Combination PIV3/hMPV RNA vaccines
View Patent ↗The disclosure relates to respiratory virus ribonucleic acid (RNA) vaccines and combination vaccines, as well as methods of using the vaccines and compositions comprising the vaccines.
1. A method comprising administering to a subject a respiratory virus vaccine that comprises
(a) an isolated messenger ribonucleic acid (mRNA) polynucleotide comprising an open reading frame encoding an antigenic human parainfluenza virus type 3 (hPIV3) Fusion (F) protein; and
(b) an isolated mRNA polynucleotide comprising an open reading frame encoding an antigenic human metapneumovirus (hMPV) F protein,
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,
wherein the isolated mRNA polynucleotide of (a) and the isolated mRNA polynucleotide of (b) are not self-replicating RNA, and wherein the vaccine is administered to the subject in an effective amount to induce an immune response in the subject.
2. The method of claim 1 , wherein the isolated mRNA polynucleotide of (a) and/or (b) further encodes a 5′ terminal cap, 7mG(5′)ppp(5′)NlmpNp.
3. The method of claim 1 , wherein at least 80% of the uracil in the open reading frame of (a) and/or (b) have a chemical modification selected from N1-methyl-pseudouridine or N1-ethyl-pseudouridine.
4. The method of claim 3 , wherein the chemical modification is in the 5-position of the uracil.
5. The method 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.
6. The method of claim 5 , wherein the efficacy of the vaccine in vaccinated subjects is at least 70%, relative to unvaccinated subjects, following a single dose of the vaccine.
7. The method of claim 6 , wherein the efficacy of the vaccine in vaccinated subjects is at least 80%, relative to unvaccinated subjects, following a single dose of the vaccine.
8. The method of claim 7 , wherein the efficacy of the vaccine in vaccinated subjects is at least 90%, relative to unvaccinated subjects, following a single dose of the vaccine.
9. The method of claim 1 , wherein the effective amount is sufficient to produce detectable levels of hPIV3 F protein and/or hMPV F protein as measured in serum of a subject vaccinated with at least one dose of the vaccine at 1-72 hours post administration.
10. The method of claim 1 , wherein the effective amount is sufficient to produce a 1,000-10,000 neutralization titer produced by neutralizing antibody against the antigenic hPIV3 F protein and/or against the antigenic hMPV F protein as measured in serum of a subject vaccinated with at least one dose of the vaccine at 1-72 hours post administration.
11. The method of claim 10 , wherein the 1,000-10,000 neutralization titer is produced in the absence of antibody-dependent enhancement (ADE) of a hPIV3-associated and/or hMPV-associated disease.
12. The method of claim 11 , wherein the hPIV3-associated and/or hMPV-associated disease is alevolitis interstitial pneumonia.
13. The method of claim 1 , wherein an anti-hPIV3 F protein antibody titer and/or anti-hMPV F protein 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-hPIV3 F protein antibody titer and/or anti-hMPV F protein antibody titer produced in a subject who has not been administered a vaccine against hPIV3 and/or hMPV.
14. The method of claim 1 , wherein an anti-hPIV3 F protein antibody titer and/or anti-hMPV F protein 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-hPIV3 F protein antibody titer and/or anti-hMPV F protein antibody titer produced in a subject who has not been administered a vaccine against hPIV3 and/or hMPV.
15. The method of claim 1 , wherein the effective amount is a total dose of 25 μg-200 μg.
16. The method of claim 15 , wherein the effective amount is a total dose of 25 μg-100 μg.
17. The method of claim 1 , wherein the ionizable cationic lipid comprises the following compound:
18. The method of claim 1 , wherein the antigenic hPIV3 F protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence identified by SEQ ID NO: 13.
19. The method of claim 18 , wherein the antigenic hPIV3 F protein comprises an amino acid sequence identified by SEQ ID NO: 13.
20. The method of claim 1 , wherein the antigenic hMPV F protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence identified by SEQ ID NO: 5.
21. The method of claim 20 , wherein the antigenic hMPV F protein comprises an amino acid sequence identified by SEQ ID NO: 5.
22. The method of claim 1 , wherein the isolated mRNA polynucleotide of (a) comprises an open reading frame that comprises a nucleotide sequence that has at least 90% identity to the RNA sequence identified by SEQ ID NO: 64.
23. The method of claim 22 , wherein the isolated mRNA polynucleotide of (a) comprises an open reading frame that comprises the nucleotide sequence identified by SEQ ID NO: 64.
24. The method of claim 1 , wherein the isolated mRNA polynucleotide of (b) comprises an open reading frame that comprises a nucleotide sequence that has at least 90% identity to the RNA sequence identified by SEQ ID NO: 57.
25. The method of claim 24 , wherein the isolated mRNA polynucleotide of (b) comprises an open reading frame that comprises the nucleotide sequence identified by SEQ ID NO: 57.