JPWO2021050864A5

JPWO2021050864A5 -

Info

Publication number: JPWO2021050864A5
Application number: JP2022515906A
Authority: JP
Publication date: 2023-09-20

Claims

An immunogenic composition for use in a method of preventing and/or treating human cytomegalovirus (hCMV) infection in a human subject, comprising:
The immunogenic composition comprises (a) a messenger ribonucleic acid (mRNA) polynucleotide comprising an open reading frame encoding an hCMV gH polypeptide; and (b) an mRNA polynucleotide comprising an open reading frame encoding an hCMV gL polypeptide. (c) an mRNA polynucleotide comprising an open reading frame encoding an hCMV UL128 polypeptide; (d) an mRNA polynucleotide comprising an open reading frame encoding an hCMV UL130 polypeptide; and (e) an hCMV UL131A polypeptide. (f) an mRNA polynucleotide comprising an open reading frame encoding an hCMV gB polypeptide ; and (g) a lipid nanoparticle ;
The method comprises administering to a human subject a dose of 30 μg to 300 μg of the immunogenic composition;
thereby inducing an antigen-specific immune response against hCMV in said subject;
i) after administration of said immunogenic composition, the geometric mean titer (GMT) of neutralizing antibodies against epithelial cell infection increases by at least 3-fold over baseline in said human subject;
ii) after administration of said immunogenic composition, the geometric mean ratio (GMR) of neutralizing antibodies to epithelial cell infection is between about 9 and 41 in said human subject; or
iii) an immunogenic composition that, after administration of said immunogenic composition, has a geometric mean ratio (GMR) of neutralizing antibodies to fibroblast infection of about 4 to 8 in said human subject.

2. An immunogenic composition for use according to claim 1 , wherein said immunogenic composition is administered at a dose of 30[mu]g , 90[mu]g, 180[mu]g or 300[mu]g .

At least two doses or at least three doses of said immunogenic composition are administered, optionally three doses of said immunogenic composition are administered, and further optionally said immunogen is administered. Three doses of the sexual composition are administered (i) on day 1, (ii) around the beginning of month 2, and (iii) around the beginning of month 6.
Immunogenic composition for use according to claim 1 or 2 .

An immunogenic composition for use according to any one of claims 1 to 3 , wherein a single dose of the immunogenic composition elicits serum neutralizing antibody titers against hCMV.

the GMT of neutralizing antibodies against epithelial cell infection is increased by at least 3-fold over baseline in the human subject after a single dose, after 2 doses, or after 3 doses of the immunogenic composition; Optionally,
After two doses of the vaccine composition, the GMT of neutralizing antibodies against epithelial cell infection is increased 9-20 times over baseline in said human subject, or
After three doses of the vaccine composition, the GMT of neutralizing antibodies against epithelial cell infection is increased 20-40 times over baseline in said subject.
An immunogenic composition for use according to claim 1.

(i) within seropositive subjects who have received at least two doses of 30 μg or more of said immunogenic composition, the GMR of neutralizing antibodies against epithelial cell infection is within the range of 14 to 26;
(ii) within a seropositive subject who has received at least three doses of said immunogenic composition of 30 μg or more, the GMR of neutralizing antibodies against epithelial cell infection is within the range of 14-26; or
(iii) within a seropositive subject who has been administered at least three doses of said immunogenic composition of 30 μg or more, the GMR of neutralizing antibodies against epithelial cell infection is within the range of 14 to 41, and optionally wherein said GMR is within the range of 30 to 41, and optionally, at least three doses of 180 μg are administered to a seropositive subject.
An immunogenic composition for use according to claim 1 .

The lipid nanoparticles contain an ionizable cationic lipid, cholesterol ; 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) ; and 1,2 dimyristoyl-sn-glycerol, methoxypolyethylene glycol. (DMG-PEG) , optionally;
(i) the ionizable cationic lipid comprises Compound I;
and/or
(ii) the lipid nanoparticles contain 20-60 mol% ionizable cationic lipid, 25-55 mol% cholesterol, 5-25 mol% DSPC, and 0.5-15 mol% DMG-PEG; further optionally comprising a mixture of lipids comprising;
The lipid nanoparticles contain a mixture of lipids including 45-55 mol% ionizable cationic lipid, 35-40 mol% cholesterol, 5-15 mol% DSPC, and 1-2 mol% DMG-PEG. including, and further optionally,
The lipid nanoparticles include a mixture of lipids including 50 mol% ionizable cationic lipid, 38.5 mol% cholesterol, 10 mol% DSPC, and 1.5 mol% DMG-PEG.
Immunogenic composition for use according to any one of claims 1 to 6 .

Any one of claims 1 to 7 , wherein the weight ratio of the mRNA encoding hCMV gH, gL, UL128, UL130, UL131A, and gB proteins in the vaccine composition is 1:1:1:1:1:1. An immunogenic composition for use according to item 1.

9. The mRNA encoding hCMV gH, gL, UL128, UL130, UL131A , and gB proteins comprises a 1-methylpseudouridine chemical modification. Immunogenic compositions for use .

(i) said mRNA encoding hCMV gH protein comprises a nucleotide sequence having at least 90% identity to the sequence of SEQ ID NO: 5 ; optionally said mRNA comprises a nucleotide sequence of the sequence of SEQ ID NO: 5; including and/or
(ii) said mRNA encoding hCMV gL protein comprises a nucleotide sequence having at least 90% identity to the sequence of SEQ ID NO: 6; optionally said mRNA has a nucleotide sequence of at least 90% identity to the sequence of SEQ ID NO: 6; including and/or
(iii) said mRNA encoding hCMV UL128 protein comprises a nucleotide sequence having at least 90% identity to the sequence of SEQ ID NO:2; optionally said mRNA has a nucleotide sequence of at least 90% identity to the sequence of SEQ ID NO:2; including and/or
(iv) said mRNA encoding hCMV UL130 protein comprises a nucleotide sequence having at least 90% identity to the sequence of SEQ ID NO: 3, optionally comprising the nucleotide sequence of the sequence of SEQ ID NO: 3, and/ or
(v) said mRNA encoding hCMV UL131A protein comprises a nucleotide sequence having at least 90% identity to the sequence of SEQ ID NO: 4; include,
(vi) said mRNA encoding hCMV gB protein comprises a nucleotide sequence having at least 90% identity to the sequence SEQ ID NO: 1; optionally said mRNA comprises a nucleotide sequence having at least 90% identity to the sequence SEQ ID NO: 1; include,
Immunogenic composition for use according to any one of claims 1 to 9 .

said mRNA encoding hCMV gH protein comprises a nucleotide sequence of sequence SEQ ID NO: 5, said mRNA encoding hCMV gL protein comprises a nucleotide sequence of sequence SEQ ID NO: 6, and said mRNA encoding hCMV UL128 protein. comprises the nucleotide sequence of sequence SEQ ID NO: 2, said mRNA encoding hCMV UL130 protein comprises the nucleotide sequence of sequence SEQ ID NO: 3, and said mRNA encoding hCMV UL131A protein comprises the nucleotide sequence of sequence SEQ ID NO: 4. An immunogenic composition for use according to any one of claims 1 to 10 , wherein said mRNA comprising the sequence and encoding hCMV gB protein comprises the nucleotide sequence of the sequence SEQ ID NO: 1.

The open reading frame encoding the hCMV gH polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 11, and the open reading frame encoding the hCMV gL polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 12. wherein said open reading frame encoding said hCMV UL128 polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 8; The open reading frame encoding the hCMV UL130 polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 9, and the open reading frame encoding the hCMV UL131A polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 10. and/or said open reading frame encoding said hCMV gB polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 7. optionally ,
The open reading frame encoding the hCMV gH polypeptide comprises SEQ ID NO: 11, the open reading frame encoding the hCMV gL polypeptide comprises SEQ ID NO: 12, and the open reading frame encoding the hCMV UL128 polypeptide comprises SEQ ID NO: 12. a reading frame comprises SEQ ID NO: 8, the open reading frame encoding the hCMV UL130 polypeptide comprises SEQ ID NO: 9, and the open reading frame encoding the hCMV UL131A polypeptide comprises SEQ ID NO: 10; and/or said open reading frame encoding said hCMV gB polypeptide comprises the sequence SEQ ID NO: 7.
Immunogenic composition for use according to any one of claims 1 to 11 .

(a) said immunogenic composition is administered via intramuscular injection, and/or
(b) said human subject is CMV seropositive before being administered said hCMV mRNA immunogenic composition, or said human subject is CMV seropositive before being administered said hCMV mRNA immunogenic composition; CMV seronegative;
Immunogenic composition for use according to any one of claims 1 to 12 .

The method comprises administering a dose of 5 μg to 100 μg of a second immunogenic composition comprising at least one mRNA polynucleotide comprising an open reading frame encoding an hCMV pp65 polypeptide and a lipid nanoparticle . further comprising administering to a human subject;
Optionally,
(i) said second immunogenic composition is administered at a dose of 10 μg , 40 μg , or 80 μg; and/or
(ii) said second vaccine composition is administered via intramuscular injection;
Immunogenic composition for use according to any one of claims 1 to 13 .

(i) said mRNA encoding hCMV pp65 protein comprises a nucleotide sequence having at least 90% identity to the sequence of SEQ ID NO: 21, optionally;
the mRNA encoding the hCMV pp65 protein comprises the nucleotide sequence of SEQ ID NO: 21, or
(ii) said open reading frame encoding said hCMV pp65 polypeptide comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 23, optionally;
the open reading frame encoding the hCMV pp65 polypeptide comprises SEQ ID NO: 23;
Immunogenic composition for use according to claim 14 .