IP Library › Granted Patent US 12709635

Granted Patent B2

US 12709635 · App. 18/171,804 · Granted Aug 18, 2026

Methods and compositions for inducing an immune response using conserved element constructs

Inventors: Barbara K. Felber (Rockville, MD); George N. Pavlakis (Rockville, MD); James I. Mullins (Seattle, WA); Antonio Valentin (Frederick, MD); Siriphan Manocheewa (Seattle, WA)

Assignees: THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES; University of Washington

C07K14/005 A61K9/0009 A61K9/0019 A61K39/21 A61K39/39 C07K14/161 C07K14/535 A61K2039/53 A61K2039/54 A61K2039/545 A61K2039/55522 A61K2039/55561 A61K2039/572 A61K2039/575 C07K2319/02 C12N2740/16122 C12N2740/16134 C12N2740/16171 C12N2740/16222 C12N2740/16234 C12N2740/16271

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Quick Facts

Patent No.: US 12709635
App. No.: 18/171,804
Granted: Aug 18, 2026
Kind: B2

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Abstract

The invention provides methods and compositions for eliciting broad immune responses to HIV envelope proteins. The methods include use of nucleic acids constructs that encode conserved elements of HIV Env to induce immune responses.

Claims (70)

1 . A method of inducing an immune response to HIV Gag in a subject, the method comprising:

priming an immune response to HIV Gag, wherein priming comprises administering to the subject a conserved element (CE)-encoding expression vector that comprises a nucleic acid sequence encoding p24 Gag CE1 of SEQ ID NO: 40 fused at the N-terminus to a human GM-CSF signal peptide and a nucleic acid sequence encoding p24 Gag CE2 of SEQ ID NO: 41 fused at the N-terminus to a human GM-CSF signal peptide,

wherein the subject is not co-administered or has not previously been administered a recombinant nucleic acid construct encoding a full-length or substantially full-length HIV Gag polypeptide; and

boosting an immune response to HIV Gag,

wherein boosting comprises co-delivering the CE-encoding expression vector with an expression vector that encodes full-length HIV-1 p55 gag or substantially full-length HIV-1 p55 gag .

2 . The method of claim 1 , wherein the boosting step is performed about two months after the priming step.

3 . The method of claim 1 , wherein the method comprises two or three priming steps, each separated by about two months; and two boost steps, each separated by about two months.

4 . A nucleic acid encoding an immunogenic HIV Env conserved element polypeptide, wherein the HIV Env conserved element polypeptide comprises at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22; and the conserved elements are separated by linkers of 1 to 5 amino acids in length.

5 . The nucleic acid of claim 4 wherein the HIV Env conserved element polypeptide further comprises a V1V2 variable region sequence.

6 . The nucleic acid of claim 4 , wherein the HIV Env conserved element polypeptide comprises SEQ ID NO:24.

7 . A nucleic acid encoding an immunogenic HIV Env conserved element polypeptide, wherein the HIV Env conserved element polypeptide comprises at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO:21, and SEQ ID NO:23; and the conserved elements are separated by linkers of 1 to 5 amino acids in length.

8 . The nucleic acid of claim 7 , wherein the HIV Env conserved element polypeptide comprises at least six, seven, eight, nine, ten, or eleven conserved elements selected from SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO:21, and SEQ ID NO:23.

9 . The nucleic acid of claim 7 , wherein the HIV Env conserved element polypeptide comprises the conserved elements of SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO:21, and SEQ ID NO:23.

10 . The nucleic acid of claim 7 , further comprising a V1V2 variable region sequence.

11 . The nucleic acid of claim 6 , wherein the HIV Env conserved element polypeptide comprises SEQ ID NO:25.

12 . The nucleic acid of claim 4 , wherein the HIV Env conserved element polypeptide comprises a signal peptide.

13 . The nucleic acid of claim 12 , wherein the signal peptide is the signal peptide of GM-CSF.

14 . An immunogenic HIV Env conserved element polypeptide, comprising at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22, wherein the conserved elements are separated by linkers of 1 to 5 amino acids in length.

15 . The immunogenic HIV Env conserved element polypeptide of claim 14 , wherein the polypeptide comprises at least six, seven, eight, nine, ten, or eleven conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22.

16 . The immunogenic HIV Env conserved element polypeptide of claim 14 , wherein the polypeptide comprises the conserved elements of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22.

17 . The immunogenic HIV Env conserved element polypeptide of claim 14, 15, or 16 , wherein the polypeptide further comprises a V1V2 variable region sequence.

18 . The immunogenic HIV Env conserved element polypeptide of claim 14 , wherein the polypeptide comprises SEQ ID NO:24.

19 . A method of inducing an immune response to HIV Env, the method comprising administering a nucleic acid construct of claim 4 to a subject or an HIV Env conserved element polypeptide of claim 16 to the subject.

20 . A method of inducing an immune response to HIV Env, the method comprising administering:

a first nucleic acid encoding a first immunogenic HIV Env conserved element polypeptide that comprises at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22,

wherein the conserved elements are separated by linkers of 1 to 5 amino acids in length; and

a second nucleic acid encoding a second immunogenic HIV Env conserved element polypeptide comprises at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, and SEQ ID NO:23,

wherein the conserved elements are separated by linkers of 1 to 5 amino acids in length.

21 . The method of claim 20 , wherein:

the first immunogenic HIV Env conserved element polypeptide comprises at least six, seven, eight, nine, ten, or eleven conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22; and

the second immunogenic HIV Env conserved element polypeptide comprises at least six, seven, eight, nine, ten, or eleven conserved elements selected from SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, and SEQ ID NO:23.

22 . The method of claim 20 , wherein:

the first immunogenic HIV Env conserved element polypeptide comprises the conserved elements of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22; and

the second immunogenic HIV Env conserved element polypeptide comprises the conserved elements of SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO:21, and SEQ ID NO:23.

23 . The method of claim 20 , wherein the first immunogenic HIV Env conserved element polypeptide or the second immunogenic HIV Env conserved element polypeptide; or both the first immunogenic HIV Env conserved element polypeptide and the second immunogenic HIV Env conserved element polypeptide further comprise a V1V2 variable region sequence.

24 . The method of claim 20 , wherein the first immunogenic HIV Env conserved element comprises the amino acid sequence of SEQ ID NO:24 and the second immunogenic HIV Env conserved element polypeptide comprises the amino acid sequence of SEQ ID NO:25.

25 . The nucleic acid of claim 4 , wherein the HIV Env conserved element polypeptide comprises at least six, seven, eight, nine, ten, or eleven conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO: 6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22.

26 . The nucleic acid of claim 4 , wherein the HIV Env conserved element polypeptide comprises the conserved elements of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22.

27 . The method of claim 22 , wherein the first nucleic acid and second nucleic acid are contained in separate expression vectors.

28 . The method of claim 22 wherein the first nucleic acid and second nucleic acid are contained in the same expression vector.

29 . The method of claim 22 , wherein the first and the second nucleic acids are administered sequentially.

30 . The method of claim 22 , wherein the first and second nucleic acids are administered concurrently.

31 . The method of claim 22 , wherein a nucleic acid encoding a full-length Env polypeptide, or substantially full-length Env polypeptide, is administered as a boost after the first and the second nucleic acid encoding the first and the second HIV conserved element polypeptides.

32 . The method of claim 22 , wherein the nucleic acid constructs are administered intramuscularly by in vivo electroporation.

33 . A method of inducing an immune response to HIV Env, the method comprising administering:

a first immunogenic HIV Env conserved element polypeptide that comprises at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO: 4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, and SEQ ID NO:22,

wherein the conserved elements are separated by linkers of 1 to 5 amino acids in length; and

a second immunogenic HIV Env conserved element polypeptide comprises at least five conserved elements selected from SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO: 5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO:21, and SEQ ID NO:23,

wherein the conserved elements are separated by linkers of 1 to 5 amino acids in length.

34 . The method of claim 33 , wherein:

35 . The method of claim 33 , wherein:

36 . The method of claim 33 , wherein the first immunogenic HIV Env conserved element polypeptide or the second immunogenic HIV Env conserved element polypeptide; or both the first immunogenic HIV Env conserved element polypeptide and the second immunogenic HIV Env conserved element polypeptide further comprise a V1V2 variable region sequence.

37 . The method of claim 33 , wherein the first immunogenic HIV Env conserved element comprises the amino acid sequence of SEQ ID NO:24 and the second immunogenic HIV Env conserved element polypeptide comprises the amino acid sequence of SEQ ID NO:25.

38 . The method of claim 33 , wherein the first and the second immunogenic HIV Env conserved element polypeptides are administered sequentially.

39 . The method of claim 33 , wherein the first and the second immunogenic HIV Env conserved element polypeptides are administered concurrently.

40 . The method of claim 33 , wherein a full-length Env polypeptide, or substantially full-length Env polypeptide, is administered after the first and the second HIV conserved element polypeptides.

41 . An HIV Gag CE polypeptide comprising:

(a) SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO: 35, and/or SEQ ID NO:37; or

(b) SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO: 36, and/or SEQ ID NO:38.

42 . An HIV Gag CE polypeptide, comprising:

p24CE8-1 of SEQ ID NO: 57, p24CE9-1 of SEQ ID NO: 59, p24CE3-1 of SEQ ID NO: 28, p24CE10-1 of SEQ ID NO: 61, p24CE5-1 of SEQ ID NO: 30, p24CE11-1 of SEQ ID NO: 63, p24CE6-1 of SEQ ID NO: 31, p24CE12-1 of SEQ ID NO: 65, p24CE13-1 of SEQ ID NO: 67 as shown in FIG. 23 ; or

p24CE8-1 of SEQ ID NO: 57, p24CE9-2 of SEQ ID NO: 60, p24CE3-2 of SEQ ID NO: 35, p24CE10-2 of SEQ ID NO: 62, p24CE5-2 of SEQ ID NO: 37, p24CE11-2 of SEQ ID NO: 64, p24CE6-2 of SEQ ID NO: 38, p24CE1 2-2 of SEQ ID NO: 66, p24CE13-2 of SEQ ID NO: 68.

43 . The method of claim 21 , further comprising administering an immunogenic composition to induce an immune response to HIV Gag, wherein the immunogenic composition is an HIV Gag CE polypeptide comprising p24 CE1 of SEQ ID NO: 26, CE2 of SEQ ID NO: 27, CE3 of SEQ ID NO: 28, CE4 of SEQ ID NO: 29, CE5 of SEQ ID NO: 30, CE6 of SEQ ID NO: 31, and CE7 of SEQ ID NO: 32; or an HIV Gag CE polypeptide of claim 41 or 42 .

44 . The method of claim 21 , further comprising administering an immunogenic composition to induce an immune response to HIV Gag, wherein the method comprises administering an HIV Gag CE polypeptide comprising p24CE8-1 of SEQ ID NO: 57, p24CE9-1 of SEQ ID NO: 59, p24CE3-1 of SEQ ID NO: 28, p24CE10-1 of SEQ ID NO: 61, p24CE5-1 of SEQ ID NO: 30, p24CE11-1 of SEQ ID NO: 63, p24CE6-1 of SEQ ID NO: 31, p24CE12-1 of SEQ ID NO: 65, p24CE 13-1 of SEQ ID NO: 67 and P24CE8-1 of SEQ ID NO: 57, p24CE9-2 of SEQ ID NO: 60, p24CE3-2 of SEQ ID NO: 35, p24CE10-2 of SEQ ID NO: 62, p24CE5-2_of SEQ ID NO: 37, p24CE11-2 of SEQ ID NO: 64, p24CE6-2_of SEQ ID NO: 38, p24CE12-2 of SEQ ID NO: 66, p24CE13-2 of SEQ ID NO: 68.

45 . A nucleic acid construct encoding an HIV Gag CE polypeptide of claim 42 .

46 . The method of claim 43 , wherein the HIV Gag CE polypeptide is administered as a nucleic acid that encodes the HIV Gag CE polypeptide.