IP Library › Granted Patent US 12,600,752
Granted Patent B2
US 12,600,752 · App. 17/778,055 · Granted Apr 14, 2026

Methods and compositions for recombinant dengue viruses or vaccine and diagnostic development

Inventors: Ralph Baric (Haw River, NC); Ellen Young (Hillsborough, NC); Jennifer Munt (Durham, NC)
Assignee: The University of North Carolina at Chapel Hill
C07K14/1825A61K39/12C12N7/00
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Quick Facts
Patent No.
US 12,600,752
App. No.
17/778,055
Granted
Apr 14, 2026
Kind
B2
Abstract

The present invention provides compositions and methods of use comprising a chimeric dengue virus E glycoprotein comprising a dengue virus E glycoprotein backbone, which comprises amino acid substitutions that may introduce an epitope that is recognized by an antibody from a dengue virus serotype that is different from the dengue virus serotype of the dengue virus E glycoprotein backbone.

Claims (60)

1 . A chimeric dengue virus E glycoprotein, comprising the following amino acid substitutions wherein the numbering is based on the reference amino acid sequence of an E glycoprotein of dengue virus serotype 3 (DENV3) identified as SEQ ID NO: 1:

T138S, Q156H, V158T, S167P, A171I, I172Q, P174T, E175D, N270T, G273T, S275T, and D382E, and wherein said dengue virus E glycoprotein further comprises an insertion of the amino acid residues T and E between amino acid residues 155 and 156.

2 . A chimeric dengue virus E glycoprotein, comprising the following amino acid substitutions wherein the numbering is based on the reference amino acid sequence of an E glycoprotein of dengue virus serotype 3 (DENV3) identified as SEQ ID NO: 1:

(i) Q46L, A50V, L53P, T55V, T138S, Q156H, V158T, T159I, E161T, S167P, T169S, A171I, I172Q, P174T, E175D, T178A, N270T, G273T, S275T, D382E, and N383K;

(ii) Q46L, T138S, I141V, Q156H, V158T, T159I, E161T, S167P, T169S, A171I, I172Q, P174T, E175D, T178A, G180T, E182D, N270T, G273T, S275T, E291T, N302G, T303S, V305K, E323K, K325E, E327T, N375Y, I378V, I380A, D382E, N383K, I387L; or

(iii) Q46L, Q52N, L53P, T138S, I141V, Q156H, V158T, T159I, E161T, S167P, T169S, A171I, I172Q, P174T, E175D, T178A, G180T, E182D, N270T, G273T, S275T, E291T, N302G, T303S, V305K, E323K, K325E, E327T, N375Y, I378V, I380A, D382E, N383K, I387L, and N388S,

and wherein said dengue virus E glycoprotein further comprises an insertion of the amino acid residues T and E between amino acid residues 155 and 156.

3 . The chimeric dengue virus E glycoprotein of claim 2 , comprising the amino acid sequence of SEQ ID NO:1,

wherein said amino acid sequence comprises the following amino acid substitutions:

(i) Q46L, A50V, L53P, T55V, T138S, Q156H, V158T, T159I, E161T, S167P, T169S, A1711, I172Q, P174T, E175D, T178A, N270T, G273T, S275T, D382E, and N383K;

(ii) Q46L, T138S, I141V, Q156H, V158T, T159I, E161T, S167P, T169S, A171I, I172Q, P174T, E175D, T178A, G180T, E182D, N270T, G273T, S275T, E291T, N302G, T303S, V305K, E323K, K325E, E327T, N375Y, I378V, I380A, D382E, N383K, I387L, and N388S; and/or

(iii) Q46L, Q52N, L53P, T138S, I141V, Q156H, V158T, T159I, E161T, S167P, T169S, A171I, I172Q, P174T, E175D, T178A, G180T, E182D, N270T, G273T, S275T, E291T, N302G, T303S, V305K, E323K, K325E, E327T, N375Y, I378V, I380A, D382E, N383K, I387L, and N388S,

and wherein said dengue virus E glycoprotein further comprises an insertion of the amino acid residues T and E between amino acid residues 155 and 156.

4 . The chimeric dengue virus E glycoprotein of claim 3 , comprising the amino acid sequence of any one of SEQ ID NOs: 3-5.

5 . A chimeric dengue virus E glycoprotein, comprising the following amino acid substitutions wherein the numbering is based on the reference amino acid sequence of an E glycoprotein of dengue virus serotype 1 (DENV1) identified as SEQ ID NO: 2:

(i) L46Q, N52Q, S138T, T156Q, E157S, T160V, I161T, T163E, S171T, I173A, Q174I, T176P, D177E, T272N, T275G, T277S, E384D, and K385N;

(ii) L46Q, S138T, V141I, T156Q, T160V, I161T, T163E, P169S, S171T, I173A, Q174I, T176P, D177E, A180T, T182G, D184E, T272N, T275G, T277S, and T293E, and wherein said dengue virus E glycoprotein further comprises a deletion of the amino acid residues E157 and H158;

(iii) P53L, V55T, A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, I129V, V197I, K203N, S205A, L207M, K210R, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, and T272N;

(iv) A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, and T272N;

(v) L46Q, V50A, N52Q, P53L, V55T, A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, I129V, V197I, K203N, S205A, L207M, K210R, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, T272N, T275G, and T277S;

(vi) V50A, N52Q, P53L, V55T, A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, I129V, V197I, K203N, S205A, L207M, K210R, L214F, S225T, S227E, Q228T, E229P, Q234K, D23SE, T242N, T272N, T275G, and T277S;

(vii) V300A, G304N, S305T, K307V, E309K, A313S, V320I, V322I, Q323K, K325E, E327K, T329E, S339T, Q340E, V345K, Q347H, I357V, D360K, K363E, Y377N, V380I, A382I, E384D, K385N, L389I, and S390N;

(viii) V300A, G304N, S305T, K307V, E309K, A313S, V320I, V322I, Q323K, K325E, E327K, T329E, S339T, Q340E, V345K, T346A, Q347H, I357V, D360K, K363E, Y377N, V380I, A382I, E384D, K385N, L389I, and S390N; or

(ix) V300A, G304N, S305T, K307V, E309K, A313S, V320I, V322I, Q323K, K325E, E327K, T329E, S339T, Q340E, E342G, K343Q, V345K, T346A, Q347H, I357V, D360K, K363E, Y377N, V380I, A382I, E384D, K385N, L389I, and S390N.

6 . The chimeric dengue virus E glycoprotein of claim 5 , comprising the amino acid sequence of SEQ ID NO:2,

wherein said amino acid sequence comprises the following amino acid substitutions:

(i) L46Q, N52Q, S138T, T156Q, E157S, T160V, I161T, T163E, S171T, I173A, Q174I, T176P, D177E, T272N, T275G, T277S, E384D, and K385N;

(ii) L46Q, S138T, V141I, T156Q, T160V, I161T, T163E, P169S, S171T, I173A, Q174I, T176P, D177E, A180T, T182G, D184E, T272N, T275G, T277S, and T293E, and wherein said dengue virus E glycoprotein further comprises a deletion of the amino acid residues E157 and H158;

(iii) P53L, V55T, A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, I129V, V197I, K203N, S205A, L207M, K210R, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, and T272N;

(iv) A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, and T272N;

(v) L46Q, V50A, N52Q, P53L, V55T, A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, I129V, V197I, K203N, S205A, L207M, K210R, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, T272N, T275G, and T277S;

(vi) V50A, N52Q, P53L, V55T, A63G, S66T, T68I, T81V, V83P, T88Q, F90Y, R93K, R94H, F96Y, I114V, K120Q, V122L, T123E, K124P, L125I, I129V, V197I, K203N, S205A, L207M, K210R, L214F, S225T, S227E, Q228T, E229P, Q234K, D235E, T242N, T272N, T275G, and T277S;

(vii) V300A, G304N, S305T, K307V, E309K, A313S, V320I, V322I, Q323K, K325E, E327K, T329E, S339T, Q340E, V345K, Q347H, I357V, D360K, K363E, Y377N, V380I, A382I, E384D, K385N, L389I, and S390N;

(viii) V300A, G304N, S305T, K307V, E309K, A313S, V320I, V322I, Q323K, K325E, E327K, T329E, S339T, Q340E, V345K, T346A, Q347H, I357V, D360K, K363E, Y377N, V380I, A382I, E384D, K385N, L389I, and S390N; and/or

(ix) V300A, G304N, S305T, K307V, E309K, A313S, V320I, V322I, Q323K, K325E, E327K, T329E, S339T, Q340E, E342G, K343Q, V345K, T346A, Q347H, I357V, D360K, K363E, Y377N, V380I, A382I, E384D, K385N, L389I, and S390N.

7 . The chimeric dengue virus E glycoprotein of claim 6 comprising the amino acid sequence of any one of SEQ ID NOs: 6-14.

8 . A flavivirus particle or virus like particle (VLP) comprising the E glycoprotein of claim 2 .

9 . An isolated nucleic acid molecule encoding the E glycoprotein of claim 2 .

10 . An isolated nucleic acid molecule encoding the flavivirus particle or VLP of claim 8 .

11 . A population of flavivirus particles comprising the flavivirus particle of claim 8 .

12 . A composition comprising the E glycoprotein of claim 2 , in a pharmaceutically acceptable carrier.

13 . A method of producing an immune response to a dengue virus in a subject, comprising administering to the subject an effective amount of the E glycoprotein of claim 2 .

14 . A method of treating a dengue virus infection in a subject, comprising administering to the subject an effective amount of the E glycoprotein of claim 2 .

15 . A method of protecting a subject from the effects of dengue virus serotype 1 (DENV1) infection and dengue virus serotype 3 (DENV3) infection, comprising administering to the subject an effective amount of the E glycoprotein of claim 2 .

16 . A flavivirus particle or virus like particle (VLP) comprising the E glycoprotein of claim 1 .

17 . An isolated nucleic acid molecule encoding the E glycoprotein of claim 1 .

18 . An isolated nucleic acid molecule encoding the flavivirus particle or VLP of claim 16 .

19 . A population of flavivirus particles comprising the flavivirus particle of claim 16 .

20 . A composition comprising the E glycoprotein of claim 1 , in a pharmaceutically acceptable carrier.

21 . A method of producing an immune response to a dengue virus in a subject, comprising administering to the subject an effective amount of the E glycoprotein of claim 1 .

22 . A method of treating a dengue virus infection in a subject, comprising administering to the subject an effective amount of the E glycoprotein of claim 1 .

23 . A method of protecting a subject from the effects of dengue virus serotype 1 (DENV1) infection and dengue virus serotype 3 (DENV3) infection comprising administering to the subject an effective amount of the E glycoprotein of claim 1 .

24 . A flavivirus particle or virus like particle (VLP) comprising the E glycoprotein of claim 5 .

25 . An isolated nucleic acid molecule encoding the E glycoprotein of claim 5 .

26 . An isolated nucleic acid molecule encoding the flavivirus particle or VLP of claim 24 .

27 . A population of flavivirus particles comprising the flavivirus particle of claim 24 .

28 . A composition comprising the E glycoprotein of claim 5 , in a pharmaceutically acceptable carrier.

29 . A method of producing an immune response to a dengue virus in a subject, comprising administering to the subject an effective amount of the E glycoprotein of claim 5 .

30 . A method of treating a dengue virus infection in a subject, comprising administering to the subject an effective amount of the E glycoprotein of claim 5 .

31 . A method of protecting a subject from the effects of dengue virus serotype 1 (DENV1) infection and dengue virus serotype 3 (DENV3) infection comprising administering to the subject an effective amount of the E glycoprotein of claim 5 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 19, 2022
From: BARIC, RALPH; YOUNG, ELLEN; MUNT, JENNIFER
To: THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Reel/Frame 059955/0605 →
Continuity (2)
Provisional Application 62938133 · Nov 20, 2019
Related Publication 20230018080A1 · Jan 19, 2023
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