Development of dengue virus vaccine components
Inventors
Whitehead, Stephen S. • Blaney, Joseph E. • Murphy, Brian R. • Lai, Ching-Juh
Assignees
Government Of United States Of American REPRESENTED BY SECRETARY Department Of Health And Human Services AS • US Department of Health and Human Services
Publication Number
US-11746335-B2
Publication Date
2023-09-05
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 dengue viruses or chimeric dengue viruses that contain mutations in the 3′ untranslated region (3′-UTR) of the viral genome. Specifically, these mutations include a Δ30 mutation that removes the TL-2 homologous structure in each of the four dengue virus serotypes (1, 2, 3, and 4), as well as nucleotides additional to the Δ30 mutation deleted from the 3′-UTR extending in the 5′ direction as far as the 5′ boundary of the TL-3 homologous structure in each serotype. Also included are chimeric viruses where the 3′-UTR of a dengue virus of one serotype is replaced with the 3′-UTR of a dengue virus of another serotype, optionally also containing the Δ30 mutation and additional deletions.
The problem addressed by the invention is the lack of a safe, effective, and economical dengue vaccine capable of providing simultaneous protection against all four dengue virus serotypes. While there exists an attenuated DEN4 virus with the Δ30 mutation, the same mutation does not effectively attenuate DEN3. Therefore, there is a need to develop dengue viruses and chimeric dengue viruses with specific 3′-UTR mutations that result in attenuation and maintain immunogenicity, suitable for use as vaccine components to protect against dengue virus infection.
The invention provides various mutant dengue viruses and chimeric dengue viruses with deletions in the 3′-UTR that attenuate growth characteristics of the virus while maintaining immunogenicity. Two main approaches are described: first, deleting nucleotides in the 3′-UTR beyond the Δ30 mutation, including deletion of the TL-2 and TL-3 homologous structures; second, replacing the 3′-UTR of a dengue virus of one serotype with the 3′-UTR from another serotype, optionally with Δ30 and additional deletions. The invention also encompasses immunogenic compositions, methods of inducing an immune response, and methods for producing these viruses.
Claims Coverage
The patent contains two independent claims focusing on tetravalent immunogenic compositions containing dengue nucleic acids with specific 3′-UTR mutations and methods of inducing immune responses using these compositions.
Tetravalent immunogenic composition with Δ30/Δ31 mutation in the 3′-UTR
An immunogenic composition comprising nucleic acids encoding dengue virus serotypes 1, 2, 3, and 4, wherein each nucleic acid contains a Δ30/Δ31 mutation in the 3′ untranslated region. This mutation deletes specific nucleotides in the 3′-UTR for each serotype, removing nucleotides 174-145 and 258-228 for DEN1, 173-144 and 258-228 for DEN2, 173-143 and 258-228 for DEN3, and 172-143 and 258-228 for DEN4, using a reverse order numbering system.
Method of inducing an immune response using the Δ30/Δ31 immunogenic composition
A method of inducing an immune response to dengue virus in a patient by administering the tetravalent immunogenic composition with the Δ30/Δ31 mutation in the 3′-UTR described above.
Tetravalent immunogenic composition with Δ86 mutation in the 3′-UTR
An immunogenic composition comprising nucleic acids encoding dengue virus serotypes 1, 2, 3, and 4, each containing a Δ86 mutation in the 3′ untranslated region. This mutation deletes nucleotides 228-145 of DEN1, 228-144 of DEN2, 228-143 of DEN3, and 228-143 of DEN4, designated using a reverse order numbering system.
Method of inducing an immune response using the Δ86 immunogenic composition
A method of inducing an immune response to dengue virus in a patient by administering the tetravalent immunogenic composition with the Δ86 mutation in the 3′-UTR described above.
The claims cover tetravalent vaccine compositions encoding dengue serotypes that carry defined deletions (Δ30/Δ31 or Δ86) in the 3′ untranslated region to attenuate the viruses, along with methods to induce immune responses by administering such compositions.
Stated Advantages
The mutations in the 3′-UTR attenuate dengue virus replication, resulting in safer vaccine components.
The mutant viruses retain immunogenicity, inducing neutralizing antibody responses and protection against wild type virus challenge.
The Δ30/Δ31 and Δ86 mutations provide attenuation across all four dengue serotypes, enabling development of tetravalent vaccines.
The approach allows generation of vaccine strains suitable for safe and economical manufacture with robust replication in Vero cells.
Attenuated viruses exhibit restricted replication in mosquito cells and mosquitoes, potentially reducing transmission risk.
Documented Applications
The viruses and immunogenic compositions are used as vaccine components for inducing immunity against dengue virus serotypes 1, 2, 3, and 4 in humans.
The vaccines can be administered prophylactically to adults or children at risk, including inhabitants of dengue endemic or epidemic regions, foreign travelers, and military personnel.
The method includes administration of the immunogenic compositions by intramuscular, subcutaneous, or intradermal routes.
Nucleic acid probes and primers corresponding to the deletion or chimeric 3′-UTRs are used to detect or quantify vaccine strains or monitor therapy progress.
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