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-11332722-B2
Publication Date
2022-05-17
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 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 virus comprising mutations in the 3′ untranslated region (3′-UTR) of the virus genome, specifically involving a Δ30 mutation that removes the TL-2 homologous structure in the 3′-UTR, and additional nucleotide deletions extending to the 5′ boundary of the TL-3 homologous structure, or replacement of the 3′-UTR of a dengue virus of one serotype with that of another serotype. These modifications are applied to the four dengue virus serotypes 1, 2, 3, and 4.
The problem addressed by the invention is the lack of a safe and effective vaccine for dengue virus, which includes four serotypes causing widespread disease with significant morbidity and mortality. While the Δ30 mutation has been shown to attenuate DEN4 effectively in rhesus monkeys and humans, it does not sufficiently attenuate DEN3. There is a need for vaccine components that induce protection against all four serotypes and that present safe attenuation profiles suitable for vaccine development.
The invention presents alternative or improved attenuating mutations in the 3′-UTR, including deletions larger than Δ30 and chimeric replacement of 3′-UTRs between serotypes, to generate viruses with attenuated growth and robust immunogenic profiles. These mutated or chimeric dengue viruses can be used in immunogenic compositions, methods to induce immune responses, and vaccine production.
Claims Coverage
The patent claims include immunogenic compositions, nucleic acids, methods of inducing immune responses, and methods of making dengue or chimeric dengue viruses, focusing on mutations in the 3′-UTR of the dengue virus genome for attenuation and chimerization.
Immunogenic composition with chimeric dengue virus having 3′-UTR replaced by DEN4Δ30
An immunogenic composition that is tetravalent for dengue serotypes 1, 2, 3, and 4 comprising nucleic acid encoding a chimeric dengue virus with the dengue 3 serotype wherein its 3′-UTR is replaced with the dengue 4 3′-UTR containing the Δ30 deletion mutation deleting nucleotides about 172 to 143 of the DEN4 3′-UTR (reverse numbering).
Deletion of nucleotides additional to the Δ30 mutation in chimeric dengue virus
The nucleic acid encoding the chimeric dengue virus with rDEN3 3′-UTR replaced by DEN4Δ30 further comprising deletions of nucleotides additional to the Δ30 mutation, including various defined deletion regions with specific nucleotide ranges and deletion junctions in the 3′-UTR of DEN3 Sleman/78 strain.
Immunogenic compositions comprising chimeric dengue viruses with rDEN2/4Δ30
Immunogenic composition comprising nucleic acid encoding chimeric dengue virus rDEN2/4Δ30 with the Δ30 mutation deleting nucleotides about 172 to 143 of the DEN4 3′-UTR (reverse numbering).
Method of inducing immune response with immunogenic compositions
Methods of inducing an immune response to dengue virus in patients by administering the immunogenic compositions comprising the chimeric dengue virus with 3′-UTR replaced by DEN4Δ30 mutation.
Method of producing nucleic acids encoding dengue virus with 3′-UTR mutations
Methods of producing nucleic acid encoding dengue virus or chimeric dengue virus comprising introducing: a Δ30 mutation removing the TL-2 homologous structure in the 3′-UTR, and additional mutations corresponding to defined nucleotide deletions in the 3′-UTR of DEN3 Sleman/78 with specific deletion junction sequences.
The independent claims focus on compositions comprising chimeric dengue viruses with 3′-UTR mutations including Δ30 and additional deletions, methods of inducing immune responses using these compositions, and nucleic acid construction methods introducing these mutations for attenuation and vaccination against dengue virus serotypes.
Stated Advantages
The Δ30 mutation attenuates dengue virus serotype 4 in rhesus monkeys and humans, reducing viremia while maintaining immunogenicity.
Mutations additional to Δ30 and 3′-UTR replacement strategies provide attenuation in serotypes not attenuated by Δ30 alone, such as dengue serotype 3.
The attenuated viruses replicate to high titers in Vero cells, supporting feasibility of vaccine manufacture.
Vaccines comprising these mutated viruses induce protective immune responses including neutralizing antibodies and provide complete protection from challenge with wild type virus in animal models.
The Δ30/31 mutations reduce replication in mosquito vector cells and mosquitoes themselves, indicating a favorable safety profile by restricting transmission potential.
Documented Applications
Primary prophylactic vaccination of adults or children at risk of dengue virus infection, including inhabitants of endemic regions, foreign travelers, military personnel, and populations undergoing dengue epidemics.
Secondary treatment of dengue virus-infected patients.
Use in tetravalent live attenuated dengue vaccines that protect against all four dengue serotypes.
Interested in licensing this patent?