Adjuvanted formulations of booster vaccines

Patent metadata

Field	Value
Publication number	US-9375471-B2
Application number	US-201313790948-A
Country	US
Kind code	B2
Filing date	Mar 8, 2013
Priority date	Mar 8, 2012
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The invention improves TdaP vaccines by including a TLR agonist in them. This agonist can provide stronger protection, longer-lasting protection, and/or can reduce the amount of antigen which is required to achieve a particular immune response.

First claim

The invention claimed is:

1. An immunogenic composition comprising a diphtheria toxoid, a tetanus toxoid, a pertussis toxoid, an aluminium salt adjuvant, and a toll-like receptor (TLR) agonist, wherein the TLR agonist includes at least one adsorptive moiety, at least 50% (by mass) of TLR agonist is adsorbed to the aluminium salt adjuvant, and the composition includes an excess (measured in Lf units) of tetanus toxoid relative to diphtheria toxoid.

2. The composition of claim 1 , wherein the TLR agonist is a TLR4 agonist or a TLR7 agonist.

3. The composition of claim 1 , wherein at least 99% of the TLR agonist is adsorbed to the aluminium salt adjuvant.

4. The composition of claim 1 , with an Al +++ concentration ≦0.5 mg/ml.

5. The composition of claim 1 , wherein the aluminium salt is an aluminium hydroxide.

6. The composition of claim 1 , wherein the TLR agonist is a compound of formula ‘K’

wherein: R1 is H, C 1 -C 6 alkyl, —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or -OL 2 R 6 ;
L 1 is —C(O)— or —O—;
L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene or —((CR 4 R 4 ) p O) q (CH 2 ) p , wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 2 are optionally substituted with 1 to 4 fluoro groups;
each L 3 is independently selected from C 1 -C 6 alkylene and —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 3 is optionally substituted with 1 to 4 fluoro groups;
L 4 is arylene or heteroarylene;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from C 1 -C 4 alkyl, -L 3 R 5 , -eR5, -L3R7, -L3L4L3R7, -L3L4R5, -L3L4eR5, OL3R5, —OL3R7, —OL3L4R7, —OL3L4eR7, —OR8, —OL3L4R5, —OL3L4eR5 and —C(R5) 20H;
each R 4 is independently selected from H and fluoro;
R 5 is —P(O)(OR 9 ) 2 ;
R 6 is —CF 2 P(O)(OR 9 ) 2 or —C(O)OR 10 ;
R 7 is —CF 2 P(O)(OR 9 ) 2 or —C(O)OR 10 ;
R 8 is H or C 1 -C 4 alkyl;
each R 9 is independently selected from H and C 1 -C 6 alkyl;
R 19 is H or C 1 -C 4 alkyl;
each p is independently selected from 1, 2, 3, 4, 5 and 6; and
q is 1, 2, 3 or 4,
or a pharmaceutically acceptable salt thereof.

7. The composition of claim 1 , wherein the TLR agonist is compound K2

8. The composition of claim 1 , wherein the at least one adsorptive moiety is a phosphate or a phosphonate.

9. The composition of claim 1 , wherein the TLR agonist has a formula selected from the group consisting of:

wherein:
(a) P 3 is selected from H, C 1 -C 6 alkyl, CF 3 , and —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O) (OR X )(OR Y ); and P 4 is selected from H, C 1 -C 6 alkyl, —C 1 -C 6 alkylaryl and —Y-L-X—P(O) (OR X )(OR Y ); with the proviso that at least one of P 3 and P 4 is —Y-L-X—P(O) (OR X )(OR Y );
(b) P 5 is selected from H, C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); P 6 is selected from H, C 1 -C 6 alkyl each optionally substituted with 1 to 3 substituents selected from C 1 -C 4 alkyl and OH, and —Y-L-X—P(O)(OR X )(OR Y ); and P 7 is selected from H, C 1 -C 6 alkyl, —((CH 2 ) p O) q (CH 2 ) p O s —, —NHC 1 -C 6 alkyl and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 5 , P 6 and P 7 is —Y-L-X—P(O)(OR X )(OR Y );
(c) P 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl each optionally substituted with OH, and —Y-L-X—P(O)(OR X )(OR Y ); and P 9 and P 10 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl each optionally substituted with OH and C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 8 , P 9 or P 10 is —Y-L-X—P(O)(OR X )(OR Y );
(d) P 16 and each P 18 are each independently selected from H, C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); P 17 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 1 -C 6 alkylaryl, C 1 -C 6 alkyl heteroaryl, C 1 -C 6 alkylaryl-Y-L-X—P(O)(OR X )(OR Y ) and —Y-L-X—P(O) (OR X )(OR Y ), each optionally substituted with 1 to 2 substituents selected from C 1 -C 6 alkyl or heterocyclyl with the proviso that at least one of P 16 , P 17 or a P 18 contains a —Y-L-X—P(O)(OR X )(OR Y ) moiety;
R X and R Y are independently selected from H and C 1 -C 6 alkyl;
R C , R D and R H are each independently selected from H and C 1 -C 6 alkyl;
X C is selected from CH and N;
R E is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)C 1 -C 6 alkyl, halogen and —((CH 2 ) p O) q (CH 2 ) p —;
X E is selected from a covalent bond, CR E2 R E3 and NR E4 ;
R E2 , R E3 and R E4 are independently selected from H and C 1 -C 6 alkyl;
X H1 -X H2 is selected from —CR H2 R H3 —, —CR H2 R H3 —CR H2 R H3 —, —C(O)CR H2 R H3 —, —C(O)CR H2 R H3 —, —CR H2 R H3 C(O)—, —NR H4 C(O)—, C(O)NR H4 —, CR H2 R H3 S(O) 2 and —CR H2 ═CR H2 —;
R H2 , R H3 and R H4 are each independently selected from H, C 1 -C 6 alkyl and P 18 ;
X H3 is selected from N and CN;
X is selected from a covalent bond, O and NH;
Y is selected from a covalent bond, O, C(O), S and NH;
L is selected from, a covalent bond C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ;
m is selected from 0 or 1;
each p is independently selected from 1, 2, 3, 4, 5 and 6;
q is selected from 1, 2, 3 and 4; and
s is selected from 0 and 1,

wherein:
X 3 is N;
X 4 is N or CR 3
X 5 is —CR 4 ═CR 5 —;
R 1 and R 2 are H;
R 3 is H;
R 4 and R 5 are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 )2. —NHN(R 9 )2, —SR 7 , —(CH2)n0R 7 , —(CH2)nR 7 , -LR 8 , -LR 10 , -OLR 8 , -OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 and R 5 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 )2, and —NR 9 S(O) 2 R 8 ;
or, R 3 and R 4 , or R 4 and R 5′ or R 5 and R 6 , when present on adjacent ring atoms, can optionally be linked together to form a 5-6 membered ring, wherein the 5-6 membered ring is optionally substituted with R 7 ;
each L is independently selected from a bond, —(O(CH 2 ) m ) t —, C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R 8 , —OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , and —OP(O)(OR 10 ) 2 ;
R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalko

Assignees

• Novartis Ag
• Glaxosmithkline Biolog Sa

Inventors

• Baudner Barbara
• O'Hagan Derek
• Singh Manmohan
• Bufali Simone

Classifications

• A61K2039/55505

  Inorganic adjuvants · CPC title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title

• A61K2039/55572

  Lipopolysaccharides; Lipid A; Monophosphoryl lipid A · CPC title

• A61K2039/55511

  Organic adjuvants · CPC title

• A61K2039/55566

  Emulsions, e.g. Freund's adjuvant, MF59 · CPC title