Dengue virus vaccine compositions and methods of use thereof
View Patent ↗The present invention relates to dengue virus vaccine compositions comprising a first and a second dengue vaccine, wherein the first dengue vaccine comprises at least one live, 5 attenuated dengue virus or live, attenuated chimeric dengue virus and the second dengue vaccine is a recombinant dengue subunit vaccine, a DNA vaccine, a conjugate vaccine, or an inactivated dengue vaccine; wherein the genome of the live attenuated dengue virus or the live attenuated chimeric dengue virus comprises a 30 nucleotide deletion of the TL2 stem-loop structure of the 3′ untranslated region. The dengue virus vaccine compositions of the invention may further 10 comprise one or more adjuvants. In preferred embodiments of the invention, the first and the second dengue vaccine are tetravalent. The invention also relates to methods of using the dengue virus vaccine compositions of the invention to treat or prevent dengue infection, or to prevent, ameliorate, or delay the onset or progression of the clinical manifestations thereof.
1. A dengue virus immunogenic composition comprising a pharmaceutically effective amount of:
(a) a tetravalent live attenuated dengue immunogenic composition comprising at least one live attenuated dengue virus (LAV) or at least one live attenuated chimeric flavivirus (LACV), wherein the LAV and the LACV comprise a viral genome that contains a deletion of about 30 nucleotides corresponding to the TL-2 stem-loop structure of the 3′ untranslated region (UTR), wherein the about 30 nucleotides corresponds to nucleotides 172 to 143 from the 3′ end of the viral genome; and
(b) a tetravalent dengue subunit immunogenic composition which comprises truncated dengue E proteins, or fragments thereof, from dengue virus type 1 (DEN1), dengue virus type 2 (DEN2), dengue virus type 3 (DEN3), and dengue virus type 4 (DEN4), wherein each of the truncated dengue E proteins constitute about 80% of the length of wild type dengue E proteins of DEN1, DEN2, DEN3and DEN4, respectively, starting from amino acid residue 1 at its N-terminus.
2. The composition of claim 1 , further comprising an adjuvant.
3. The composition of claim 2 , wherein the adjuvant is an aluminum salt adjuvant.
4. The composition of claim 3 , wherein the amount of elemental aluminum in the composition is from about 50 μg to about 1.25 mg.
5. The composition of claim 4 , wherein the amount of elemental aluminum in the composition is from about 200 μg to about 850 μg.
6. The composition of claim 2 , wherein the adjuvant is a saponin-based adjuvant.
7. The composition of claim 1 , wherein the amount of each E protein in the composition is from about 0.5 μg to about 500 μg.
8. The composition of claim 7 , wherein the amount of each E protein in the composition is from about 1.0 μg to about 100 μg.
9. The composition of claim 8 , wherein the amount of DEN4 E protein is about 1.5 to about 2.5 times the amount of each of DEN1, DEN2,and DEN3 E proteins.
10. The composition of claim 7 , wherein each E protein is recombinantly produced and expressed in insect host cells.
11. The composition of claim 1 , wherein the live attenuated dengue immunogenic composition comprises one LACV that is immunogenic against dengue serotype 2 and three LAVs that are immunogenic against dengue serotypes 1, 3, and 4 wherein the one LACV and the three LAVs each comprise a viral genome that contains a deletion of about 30 nucleotides corresponding to the TL-2 stem-loop structure of the 3′ untranslated region (UTR), wherein the about 30 nucleotides corresponds to nucleotides 172 to 143 from the 3′ end of the viral genome.
12. The composition of claim 11 , wherein the viral genome of the LACV comprises preMembrane (prM) and envelope (E) genes of dengue serotype 2 and capsid and non-structural genes of a different dengue serotype.
13. The composition of claim 12 , wherein the different dengue serotype is dengue serotype 4.
14. The composition of claim 1 , wherein the live attenuated dengue immunogenic composition comprises a LAV that is immunogenic against dengue serotype 3, wherein the viral genome of the LAV further contains a deletion of nucleotides upstream from the Δ30 deletion corresponding to the TL-3 structure of the 3′ UTR.
15. The composition of claim 1 , wherein the potency of the live attenuated dengue immunogenic composition is from 10 to about 1×10 7 plaque forming units (PFU's).
16. The composition of claim 15 , wherein the potency of the live attenuated dengue immunogenic composition is from about 1×10 3 to about 1×10 5 PFU's.
17. A method of (i) inducing an immune response against dengue, (ii) reducing the likelihood of dengue infection, or (iii) preventing or ameliorating the symptoms of dengue infection, in a patient in need thereof, comprising administering an effective amount of the dengue virus immunogenic composition of claim 1 to the patient.
18. A method of reducing the likelihood of dengue infection, or preventing or ameliorating the symptoms of dengue infection, comprising the steps of:
(a) mixing a first and a second dengue immunogenic composition to form a dengue virus immunogenic composition, wherein the first dengue immunogenic composition is a tetravalent live attenuated dengue immunogenic composition comprising at least one live attenuated dengue virus (LAV) or at least one live attenuated chimeric flavivirus (LACV), wherein the LAV and the LACV comprise a viral genome that contains a deletion of about 30 nucleotides corresponding to the TL-2 stem-loop structure of the 3′ untranslated region (UTR), wherein the about 30 nucleotides corresponds to nucleotides 172 to 143 from the 3′ end of the viral genome; and wherein the second dengue immunogenic composition is a tetravalent dengue subunit immunogenic composition which comprises truncated dengue E proteins, or fragments thereof, from dengue virus type 1 (DEN1), dengue virus type 2 (DEN2), dengue virus type 3 (DEN3), and dengue virus type 4 (DEN4), wherein each of the truncated dengue E proteins constitute about 80% of the length of wild type dengue E proteins of DEN1, DEN2, DEN3 and DEN4, respectively, starting from amino acid residue 1 at its N-terminus; and
(b) administering the dengue virus immunogenic composition of step (a) to a patient in need thereof.
19. A method of reducing the likelihood of dengue infection, in a patient in need thereof, comprising the steps of:
(a) administering a first dengue virus immunogenic composition according to claim 1 to the patient;
(b) waiting for a predetermined amount of time to pass after step (a); and
(c) administering to the patient a second dengue virus immunogenic composition according to claim 1 ; whereby the likelihood of being infected with dengue is reduced in the patient.