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-10160957-B2
Publication Date
2018-12-25
Expiration Date
2027-08-15
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 viruses or chimeric dengue viruses containing mutations in the 3′ untranslated region (3′-UTR) of the viral genome, specifically comprising a Δ30 mutation that removes the TL-2 homologous structure in the 3′-UTR across dengue virus serotypes 1, 2, 3, and 4. The mutations may also include additional nucleotides deleted from the 3′-UTR in the 5′ direction up to the 5′ boundary of the TL-3 homologous structure or the replacement of the 3′-UTR of a dengue virus of one serotype with that of another serotype, optionally containing the Δ30 mutation and additional deletions.
The problem addressed by this invention arises from the need to develop a live attenuated dengue vaccine that is safe, effective, and provides simultaneous protection against all four dengue virus serotypes. Prior work showed that a Δ30 mutation attenuates dengue virus type 4 (DEN4) effectively in rhesus monkeys and humans; however, this same mutation did not attenuate dengue virus type 3 (DEN3) sufficiently. The invention seeks to create new mutations as well as chimeric dengue viruses that attenuate viral growth characteristics across all serotypes, including types where the Δ30 mutation alone is not adequate, thereby enabling the formulation of a tetravalent dengue vaccine.
Claims Coverage
The patent includes six claims with one independent claim covering a nucleic acid encoding a dengue virus or chimeric dengue virus with specific mutations in the 3′ untranslated region. The main inventive features focus on the mutations introduced in the 3′-UTR and their use in immunogenic compositions and methods of inducing immune responses.
Mutation in the 3′ untranslated region comprising the Δ30 mutation and additional deletions
A nucleic acid encoding a dengue virus or chimeric dengue virus comprising a mutation in the 3′-UTR that includes a Δ30 mutation removing nucleotides 173 to 144 of dengue serotype 2 or nucleotides 172 to 143 of dengue serotype 4, along with additional nucleotide deletions from the 3′-UTR in the 5′ direction. These additional deletions include nucleotides from about 228 to about 144 in DEN 2 or about 228 to about 143 in DEN4, and nucleotides from about 258 to about 228, as defined by the reverse-direction numbering system.
Immunogenic composition comprising the mutant nucleic acid or virus
An immunogenic composition comprising a nucleic acid encoding the dengue virus or chimeric dengue virus as defined by the Δ30 and additional 3′-UTR nucleotide deletions, or comprising the dengue virus or chimeric dengue virus itself.
Tetravalent immunogenic composition
An immunogenic composition that is tetravalent, comprising components for dengue serotypes 1, 2, 3, and 4, incorporating the nucleic acid or viruses with the specified 3′-UTR mutations.
Method of inducing an immune response
A method of inducing an immune response in a patient by administering the immunogenic composition containing the dengue virus or chimeric dengue virus with the specified 3′-UTR mutations.
Method of producing mutant nucleic acid
A method of producing nucleic acid encoding dengue virus or chimeric dengue virus by introducing the Δ30 mutation and additional nucleotide deletions in the 3′-UTR as described for dengue serotype 2 or 4.
Dengue virus or chimeric dengue virus comprising the nucleic acid
A dengue virus or chimeric dengue virus comprising the nucleic acid encoding the mutation in the 3′-UTR combining the Δ30 mutation and additional nucleotide deletions.
The independent claims cover the dengue virus nucleic acid sequences encoding 3′-UTR mutations comprising the Δ30 deletion and additional adjacent deletions, immunogenic compositions using such viruses or nucleic acids, tetravalent formulations, methods of immune induction, and methods of producing these mutant nucleic acids and viruses.
Stated Advantages
The mutations in the 3′-UTR, including the Δ30 and additional deletions, attenuate dengue viruses effectively across multiple serotypes, addressing the insufficiency of the Δ30 mutation alone in DEN3.
The attenuated viruses maintain immunogenicity while having reduced replication, resulting in safer vaccine candidates with reduced reactogenicity.
The chimeric dengue viruses combining 3′-UTRs from different serotypes enable flexibility in vaccine design and may improve attenuation or replication properties in cell culture or hosts.
The described vaccine components demonstrate the potential for inducing protective immune responses without detectable viremia in animal models, indicating safety and efficacy potential in humans.
Some mutant viruses reached high titers in Vero cells, making them suitable for cost-effective manufacturing.
Documented Applications
Use of the mutant dengue viruses and chimeric dengue viruses as live attenuated vaccine components in single or tetravalent formulations for prevention of dengue virus infection in humans.
Administration of immunogenic compositions containing the attenuated dengue viruses to induce an immune response in adults and children at risk of dengue infection, including inhabitants of endemic or epidemic areas and travelers.
Use of nucleic acid probes and primers selective for the mutant or chimeric 3′-UTRs for detection, quantification, and monitoring of dengue virus vaccine strains or infections in samples.
Interested in licensing this patent?