Development of dengue virus vaccine components

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.

What is claimed is: 
     
       1. A nucleic acid encoding a dengue virus or chimeric dengue virus comprising
 a Δ30 mutation that removes the TL-2 homologous structure in DEN1 or DEN3, and nucleotides additional to the Δ30 mutation deleted from the 3′-UTR that removes one or more nucleotides in the 5′ direction up to and including nucleotide 258 with reverse-direction numbering. 
 
     
     
       2. The nucleic acid encoding a dengue virus or chimeric dengue virus of  claim 1  wherein the mutation removes the TL-2 homologous structure and removes the additional nucleotides in a contiguous manner contiguous to the Δ30 mutation. 
     
     
       3. The nucleic acid encoding a dengue virus or chimeric dengue virus of  claim 2  wherein the mutation is the Δ86 mutation, such that the Δ86 mutation deletes nucleotides from about 228 to about 145 of DEN1, or nucleotides from about 228 to about 143 of DEN3, designated with the reverse-direction numbering system. 
     
     
       4. The nucleic acid encoding a dengue virus or chimeric dengue virus of  claim 3  wherein the serotype is DEN3. 
     
     
       5. The nucleic acid encoding a dengue virus or chimeric dengue virus of  claim 1  wherein the mutation removes both the TL-2 homologous structure and the additional nucleotides in a noncontiguous manner noncontiguous to the Δ30 mutation. 
     
     
       6. The nucleic acid encoding a dengue virus or chimeric dengue virus of  claim 5  wherein the mutation is the Δ30/31 mutation, such that the Δ30 mutation deletes nucleotides from about 174 to about 145 of DEN 1, or nucleotides from about 173 to about 143 of DEN3, designated with the reverse-order numbering system, and the Δ31 mutation deletes nucleotides from about 258 to about 228 of DEN1 or nucleotides from about 258 to about 228 of DEN3, designated with the reverse-order numbering system. 
     
     
       7. The nucleic acid encoding a dengue virus or chimeric dengue virus of  claim 6  wherein the serotype is DEN3. 
     
     
       8. An immunogenic composition comprising a nucleic acid encoding a dengue virus or chimeric dengue virus according to  claim 1  or a dengue virus or chimeric dengue virus comprising said nucleic acid. 
     
     
       9. A method of inducing an immune response to a dengue virus in a patient comprising administering the immunogenic composition of  claim 8  to a patient to induce an immune response to a dengue virus. 
     
     
       10. A method of producing a nucleic acid encoding a dengue virus or chimeric dengue virus comprising introducing a mutation into the 3′ untranslated region (3′-UTR) of DENI or DEN3, wherein the mutation is
 a Δ30 mutation that removes the TL-2 homologous structure in DEN1 or DEN3, and nucleotides additional to the Δ30 mutation deleted from the 3′-UTR that removes one or more nucleotides in the 5′ direction up to and including nucleotide 258 with reverse-direction numbering. 
 
     
     
       11. A dengue virus or chimeric dengue virus comprising the nucleic acid encoding the dengue virus or chimeric dengue virus of  claim 1 . 
     
     
       12. A dengue virus or chimeric dengue virus comprising the nucleic acid encoding the dengue virus or chimeric dengue virus of  claim 3 . 
     
     
       13. A dengue virus or chimeric dengue virus comprising the nucleic acid encoding the dengue virus or chimeric dengue virus of  claim 6 . 
     
     
       14. A tetravelent immunogenic composition comprising nucleic acids encoding each of DEN1, DEN2, DEN3, and DEN4, wherein each nucleic acid has a Δ30 mutation that removes the TL-2 homologous structure and nucleotides additional to the Δ30 mutation deleted from the 3′-UTR that removes one or more nucleotides in the 5′ direction up to and including nucleotide 258 with reverse-direction numbering.