Human cytomegalovirus RNA vaccines
The disclosure describes HCMV ribonucleic acid (RNA) vaccines, as well as methods of using the vaccines and compositions comprising the vaccines.
1. A human cytomegalovirus (hCMV) vaccine comprising:
(a) at least one messenger ribonucleic acid (mRNA) polynucleotide comprising nucleotides 46-2437 of SEQ ID NO: 108 encoding hCMV gH; (b) at least one mRNA polynucleotide comprising nucleotides 46-1045 of SEQ ID NO: 109 encoding hCMV gL; (c) at least one mRNA polynucleotide comprising nucleotides 46-724 of SEQ ID NO: 110 encoding hCMV UL128; (d) at least one mRNA polynucleotide comprising nucleotides 46-853 of SEQ ID NO: 93 encoding hCMV UL130; (e) at least one mRNA polynucleotide comprising nucleotides 46-598 of SEQ ID NO: 112 encoding hCMV UL131A; and (f) at least one mRNA polynucleotide comprising nucleotides 46-2932 of SEQ ID NO: 83 encoding hCMV gB, wherein each of the mRNA polynucleotides of (a)-(f) further comprises a polyA tail, and wherein the mRNA polynucleotides of (a)-(f) are formulated in at least one lipid nanoparticle that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, in an effective amount to induce an immune response in a subject administered at least one dose of the vaccine.
2. The hCMV vaccine of claim 1 , wherein the at least one mRNA polynucleotide of (a)-(f) further encodes at least one 5′ terminal cap, 7mG(5′)ppp(5′)NlmpNp.
3. The hCMV vaccine of claim 1 , wherein at least 80% of the uracil in the open reading frame of (a)-(f) have a chemical modification selected from N1-methyl-pseudouridine or N1-ethyl-pseudouridine.
4. The hCMV vaccine of claim 3 , wherein the chemical modification is in the carbon-5 position of the uracil.
5. The hCMV vaccine of claim 1 , wherein the ionizable cationic lipid comprises the following compound:
6. The hCMV vaccine of claim 1 , wherein the polyA tail is 100 nucleotides in length.
7. A human cytomegalovirus (hCMV) vaccine comprising: (a) at least one messenger ribonucleic acid (mRNA) polynucleotide encoded by a DNA polynucleotide of SEQ ID NO: 58 encoding hCMV gH; (b) at least one mRNA polynucleotide encoded by a DNA polynucleotide of SEQ ID NO: 60 encoding hCMV gL; (c) at least one mRNA polynucleotide encoded by a DNA polynucleotide of SEQ ID NO: 62 encoding hCMV UL128; (d) at least one mRNA polynucleotide encoded by a DNA polynucleotide of SEQ ID NO: 15 encoding hCMV UL130; (e) at least one mRNA polynucleotide encoded by a DNA polynucleotide of SEQ ID NO: 66 encoding hCMV UL131A; and (f) at least one mRNA polynucleotide encoded by a DNA polynucleotide of SEQ ID NO: 5 encoding hCMV gB, wherein each of the mRNA polynucleotides of (a)-(f) further comprises a polyA tail, and wherein the mRNA polynucleotides of (a)-(f) are formulated in at least one lipid nanoparticle that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, in an effective amount to induce an immune response in a subject administered at least one dose of the vaccine.
8. The hCMV vaccine of claim 7 , wherein the polyA tail is 100 nucleotides in length.
9. A human cytomegalovirus (hCMV) vaccine comprising: (a) at least one mRNA polynucleotide comprising a sequence that has at least 90% identity to nucleotides 46-2437 of SEQ ID NO: 108 encoding hCMV gH; (b) at least one mRNA polynucleotide comprising a sequence that has at least 90% identity to nucleotides 46-1045 of SEQ ID NO: 109 encoding hCMV gL; (c) at least one mRNA polynucleotide comprising a sequence that has at least 90% identity to nucleotides 46-724 of SEQ ID NO: 110 encoding hCMV UL128; (d) at least one mRNA polynucleotide comprising a sequence that has at least 90% identity to nucleotides 46-853 of SEQ ID NO: 93 encoding hCMV UL130; (e) at least one mRNA polynucleotide comprises a sequence that has at least 90% identity to nucleotides 46-598 of SEQ ID NO: 112 encoding hCMV UL131A; and (f) at least one mRNA polynucleotide comprising a sequence that has at least 90% identity to nucleotides 46-2932 of SEQ ID NO: 83 encoding hCMV gB, wherein each of the mRNA polynucleotides of (a)-(f) further comprises a polyA tail, and wherein the mRNA polynucleotides of (a)-(f) are formulated in at least one lipid nanoparticle that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, in an effective amount to induce an immune response in a subject administered at least one dose of the vaccine.
10. The hCMV vaccine of claim 9 , wherein the polyA tail is 100 nucleotides in length.
11. A human cytomegalovirus (hCMV) vaccine comprising:
(a) at least one mRNA polynucleotide encoding an hCMV gH polypeptide comprising the amino acid sequence of SEQ ID NO: 59; (b) at least one mRNA polynucleotide encoding an hCMV gL polypeptide comprising the amino acid sequence of SEQ ID NO: 61; (c) at least one mRNA polynucleotide encoding an hCMV UL128 polypeptide comprising the amino acid sequence of SEQ ID NO: 63; (d) at least one mRNA polynucleotide encoding an hCMV UL130 polypeptide comprising the amino acid sequence of SEQ ID NO: 65; (e) at least one mRNA polynucleotide encoding an hCMV UL131A polypeptide comprising the amino acid sequence of SEQ ID NO: 67; and (f) at least one mRNA polynucleotide encoding an hCMV gB protein comprising the amino acid sequence of SEQ ID NO: 69, wherein the mRNA polynucleotides of (a)-(f) are formulated in at least one lipid nanoparticle that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, in an effective amount to induce an immune response in a subject administered at least one dose of the vaccine.
12. The hCMV vaccine of claim 1 , wherein the mRNA polynucleotides of (a)-(f) are not self-replicating RNA.
13. The hCMV vaccine of claim 7 , wherein the mRNA polynucleotides of (a)-(f) are not self-replicating RNA.
14. The hCMV vaccine of claim 9 , wherein the mRNA polynucleotides of (a)-(f) are not self-replicating RNA.
15. The hCMV vaccine of claim 11 , wherein the mRNA polynucleotides of (a)-(f) are not self-replicating RNA.
16. The hCMV vaccine of claim 1 , wherein the effective amount is a total dose of 25 μg-200 μg.
17. The hCMV vaccine of claim 1 , wherein the effective amount is a total dose of 25 μg-100 μg.
18. The hCMV vaccine of claim 1 , wherein the efficacy of the vaccine in vaccinated subjects is at least 60%, relative to unvaccinated subjects, following a single dose of the vaccine.
19. The hCMV vaccine of claim 18 , wherein the efficacy of the vaccine in vaccinated subjects is at least 70%, relative to unvaccinated subjects, following a single dose of the vaccine.
20. The hCMV vaccine of claim 19 , wherein the efficacy of the vaccine in vaccinated subjects is at least 80%, relative to unvaccinated subjects, following a single dose of the vaccine.
21. The hCMV vaccine of claim 20 , wherein the efficacy of the vaccine in vaccinated subjects is at least 90%, relative to unvaccinated subjects, following a single dose of the vaccine.
22. The hCMV vaccine of claim 1 , wherein the effective amount is sufficient to produce detectable levels of hCMV gH, gL, UL128, UL130, UL131A and/or gB polypeptide as measured in serum of a subject vaccinated with at least one dose of the vaccine at 1-72 hours post administration.
23. The hCMV vaccine of claim 1 , wherein the effective amount is sufficient to produce a 1,000-10,000 neutralization titer produced by neutralizing antibody against the hCMV gH, gL, UL128, UL130, UL131A and/or gB polypeptide as measured in serum of a subject vaccinated with at least one dose of the vaccine at 1-72 hours post administration.
24. The hCMV vaccine of claim 1 , wherein an anti-hCMV gH, gL, UL128, UL130, UL131A and/or gB polypeptide antibody titer produced in a subject vaccinated with at least one dose of the vaccine is increased by at least 1 log relative to a control, wherein the control is an anti-hCMV gH, gL, UL128, UL130, UL131A and/or gB polypeptide antibody titer produced in a subject who has not been administered a vaccine against hCMV.
25. The hCMV vaccine of claim 1 , wherein the anti-hCMV gH, gL, UL128, UL130, UL131A and/or gB polypeptide antibody titer produced in a subject vaccinated with at least one dose of the vaccine is increased at least 2 times relative to a control, wherein the control is an anti-hCMV gH, gL, UL128, UL130, UL131A and/or gB polypeptide antibody titer produced in a subject who has not been administered a vaccine against hCMV.