Method of inducing an antigen-specific immune response by administering a synergistic combination of adjuvants comprising unmethylated CpG-containing nucleic acids and a non-nucleic acid adjuvant
View Patent ↗The present invention relates generally to adjuvants, and in particular to methods and products utilizing a synergistic combination of immunostimulatory oligonucleotides having at least one unmethylated CpG dinucleotide (CpG ODN) and a non-nucleic acid adjuvant. Such combinations of adjuvants may be used with an antigen or alone. The present invention also relates to methods and products utilizing immunostimulatory oligonucleotides having at least one unmethylated CpG dinucleotide (CpG ODN) for induction of cellular immunity in infants.
1. A method of inducing an antigen specific immune response in a subject, comprising:
administering to the subject in order to induce an antigen specific immune response an antigen and a combination of adjuvants, wherein the combination of adjuvants includes at least one oligonucleotide containing at least one unmethylated CpG dinucleotide and at least one non-nucleic acid adjuvant, wherein the non-nucleic acid adjuvant is an immune stimulating adjuvant selected from the group consisting of PCPP polymer, derivatives of lipopolysaccharides, MPL, MDP, t-MDP, OM-174 and Leishmania elongation factor, wherein the combination of adjuvants is administered in an effective amount for inducing a synergistic adjuvant response, and wherein the oligonucleotide is 8-100 nucleotides in length and has at least one phosphorothioate backbone modification.
2. The method of claim 1 , wherein the combination of adjuvants is administered with a priming dose of antigen.
3. The method of claim 1 , wherein the combination of adjuvants is administered with a boost dose of antigen.
4. The method of claim 2 , wherein the subject is administered a boost dose of antigen and oligonucleotide containing at least one unmethylated CpG dinucleotide after the priming dose.
5. The method of claim 3 , wherein the subject is administered a priming dose of antigen and oligonucleotide containing at least one unmethylated CpG dinucleotide before the boost dose.
6. The method of claim 1 , wherein the oligonucleotide containing at least one unmethylated CpG dinucleotide has a sequence including at least the following formula:
5′ X 1 X 2 CGX 3 X 4 3′
wherein C and G are unmethylated, wherein X 1 X 2 and X 3 X 4 are nucleotides.
7. The method of claim 6 , wherein the 5′ X 1 X 2 CGX 3 X 4 3′ sequence is a non-palindromic sequence.
8. The method of claim 6 , wherein X 1 X 2 are nucleotides selected from the group consisting of: GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT, and TpG; and X 3 X 4 are nucleotides selected from the group consisting of: TpT, CpT, ApT, TpG, ApG, CpG, TpC, ApC, CpC, TpA, ApA, and CpA.
9. The method of claim 6 , wherein X 1 X 2 are selected from the group consisting of GpA and GpT and X 3 X 4 are TpT.
10. The method of claim 6 , wherein X 1 X 2 are both purines and X 3 X 4 are both pyrimidines.
11. The method of claim 6 , wherein X 2 is a T and X 3 is a pyrimidine.
12. The method of claim 6 , wherein the oligonucleotide is 8 to 40 nucleotides in length.
13. The method of claim 6 , wherein the oligonucleotide is isolated.
14. The method of claim 6 , wherein the oligonucleotide is a synthetic oligonucleotide.
15. The method of claim 1 , wherein the subject is an infant.
16. The method of claim 1 , wherein the antigen is derived from an infectious organism selected from the group consisting of a virus, bacterium, fungus and parasite.
17. The method of claim 1 , wherein the antigen is a tumor antigen.
18. The method of claim 1 , wherein the antigen is an allergen.
19. The method of claim 1 , wherein the antigen is in the form of a crude extract.
20. The method of claim 1 , wherein the antigen is in the form of a purified molecule including a protein or a polysaccharide.
21. The method of claim 1 , wherein the antigen is in the form of a recombinant molecule including a protein, polypeptide, peptide or peptide mimic of a polysaccharide antigen.
22. The method of claim 1 , wherein the non-nucleic acid adjuvant by itself gives a Th1 immune response (e.g., MPL) but when used in combination with the CpG oligonucleotide gives a stronger Th1 response.