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-9090873-B2
Publication Date
2015-07-28
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 virus 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 virus or chimeric dengue viruses comprising mutations in the 3′ untranslated region (3′-UTR) of the viral genome that attenuate the virus. One specific mutation, termed the Δ30 mutation, deletes 30 nucleotides removing the TL-2 homologous structure in the 3′-UTR of dengue virus serotypes 1, 2, 3, and 4. Additional deletions nucleotides extending beyond the Δ30 mutation can be made up to the 5′ boundary of the TL-3 homologous structure. Another approach involves replacing the 3′-UTR of a dengue virus serotype with the 3′-UTR of another serotype, optionally containing the Δ30 mutation and additional deletions.
The problem addressed is the lack of a vaccine effective against all four dengue virus serotypes, since partial immunity can increase disease severity. While the Δ30 mutation attenuates the DEN4 serotype, it was ineffective in attenuating DEN3 in rhesus monkeys. The invention aims to create live attenuated dengue vaccine components by introducing mutations or chimerism in the 3′-UTR to produce viruses that are attenuated yet immunogenic for use in protective vaccines.
Claims Coverage
The patent includes one independent claim focusing on nucleic acids encoding dengue virus or chimeric dengue viruses with replaced 3′-UTRs.
Replacement of 3′-UTR between different dengue virus serotypes
A dengue virus or chimeric dengue virus wherein the first 3′-UTR of a dengue virus serotype is replaced with the corresponding 3′-UTR of a different dengue virus serotype, optionally containing the Δ30 mutation and additional nucleotide deletions.
Inclusion of Δ30 mutation and additional nucleotide deletions in 3′-UTR
The 3′-UTR used for replacement optionally contains the Δ30 mutation and nucleotides additional to Δ30 mutation deleted, further attenuating the virus.
Specific serotype combinations of 3′-UTR replacements
Explicit embodiments include replacement of the 3′-UTR of DEN1 with serotypes 2, 3, or 4; DEN2 with 1, 3, or 4; DEN3 with 1, 2, or 4; and DEN4 with 1, 2, or 3, optionally including the Δ30 mutation and additional deletions.
Immunogenic compositions comprising the nucleic acids or viruses
Formulations containing the nucleic acid encoding the dengue or chimeric dengue virus or the dengue or chimeric dengue virus itself are claimed, including tetravalent vaccines covering all four serotypes.
Methods of inducing immune response and producing the modified viruses
Methods of inducing immune responses in patients by administering the immunogenic compositions, and methods of producing nucleic acids encoding dengue viruses with replaced 3′-UTRs containing optional Δ30 mutations and additional deletions are included.
The claim coverage centers on dengue virus nucleic acids and viruses with mutations or replacements in the 3′-UTR between serotypes, focusing on the Δ30 deletion and additional deletions for attenuation, as well as their immunogenic uses and production methods.
Stated Advantages
Attenuation of dengue virus serotypes by mutations in the 3′-UTR increases safety for vaccine use.
The mutations enable inclusion of full complement of dengue virus proteins inducing robust humoral and cellular immunity.
Vaccine components are capable of efficient replication in manufacturing cell lines, ensuring feasible production.
Mutant viruses demonstrate protection from wild-type challenge in animal models, indicating effective immunogenicity.
Chimeric viruses with replaced 3′-UTRs can provide type-specific attenuation where single deletions (like Δ30) are ineffective.
Documented Applications
Use as live, attenuated dengue virus vaccine components for each dengue serotype 1, 2, 3, and 4.
Formulation into tetravalent dengue vaccines providing simultaneous protection against all four serotypes.
Administration for primary prophylaxis against dengue virus infection in at-risk adults and children.
Secondary treatment of patients infected with dengue virus.
Vaccination of children in endemic regions, foreign travelers, military personnel, and inhabitants of regions with expanding dengue virus presence.
Use in diagnostic applications utilizing probes and primers targeting deletions or chimeric 3′-UTRs for detection of dengue virus presence and monitoring therapy.
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