Human cytomegalovirus RNA vaccines

1. A human cytomegalovirus (hCMV) immunogenic composition comprising: (a) at least one messenger ribonucleic acid (mRNA) polynucleotide comprising an open reading frame encoding a hCMV gH polypeptide; (b) at least one mRNA polynucleotide comprising an open reading frame encoding a hCMV gL polypeptide; (c) at least one mRNA polynucleotide comprising an open reading frame encoding a hCMV UL128 polypeptide; (d) at least one mRNA polynucleotide comprising an open reading frame encoding a hCMV UL130 polypeptide; (e) at least one mRNA polynucleotide comprising an open reading frame encoding a hCMV UL131A polypeptide; and (f) at least one mRNA polynucleotide comprising an open reading frame encoding a hCMV gB polypeptide, wherein the mRNA polynucleotides of (a)-(f) are formulated in at least one lipid nanoparticle comprising 20-60 mole percent ionizable cationic lipid of Compound 25:

0.5-15 mole percent PEG-modified lipid, 25-55 mole percent sterol, and 5-25 mole percent non-cationic lipid that is not a sterol, and wherein the mRNA polynucleotides of (a)-(f) are not self-replicating RNA.

2. The hCMV immunogenic composition of claim 1 , wherein the lipid nanoparticle comprises 40-50 mole percent ionizable cationic lipid of Compound 25.

3. The hCMV immunogenic composition of claim 2 , wherein the lipid nanoparticle comprises 50 mole percent ionizable cationic lipid of Compound 25.

4. The hCMV immunogenic composition of claim 2 , wherein the lipid nanoparticle comprises 49 mole percent ionizable cationic lipid of Compound 25.

5. The hCMV immunogenic composition of claim 2 , wherein the lipid nanoparticle comprises 48 mole percent ionizable cationic lipid of Compound 25.

6. The hCMV immunogenic composition of claim 2 , wherein the lipid nanoparticle comprises 47 mole percent ionizable cationic lipid of Compound 25.

7. The hCMV immunogenic composition of claim 2 , wherein the lipid nanoparticle comprises 46 mole percent ionizable cationic lipid of Compound 25.

8. The hCMV immunogenic composition of claim 2 , wherein the lipid nanoparticle comprises 45 mole percent ionizable cationic lipid of Compound 25.

9. The hCMV immunogenic composition of claim 1 , wherein the non-cationic lipid that is not a sterol is a neutral lipid.

10. The hCMV immunogenic composition of claim 1 , wherein at least one mRNA polynucleotide comprises at least one chemical modification.

11. The hCMV immunogenic composition of claim 10 , wherein the chemical modification is selected from pseudouridine, 1-methylpseudouridine, 1-ethylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 5-methyluridine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, and 2′-O-methyl uridine.

12. The hCMV immunogenic composition of claim 11 , wherein the chemical modification is a 1-methylpseudouridine or 1-ethylpseudouridine.

13. The hCMV immunogenic composition of claim 10 , wherein the chemical modification is in the carbon 5-position of the uracil.

14. The hCMV immunogenic composition of claim 1 , wherein at least one mRNA polynucleotide further includes a 5′ terminal cap.

15. The hCMV immunogenic composition of claim 14 , wherein the 5′ terminal cap is 7mG(5′)ppp(5′)NlmpNp.

16. The hCMV immunogenic composition of claim 1 , wherein the open reading frame is codon-optimized.

17. A method of inducing an antigen-specific immune response in a subject, the method comprising administering to the subject the immunogenic composition of claim 1 in an amount effective to produce an antigen-specific immune response in the subject.

18. A method comprising administering to a woman of child-bearing age a therapeutically effective amount of the immunogenic composition of claim 1 .

19. The method of claim 18 , wherein the hCMV gH polypeptide comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 59, the hCMV gL polypeptide comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 61, the hCMV UL128 polypeptide comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 63, the hCMV UL130 polypeptide comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 65, the hCMV UL131A polypeptide comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 67, and/or the hCMV gB protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 69.

20. The method of claim 19 , wherein the hCMV gH polypeptide comprises the amino acid sequence of SEQ ID NO: 59, the hCMV gL polypeptide comprises the amino acid sequence of SEQ ID NO: 61, the hCMV UL128 polypeptide comprises the amino acid sequence of SEQ ID NO: 63, the hCMV UL130 polypeptide comprises the amino acid sequence of SEQ ID NO: 65, the hCMV UL131A polypeptide comprises the amino acid sequence of SEQ ID NO: 67, and/or the hCMV gB protein comprises the amino acid sequence of SEQ ID NO: 69.

21. The method of claim 18 , wherein the mRNA polynucleotide of (a) comprises a sequence that has at least 90% identity to the nucleotide sequence of SEQ ID NO: 108, the mRNA polynucleotide of (b) comprises a sequence that has at least 90% identity to the nucleotide sequence of SEQ ID NO: 109, the mRNA polynucleotide of (c) comprises a sequence that has at least 90% identity to the nucleotide sequence of SEQ ID NO: 110, the mRNA polynucleotide of (d) comprises a sequence that has at least 90% identity to the nucleotide sequence of SEQ ID NO: 93, the mRNA polynucleotide of (e) comprises a sequence that has at least 90% identity to the nucleotide sequence of SEQ ID NO: 112, and/or the mRNA polynucleotide of (f) comprises a sequence that has at least 90% identity to the nucleotide sequence of SEQ ID NO: 83.

22. The method of claim 18 , wherein the hCMV vaccine comprises (a) a mRNA polynucleotide comprising nucleotides 46-2437 of SEQ ID NO: 108, (b) a mRNA polynucleotide comprising nucleotides 46-1045 of SEQ ID NO: 109, (c) a mRNA polynucleotide comprising nucleotides 46-724 of SEQ ID NO: 110, (d) a mRNA polynucleotide comprising nucleotides 46-853 of SEQ ID NO: 93, (e) a mRNA polynucleotide comprising nucleotides 46-598 of SEQ ID NO: 112, and (f) a mRNA polynucleotide comprising nucleotides 46-2932 of SEQ ID NO: 83.

23. The method of claim 18 , wherein the mRNA polynucleotides further comprise polyA tails.

24. The hCMV immunogenic composition of claim 1 , wherein the sterol is cholesterol.