEN-1) virus, dengue-2 (DEN-2) virus, dengue-3 (DEN-3) virus and/or dengue-4 (DEN-4) virus. In other embodiments, manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax) viruses.
Infection with dengue virus can lead to a painful fever of varying severity. To date, four serotypes of dengue virus have been identified: dengue-1 (DEN-1), dengue-2 (DEN-2), or dengue-3 (DEN-3) in combination with dengue-4 (DEN-4). Dengue fever is caused by infection of a dengue virus. Other subtypes may be discovered in the future (e.g. DEN-5). Dengue virus serotypes 1-4 can also cause dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). The most severe consequences of infection, DHF and DSS, can be life threatening. Dengue viruses cause 50-100 million cases of debilitating dengue fever, 500,000 cases of DHF/DSS, and more than 20,000 deaths each year. To date, there is no effective vaccine to protect against dengue fever and no drug treatment for the disease. Mosquito control efforts have been ineffective in preventing dengue outbreaks in endemic areas or in preventing further geographic spread of the disease. It is estimated that 3.5 billion people are threatened by infection with dengue virus.
Embodiments herein concern compositions, methods and uses of chimeric dengue virus constructs. In some embodiments, a composition can include chimeric dengue virus constructs having an attenuated dengue virus backbone with structural genes from at least one other dengue virus serotype. Other embodiments concern at least one live, attenuated virus in combination with one or more chimeric dengue viruses. In other embodiments, an immunogenic composition is generated where when introduced to a subject, the composition produces an immune response to one or more dengue viruses in the subject. Therefore, constructs contemplated herein can be generated and passaged in vitro, and each of the passages provides an attenuated dengue virus contemplated of use in a pharmaceutically acceptable vaccine composition.
Claims Coverage
The claims include four independent claims covering modified live, attenuated dengue-2 virus strain PDK-53 and immunogenic compositions comprising chimeric dengue-1/dengue-2, dengue-3/dengue-2, and dengue-4/dengue-2 viruses.
Modified live, attenuated dengue-2 virus strain with specific prM-52 and NS5-412 mutations
A modified live, attenuated dengue-2 virus strain PDK-53 encoded by a polynucleotide molecule encoding a modified polypeptide molecule comprising at least an adenine to guanine mutation at position 592 encoding glutamic acid instead of lysine at prM-52, and an adenine to guanine mutation at position 8803 encoding valine instead of isoleucine at NS5-412.
Additional mutations increasing characteristics of modified dengue-2 strain
Further mutations include a guanine to cytosine mutation at nucleic acid position 6481 encoding proline instead of alanine at NS4A-36, and a cytosine to thymine mutation at position 7156 encoding phenylalanine instead of leucine at NS4B-111.
Modified dengue-1/dengue-2 chimera with specified backbone and structural proteins and mutations
An immunogenic composition comprising a dengue-1/dengue-2 chimera encoded by a polynucleotide molecule with a first nucleotide sequence encoding nonstructural proteins from modified dengue-2 virus strain PDK-53 backbone, and a second nucleotide sequence encoding structural protein(s) from dengue-1 with at least the following mutations: adenine to cytosine mutation at position 3823 encoding leucine instead of isoleucine at NS2A-116; adenine to thymine mutation at position 4407 encoding aspartic acid instead of glutamic acid at NS2B-92; adenine to guanine mutation at position 7311.
Modified dengue-3/dengue-2 chimera with specific backbone, structural proteins, and mutations
An immunogenic composition comprising a dengue-3/dengue-2 chimera encoded by a polynucleotide molecule comprising first nucleotide sequence encoding nonstructural proteins from modified dengue-2 virus strain PDK-53, a second nucleotide sequence encoding structural protein(s) from dengue-3, and mutations including adenine to thymine mutation at position 1603 encoding serine instead of threonine at E-223, and adenine to guanine mutation at position 7620.
Modified dengue-4/dengue-2 chimera with defined backbone, structural proteins, and mutations
An immunogenic composition comprising a dengue-4/dengue-2 chimera encoded by a polynucleotide molecule comprising first nucleotide sequence encoding nonstructural proteins from modified dengue-2 virus strain PDK-53, a second nucleotide sequence encoding structural protein(s) from dengue-4, with mutations including adenine to thymine mutation at position 225; adenine to guanine at 3674 encoding glycine instead of aspartic acid at NS2A-66; cytosine to thymine mutation at 5391; cytosine to thymine at 6437 encoding valine instead of alanine at NS4A-21; adenine to cytosine at 9750; further mutations of thymine to cytosine at 7026 and adenine to guanine at 3773 encoding arginine instead of lysine at NS2A-99; cytosine to thymine at 7538 encoding phenylalanine instead of serine at NS4B-238.
The independent claims cover modified live, attenuated dengue-2 virus strains with defined mutations, and immunogenic compositions comprising chimeric constructs of dengue-1/dengue-2, dengue-3/dengue-2, and dengue-4/dengue-2 with specified mutations and backbone characteristics that enhance immunogenicity and safety.
Stated Advantages
Improved safety and genetic stability of live-attenuated chimeric dengue vaccine viruses during manufacturing.
Retention of attenuation markers in vaccine compositions enhancing safety of dengue virus vaccines.
Reduced infectivity and transmission of vaccine viruses by mosquito vectors providing additional safety features.
Live-attenuated dengue-2 PDK-53 virus shows high immunogenicity at low doses with no apparent safety concerns.
Chimeric constructs express surface antigens of different dengue serotypes while retaining attenuation phenotypes of the backbone virus.
Documented Applications
Use of chimeric dengue virus constructs as monovalent, bivalent, trivalent or tetravalent vaccines to induce immune responses against one or more dengue virus serotypes.
Use of live, attenuated dengue-2 virus strain PDK-53 and chimeric dengue viruses in pharmaceutical compositions and immunogenic compositions for vaccination.
Combination of dengue virus chimeras with other flavivirus immunogenic compositions, such as vaccines against West Nile virus or Japanese encephalitis.
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