Development of dengue virus vaccine components
Inventors
Whitehead, Stephen S. • Blaney, Joseph E. • Murphy, Brian R. • Lai, Ching-Juh
Assignees
US Department of Health and Human Services
Publication Number
US-10724007-B2
Publication Date
2020-07-28
Expiration Date
2027-08-15
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Abstract
The invention is related to a dengue virus or chimeric dengue virus that contains a mutation in the 3′ untranslated region (3′-UTR) comprising a Δ30 mutation that removes the TL-2 homologous structure in each of the dengue virus serotypes 1, 2, 3, and 4, and nucleotides additional to the Δ30 mutation deleted from the 3′-UTR that removes sequence in the 5′ direction as far as the 5′ boundary of the TL-3 homologous structure in each of the dengue serotypes 1, 2, 3, and 4, or a replacement of the 3′-UTR of a dengue virus of a first serotype with the 3′-UTR of a dengue virus of a second serotype, optionally containing the Δ30 mutation and nucleotides additional to the Δ30 mutation deleted from the 3′-UTR; and immunogenic compositions, methods of inducing an immune response, and methods of producing a dengue virus or chimeric dengue virus.
Core Innovation
The invention relates to a dengue virus or chimeric dengue virus comprising mutations in the 3′ untranslated region (3′-UTR) specifically including a Δ30 deletion mutation that removes the TL-2 homologous structure in each of the four dengue virus serotypes (1, 2, 3, and 4). These mutations include deletions beyond the Δ30 mutation extending in the 5′ direction up to the 5′ boundary of the TL-3 homologous structure and/or replacement of the 3′-UTR of a dengue virus of a first serotype with the 3′-UTR of a dengue virus of a second serotype. The invention further relates to immunogenic compositions, methods to induce an immune response, and methods of producing such dengue or chimeric viruses containing these mutations.
The problem addressed is the lack of a safe, effective, and economical dengue vaccine that can simultaneously protect against all four serotypes, given that enhanced disease severity can result from antibodies to heterotypic dengue virus serotypes. Previous Δ30 mutations attenuate DEN4 but not DEN3 effectively, thus the invention aims to provide additional mutations or combinations thereof in the 3′-UTR to confer attenuation for each dengue serotype, including DEN3, to develop tetravalent vaccine components. Attenuation is achieved by genetic modifications to the 3′-UTR that reduce virus replication without compromising immunogenicity.
Claims Coverage
The claims define immunogenic compositions and nucleic acids encoding dengue or chimeric dengue viruses with specific mutations in the 3′-UTR, and methods of inducing immune responses using these compositions. The coverage includes multiple independent claims with inventive features relating to mutations and compositions for tetravalent dengue vaccines.
Δ30/31 mutation in dengue 3 virus 3′-UTR
The immunogenic composition comprises a nucleic acid encoding a dengue 3 virus or chimeric dengue 3 virus having a Δ30/31 deletion mutation in the 3′ untranslated region (3′-UTR), where the Δ30 mutation deletes nucleotides about 173 to 143 and the Δ31 mutation deletes nucleotides about 258 to 228 of the dengue 3 3′-UTR using reverse-order numbering.
Inclusion of chimeric dengue virus rDEN2/4Δ30 in immunogenic compositions
The immunogenic composition further includes a nucleic acid encoding a chimeric dengue virus rDEN2/4Δ30, characterized by the Δ30 deletion of nucleotides about 172 to 143 in the dengue 4 3′-UTR.
Methods of inducing immune response with mutated dengue viruses
Methods involve administering the immunogenic compositions including dengue or chimeric dengue viruses with specific 3′-UTR mutations (such as Δ30/31) to patients to elicit immune responses against dengue virus.
Nucleic acids encoding dengue or chimeric dengue viruses with Δ30 and additional deletions
Nucleic acids encoding dengue or chimeric dengue viruses comprise the Δ30 mutation in the 3′-UTR plus one or more additional mutations selected from a group including deletions Δ31, Δ50, Δ61, Δ80, Δ116(A), Δ116(B), and Δ146, each defined by precise deleted nucleotide ranges and deletion junction sequences in the 3′-UTR of DEN3 Sleman/78 strain.
Applicability to all dengue serotypes
The nucleic acids encoding the mutated dengue or chimeric dengue viruses can pertain to any of the dengue virus serotypes 1, 2, 3, or 4.
Immunogenic compositions comprising mutated nucleic acids or viruses
Immunogenic compositions include these nucleic acids encoding mutated dengue viruses or the dengue viruses themselves, with compositions formulated to be tetravalent for dengue serotypes 1 through 4.
The claims cover dengue virus or chimeric dengue virus nucleic acids and immunogenic compositions embodying Δ30 and further 3′-UTR deletion mutations to achieve attenuation, as well as methods of use for immunization. The scope encompasses multiple serotypes and chimeric constructs for tetravalent vaccine development.
Stated Advantages
Δ30 mutation effectively attenuates DEN4 and DEN1 virus strains, contributing to safe and immunogenic vaccine components.
Expanded deletion mutations in the 3′-UTR provide additional attenuation for DEN3 virus which was not sufficiently attenuated by Δ30 mutation alone.
Chimeric viruses with 3′-UTR replacements or additional deletions achieve attenuation while maintaining immunogenicity and replication levels sufficient for vaccine production.
Mutant viruses exhibit reduced replication in mosquito cells and mosquitoes, indicating potential improved safety by lowering transmission risk.
Immunogenic compositions based on these mutations induce neutralizing antibodies and complete protection from viremia upon challenge in animal models.
Documented Applications
Formulation of tetravalent vaccines comprising dengue virus or chimeric dengue virus components with Δ30 and additional 3′-UTR mutations to immunize adults or children at risk of dengue virus infection.
Use of the mutated dengue viruses as live attenuated vaccines administered by intramuscular, subcutaneous, or intradermal routes to elicit protective immune responses.
Secondary treatment of dengue virus-infected patients including children in endemic areas, foreign travelers, military personnel, and populations in epidemic regions.
Use of detection methods for vaccine-specific 3′-UTR deletions using nucleic acid probes and primers to monitor infection, vaccine take, or therapy progress.
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