Respiratory syncytial virus vaccine

Abstract

The disclosure relates to respiratory syncytial vims (RSV) ribonucleic acid (RNA) vaccines, as well as methods of using the vaccines and compositions comprising the vaccines.

1 . A messenger ribonucleic acid (mRNA) vaccine comprising:
 an mRNA polynucleotide comprising an open reading frame encoding a respiratory syncytial virus (RSV) polypeptide and;   a lipid nanoparticle comprising a cationic lipid selected from compounds 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, —CQ(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. 
     
     
         2 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those in which when R 4  is —(CH 2 ) n Q, —(CH 2 ) n CHQR, —CHQR, or —CQ(R) 2 , then (i) Q is not —N(R) 2  when n is 1, 2, 3, 4 or 5, or (ii) Q is not 5, 6, or 7-membered heterocycloalkyl when n is 1 or 2. 
     
     
         3 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those in which
 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, —CQ(R) 2 , and unsubstituted C 1-6  alkyl, where Q is selected from a C 3-6  carbocycle, a 5- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —CX 3 , —CX 2 H, —CXH 2 , —CN, —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 , —CRN(R) 2 C(O)OR, —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 a 5- to 14-membered heterocycloalkyl having one or more heteroatoms selected from N, O, and S which is substituted with one or more substituents selected from oxo (═O), OH, amino, mono- or di-alkylamino, and C 1-3  alkyl, 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,   or salts or isomers thereof.   
     
     
         4 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those in which
 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, —CQ(R) 2 , and unsubstituted C 1-6  alkyl, where Q is selected from a C 3-6  carbocycle, a 5- to 14-membered heterocycle having one or more heteroatoms selected from N, O, and S, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —CX 3 , —CX 2 H, —CXH 2 , —CN, —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 , —CRN(R) 2 C(O)OR, —N(R)R 8 , —O(C H 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 )R, —C(O)N(R)OR, and —C(═NR 9 )N(R) 2 , and each n is independently selected from 1, 2, 3, 4, and 5; and when Q is a 5- to 14-membered heterocycle and (i) R 4  is —(CH 2 ) n Q in which n is 1 or 2, or (ii) R 4  is —(CH 2 ) n CHQR in which n is 1, or (iii) R 4  is —CHQR, and —CQ(R) 2 , then Q is either a 5- to 14-membered heteroaryl or 8- to 14-membered heterocycloalkyl;   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,   or salts or isomers thereof.   
     
     
         5 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those in which
 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, —CQ(R) 2 , and unsubstituted C 1-6  alkyl, where Q is selected from a C 3-6  carbocycle, a 5- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —CX 3 , —CX 2 H, —CXH 2 , —CN, —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 , —CRN(R) 2 C(O)OR, —N(R)R 8 , —O(C H 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 )R, —C(O)N(R)OR, and —C(═NR 9 )N(R) 2 , 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,   or salts or isomers thereof.   
     
     
         6 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those in which
 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 2-14  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 —(CH 2 ) n Q or —(CH 2 ) n CHQR, where Q is —N(R) 2 , and n is selected from 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;   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 1-12  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,   or salts or isomers thereof.   
     
     
         7 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those in which
 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 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 —(CH 2 ) n Q, —(CH 2 ) n CHQR, —CHQR, and —CQ(R) 2 , where Q is —N(R) 2 , and n is 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;   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 1-12  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,   or salts or isomers thereof.   
     
     
         8 . The mRNA vaccine of  claim 1 , wherein a subset of compounds of Formula (I) includes those of Formula (IA): 
       
         
           
           
               
               
           
         
         or a salt or isomer thereof, wherein l is selected from 1, 2, 3, 4, and 5; 
         m is selected from 5, 6, 7, 8, and 9; 
         M 1  is a bond or M′; 
         R 4  is unsubstituted C 1-3  alkyl, or —(CH 2 ) n Q, in which Q is OH, —NHC(S)N(R) 2 , —NHC(O)N(R) 2 , —N(R)C(O)R, —N(R)S(O) 2 R, —N(R)R 8 , —NHC(═NR 9 )N(R) 2 , —NHC(═CHR 9 )N(R) 2 , —OC(O)N(R) 2 , —N(R)C(O)OR, heteroaryl or heterocycloalkyl; 
         M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, 
         —P(O)(OR′)O—, —S—S—, an aryl group, and a heteroaryl group; and 
         R 2  and R 3  are independently selected from the group consisting of H, C 1-14  alkyl, and C 2-14  alkenyl. 
       
     
     
         9 . The mRNA vaccine of  claim 1 , wherein the RSV polypeptide is glycoprotein G. 
     
     
         10 . The mRNA vaccine of  claim 1 , wherein the RSV polypeptide is glycoprotein F. 
     
     
         11 .- 21 . (canceled) 
     
     
         22 . The mRNA vaccine of  claim 1 , wherein the mRNA polynucleotide comprises a chemical modification. 
     
     
         23 . The mRNA vaccine of  claim 22 , wherein the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 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. 
     
     
         24 . The mRNA vaccine of  claim 1 , wherein the nanoparticle has a mean diameter of 50-200 nm. 
     
     
         25 . The mRNA vaccine of  claim 1 , wherein the lipid nanoparticle further comprises a PEG-modified lipid, a sterol, and a non-cationic lipid. 
     
     
         26 . The mRNA vaccine of  claim 25 , wherein the lipid nanoparticle comprises 20-60 mol %, 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 25-55 mol % non-cationic lipid. 
     
     
         27 .- 42 . (canceled) 
     
     
         43 . A method of inducing an antigen specific immune response in a subject, the method comprising administering to the subject the mRNA vaccine of  claim 1  in an amount effective to produce an antigen specific immune response. 
     
     
         44 .- 109 . (canceled) 
     
     
         110 . The mRNA vaccine of  claim 26 , wherein the non-cationic lipid is a neutral lipid and the sterol is a cholesterol. 
     
     
         111 . The mRNA vaccine of  claim 10 , wherein the RSV glycoprotein F is a stabilized prefusion form of RSV glycoprotein F. 
     
     
         112 . The mRNA vaccine of  claim 1 , wherein:
 R 1  is R″M′R′ or C 5-20  alkenyl;   R 2  and R 3  are each independently selected from C 1-14  alkyl and C 2-14  alkenyl;   R 4  is —(CH 2 ) n Q, wherein Q is OH and n is selected from 3, 4, and 5;   M and M′ are each independently —OC(O)— or —C(O)O—;   R 5 , R 6 , and R 7  are each H;   R′ is a linear C 1-12  alkyl, or C 1-12  alkyl substituted with C 6-9  alkyl;   R″ is C 3-14  alkyl;   m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.   
     
     
         113 . The mRNA vaccine of  claim 112 , 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.   
     
     
         114 . The mRNA vaccine of  claim 112 , 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.