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-12203100-B2
Publication Date
2025-01-21
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 containing mutations in the 3′ untranslated region (3′-UTR) of their genome, specifically including the Δ30 mutation that removes the TL-2 homologous structure in each of the dengue virus serotypes 1, 2, 3, and 4, and additional nucleotide deletions extending in the 5' direction up to the 5' boundary of the TL-3 homologous structure. Another aspect involves replacing 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 further nucleotide deletions.
The background problem addressed is the absence of a safe and effective dengue virus vaccine that provides simultaneous immunity to all four dengue serotypes, necessary because infection with one serotype can enhance the severity of infection with another serotype. Prior approaches have shown the Δ30 deletion attenuates dengue virus serotype 4, but not satisfactorily serotype 3, creating the need for additional mutations or chimerization strategies to achieve attenuation suitable for vaccine development.
The invention thus provides a set of specifically designed mutations or chimeric modifications in the 3′-UTR that attenuate dengue viruses for all four serotypes, enabling the production of live attenuated dengue vaccine components. These vaccines induce immune responses while demonstrating reduced replication in animal models and cell culture systems, offering the potential for safe, immunogenic, and economical tetravalent dengue vaccines.
Claims Coverage
The independent claims cover an immunogenic tetravalent composition encoding dengue virus serotypes 1 and 3 with specific Δ30/31 mutations, and methods of inducing immune responses using this composition, involving two main inventive features.
Tetravalent dengue virus immunogenic composition with Δ30/31 mutations
An immunogenic composition that is tetravalent for dengue serotypes 1, 2, 3, and 4, comprising nucleic acids encoding dengue 1 and dengue 3 viruses each having a Δ30/31 mutation in the 3′ untranslated region (3′ UTR), with the Δ30 mutation deleting nucleotides approximately 174 to 145 for dengue 1 and 173 to 143 for dengue 3, and the Δ31 mutation deleting nucleotides approximately 258 to 228 in the 3′ UTR designated using reverse-order numbering.
Method of inducing immune response using the tetravalent dengue immunogenic composition
A method of inducing an immune response to dengue virus in a patient by administering the described tetravalent immunogenic composition containing nucleic acids encoding dengue 1 and dengue 3 viruses with the Δ30/31 mutations, to adults or children at risk of dengue infection or infected individuals.
The claims provide coverage for specifically engineered dengue virus mutants comprising Δ30/31 deletions in their 3′ UTR comprising tetravalent vaccine compositions and methods for eliciting immune responses by administering these compositions.
Stated Advantages
Attenuation of dengue viruses is achieved by 3′-UTR mutations, enabling development of safe and effective live attenuated dengue vaccine components.
The modified viruses induce strong neutralizing antibody responses and protection against wild type dengue virus challenge.
Mutants replicate efficiently in cell cultures suitable for vaccine production, facilitating cost-effective manufacturing.
Use of complete sets of dengue virus proteins in vaccine components enhances the potential for full cellular and humoral immunity.
Reduced replication in mosquito vectors suggests decreased potential for transmission, increasing safety.
Documented Applications
Use in tetravalent dengue vaccine formulations to protect against all four dengue virus serotypes.
Administration as prophylactic vaccines to adults and children at risk of dengue virus infection.
Therapeutic use in patients infected with dengue virus.
Use in regions endemic or at risk for dengue virus expansion, including travelers and military personnel.
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