HIV RNA vaccines
Provided herein are methods and compositions for inducing in a subject abroad neutralizing antibody response to human immunodeficiency virus (HIV) infection.
1. A method of inducing in a subject an immune response to human immunodeficiency virus (HIV), the method comprising:
(a) during a first period of time, administering to a subject an initial dose and multiple autologous boost doses of a first composition comprising a messenger RNA (mRNA) encoding an HIV envelope (Env) protein and an mRNA encoding a lentivirus group-specific antigen (Gag) protein formulated in a lipid nanoparticle;
(b) during a second period of time, administering to the subject multiple heterologous boost doses of a second composition comprising an mRNA encoding an HIV Env protein and an mRNA encoding a lentivirus Gag protein formulated in a lipid nanoparticle; and
(c) producing in the subject a broadly neutralizing antibody response against multiple strains of HIV.
2. The method of claim 1 , wherein the broadly neutralizing antibody response comprises a production of neutralizing antibodies that bind to shared epitopes on proteins from the multiple strains of HIV.
3. The method of claim 2 , wherein the broadly neutralizing antibody response comprises an ID 50 titer of greater than 20 or greater than 50.
4. The method of claim 1 , wherein (i) the first period of time is 1-30 weeks following administration of the initial dose of the first composition and/or (ii) the second period of time is 8-60 weeks following administration of the initial dose of the first composition.
5. The method of claim 1 , wherein the time between any two doses of the first composition of (a) and/or the second composition of (b) is at least 1 week, is at least 4 weeks, or is 4-12 weeks.
6. The method of claim 1 , wherein the HIV is HIV type-1 (HIV-1).
7. The method of claim 1 , wherein the ratio of the mRNA encoding an HIV Env protein to the mRNA encoding an HIV Gag protein of in the first composition of (a) and/or in the second composition of (b) is 2:1 or 3:2.
8. The method of claim 1 , wherein the first composition and/or the second composition further comprises an mRNA encoding an HIV protease.
9. The method of claim 8 , wherein the ratio of the mRNA encoding an HIV Gag protein to the mRNA encoding an HIV protease to is at least 1:5, at least 1:10, at least 1:20, at least 1:40, at least 1:60, or at least 1:80.
10. The method of claim 1 , wherein the first and/or second composition further comprises an mRNA encoding furin.
11. The method of claim 10 , wherein the ratio of the mRNA encoding furin to the mRNA encoding an HIV Env protein is at least 1:5.
12. The method of claim 1 , wherein the HIV Env protein of the first composition of (a) is selected from an HIV Env protein of Group M Clade A-K, wherein the HIV Env protein of the second composition of (b) is selected from an HIV Env protein of Group M Clade A-K, and wherein the Clade(s) of the HIV Env protein of the first composition of (a) is different from the Clade(s) of the HIV Env protein of the second composition of (b).
13. The method of claim 1 , wherein the HIV Env protein of the first composition of (a) and/or the second composition of (b) comprises HIV Env SOSIP.664 mutations or is a membrane-bound HIV Env protein.
14. The method of claim 1 , wherein the cytosolic portion of the HIV Env protein of the first composition of (a) and/or the second composition of (b) is partially truncated.
15. The method of claim 13 , wherein the membrane-bound HIV Env protein is gp150 or gp160.
16. The method of claim 1 , wherein the HIV Env protein of the first composition of (a) and/or the second composition of (b) comprises a sequence of an Env protein, or a consensus sequence of variants an Env protein, of an HIV strain obtained from an infected subject who has broadly neutralizing antibodies to HIV Env protein, or comprises a sequence of a variant Env protein of an HIV strain that engages one or multiple unmutated common ancestor (UCA) antibodies to HIV Env protein from the lineages of known broadly neutralizing antibodies.
17. The method of claim 1 , wherein the HIV Env protein of the first composition of (a) and/or the second composition of (b) comprises:
(i) a mutation selected from 153E, 190G and N276D, relative to the amino acid sequence of HIV Env protein (SEQ ID NO: 2), or other mutations suitable to remove the glycans at positions 188 and 276;
(ii) a mutation selected from N460D and N463D relative to the amino acid sequence of HIV Env protein (SEQ ID NO: 4), or other suitable mutations to remove the glycans at positions 460 and 463;
(iii) a mutation selected from K295N, D386N, and 375Y, relative to the amino acid sequence of HIV Env protein (SEQ ID NO: 3); or
(iv) a mutation selected from T322N and S375Y, relative to the amino acid sequence of HIV Env protein (SEQ ID NO: 2).
18. The method of claim 1 , wherein the HIV Env protein of the first composition of (a) and/or the second composition of (b) is a tier-2 Env with all the major glycan holes filled in by insertion of the missing glycans.
19. The method of claim 1 , wherein the lentivirus is selected from human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), and murine leukemia virus (muLV).
20. The method of claim 1 , wherein the lentivirus-derived Gag is replaced by VSV-AG or VSV core protein.
21. The method of claim 17 , wherein:
the HIV Env protein (SEQ ID NO: 2) of the first composition of (a) and/or the second composition of (b) further comprises a disulfide bridge at 113C-432GCG;
the HIV Env protein (SEQ ID NO: 3) of the first composition of (a) and/or the second composition of (b) further comprises a disulfide bridge at 133C-432GCG; or
the HIV Env protein (SEQ ID NO: 2) of the first composition of (a) and/or the second composition of (b) further comprises a disulfide bridge at 113C-429GCG.