RSV RNA vaccines

1. A respiratory syncytial virus (RSV) messenger ribonucleic acid (mRNA) vaccine composition, comprising:

an mRNA that comprises an open reading frame (ORF) encoding an RSV F protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 5, wherein identity defines the percentage of amino acid residues in the RSV F protein that are identical to residues of SEQ ID NO: 5 after introducing any necessary gaps to align the two full-length sequences; and

a lipid nanoparticle comprising 20-60 mol % ionizable cationic lipid, 5-25 mol % neutral lipid, 25-55 mol % sterol, and 0.5-15 mol % PEG-modified lipid.

2. The RSV mRNA vaccine composition of claim 1 , wherein the RSV F protein comprises an F1 domain linked to an F2 subunit through a GS linker.

3. The RSV mRNA vaccine composition of claim 1 , wherein the mRNA is chemically modified.

4. The RSV mRNA vaccine composition of claim 3 , wherein the ORF of the mRNA comprises uracil and at least 80% of the uracil in the ORF of the mRNA comprises 1-methyl-pseudouridine.

5. The RSV mRNA vaccine composition of claim 4 , wherein 100% of the uracil in the ORF of the mRNA comprises 1-methyl-pseudouridine.

6. The RSV mRNA vaccine composition of claim 1 , wherein the lipid nanoparticle comprises 40-50 mol % ionizable cationic lipid, 10-20 mol % neutral lipid, 35-45 mol % cholesterol, and 1-5 mol % PEG-modified lipid.

7. The RSV mRNA vaccine composition of claim 6 , wherein the ionizable cationic lipid is a compound of Formula (I):

or a salt or isomer thereof, wherein:

R 1 is selected from the group consisting of C 5-30 alkyl, C 5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;

R 2 and R 3 are independently selected from the group consisting of H, C 1-14 alkyl, C 2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R 2 and R 3 , together with the atom to which they are attached, form a heterocycle or carbocycle;

R 4 is selected from the group consisting of a C 3-6 carbocycle, —(CH 2 ) n Q, —(CH 2 ) n CHQR, —CHQR, —CO(R) 2 , and unsubstituted C 1-6 alkyl, where Q is selected from a carbocycle, heterocycle, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —CX 3 , —CX 2 H, —CXH 2 , —CN, —N(R) 2 , —C(O)N(R) 2 , —N(R)C(O)R, —N(R)S(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(R)R 8 , —O(CH 2 ) n OR, —N(R)C(═NR 9 )N(R) 2 , —N(R)C(═CHR 9 )N(R) 2 , —OC(O)N(R) 2 , —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O) 2 R, —N(OR)C(O)OR, —N(OR)C(O)N(R) 2 , —N(OR)C(S)N(R) 2 , —N(OR)C(═NR 9 )N(R) 2 , —N(OR)C(═CHR 9 )N(R) 2 , —C(═NR 9 )N(R) 2 , —C(═NR 9 )R, —C(O)N(R)OR, and —C(R)N(R) 2 C(O)OR, and each n is independently selected from 1, 2, 3, 4, and 5;

each R 5 is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

each R 6 is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O) 2 —, —S—S—, an aryl group, and a heteroaryl group;

R 7 is selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

R 8 is selected from the group consisting of C 3-6 carbocycle and heterocycle;

R 9 is selected from the group consisting of H, CN, NO 2 , C 1-6 alkyl, —OR, —S(O) 2 R, —S(O) 2 N(R) 2 , C 2-6 alkenyl, C 3-6 carbocycle and heterocycle;

each R is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

each R′ is independently selected from the group consisting of C 1-18 alkyl, C 2-18 alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C 3-14 alkyl and C 3-14 alkenyl;

each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;

each Y is independently a C 3-6 carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.

8. The RSV mRNA vaccine composition of claim 7 , wherein:

R 1 is R″M′R′; R 2 and R 3 are each independently C 1-14 alkyl; R 4 is —(CH 2 ) n Q, wherein Q is OH and n is 4; M and M′ are each independently —OC(O)—; R 5 , R 6 , and R 7 are each H; R′ is C 1-12 alkyl substituted with C 6-9 alkyl; R″ is C 3-14 alkyl; and m is 6.

9. The RSV mRNA vaccine composition of claim 7 , wherein:

R 1 is C 5-20 alkenyl; R 2 and R 3 are each independently C 1-14 alkyl; R 4 is —(CH 2 ) n Q, wherein Q is OH and n is 3; M is —C(O)O—; R 5 , R 6 , and R 7 are each H; and m is 6.

10. The RSV mRNA vaccine composition of claim 7 , wherein the compound of Formula (I) is Compound 1:

11. The RSV mRNA vaccine composition of claim 7 , wherein the neutral lipid is 1,2 distearoyl-sn-glycero-3-phosphocholine (DSPC) and the PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol, methoxypolyethyleneglycol (PEG2000 DMG).

12. A method comprising administering to a subject the RSV mRNA vaccine composition of claim 1 in a therapeutically effective amount to induce in the subject an RSV F protein neutralizing antibody titer.

13. The method of claim 12 , wherein the vaccine is administered intramuscularly.