HPIV3 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 human parainfluenza virus type 3 (hPIV3) vaccine, comprising:
an isolated messenger ribonucleic acid (mRNA) polynucleotide comprising an open reading frame encoding an antigenic hPIV3 Fusion (F) protein formulated in a 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 a neutralizing antibody response against hPIV3 F protein in a subject administered at least one dose of the vaccine, wherein the isolated mRNA polynucleotide is not self-replicating RNA.
2. A method of inducing an antigen-specific immune response in a subject, the method comprising administering to the subject the vaccine of claim 1 to produce an antigen-specific immune response in the subject.
3. The hPIV3 vaccine of claim 1 , wherein the isolated mRNA polynucleotide further encodes a 5′ terminal cap, 7mG(5′)ppp(5′)NlmpNp.
4. The hPIV3 vaccine of claim 1 , wherein at least 80% of the uracil in the open reading frame comprises a chemical modification selected from N1-methyl-pseudouridine and N1-ethyl-pseudouridine.
5. The hPIV3 vaccine of claim 4 , wherein the chemical modification is in the 5-position of the uracil.
6. The hPIV3 vaccine of claim 1 , wherein the open reading frame encoding an antigenic hPIV3 F protein comprises a RNA sequence that has at least 90% identity to the RNA sequence set forth in SEQ ID NO: 64.
7. The hPIV3 vaccine of claim 6 , wherein the open reading frame encoding an antigenic hPIV3 F protein comprises a RNA sequence set forth as SEQ ID NO: 64.
8. The hPIV3 vaccine 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 set forth as SEQ ID NO: 13.
9. The hPIV3 vaccine of claim 8 , wherein the antigenic hPIV3 F protein comprises the amino acid sequence set forth as SEQ ID NO: 13.
10. The hPIV3 vaccine of claim 1 , formulated in an effective amount, wherein the effective amount is a total dose of 25 μg-200 μg.
11. The hPIV3 vaccine of claim 1 , wherein the isolated mRNA polynucleotide further comprises 5′ terminal cap, a 5′ UTR, a 3′ UTR, and a polyA tail.
12. The hPIV3 vaccine of claim 11 , wherein the open reading frame encoding an antigenic hPIV3 F protein comprises a RNA sequence that has at least 90% identity to the RNA sequence set forth in SEQ ID NO: 64.
13. The hPIV3 vaccine of claim 12 , wherein the open reading frame encoding an antigenic hPIV3 F protein comprises the RNA sequence set forth as SEQ ID NO: 64.
14. The hPIV3 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.
15. The hPIV3 vaccine of claim 1 , wherein a single dose of the vaccine administered to a subject is sufficient to produce detectable levels of hPIV3 F protein as measured in serum of a subject vaccinated with at least one dose of the vaccine at 1-72 hours post administration.
16. The hPIV3 vaccine of claim 1 , wherein a single dose of the vaccine administered to a subject is sufficient to produce a 1,000-10,000 neutralization titer produced by neutralizing antibody against the antigenic hPIV3 F protein as measured in serum of a subject vaccinated with at least one dose of the vaccine at 1-72 hours post administration.
17. The hPIV3 vaccine of claim 16 , wherein the 1,000-10,000 neutralization titer is produced in the absence of antibody-dependent enhancement (ADE) of a hPIV3-associated disease.
18. The hPIV3 vaccine of claim 17 , wherein the hPIV3-associated disease is alevolitis interstitial pneumonia.
19. The hPIV3 vaccine of claim 1 , wherein an anti-hPIV3 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 produced in a subject who has not been administered a vaccine against hPIV3.
20. The hPIV3 vaccine of claim 1 , wherein an anti-hPIV3 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 produced in a subject who has not been administered a vaccine against hPIV3.
21. The hPIV3 vaccine of claim 1 , wherein the ionizable cationic lipid comprises the following compound:
22. The hPIV3 vaccine of claim 1 , wherein the noncationic lipid is DSPC (1,2-Distearoyl-sn-glycero-3-phosphocholine).
23. The hPIV3 vaccine of claim 1 , wherein the PEG-modified lipid is DMG-PEG (1,2-dimyristoyl-racglycero-3-methoxypolyethylene glycol-2000).
24. The hPIV3 vaccine of claim 1 , wherein the lipid nanoparticle comprises 40-50% ionizable cationic lipid, 5-15% DSPC, 25-40% cholesterol, and 1-3.5% DMG-PEG.
25. The hPIV3 vaccine of claim 24 , wherein the lipid nanoparticle comprises 50% ionizable cationic lipid, 10% DSPC, 38.5% cholesterol, and 1.5% DMG-PEG.