Systems and methods to improve vaccine efficacy
Systems and methods to increase the efficacy of vaccines that require or are rendered more effective with T cell mediated immunity are described. The systems and methods utilize polynucleotides that genetically modify T cells to express a T cell receptor specific for an administered vaccine antigen.
1. A method, comprising
administering a vaccine antigen to a subject; and
administering an effective amount of a nanoparticle to the subject; wherein the nanoparticle comprises
(i) a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen; and
(ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on the surface of the nanoparticle.
2. The method of claim 1 , wherein the vaccine antigen comprises a cancer antigen selected from prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), mesothelin, CD19, CD20, receptor tyrosine kinase-like orphan receptor 1 (ROR1), and Wilms' tumor protein 1 (WT1) or a fragment of PSMA, PSCA, mesothelin, CD19, CD20, ROR1, and WT1 or a viral antigen selected from Nef (66-97), Nef (116-145), Gag p17 (17-35), Gag p17-p24 (253-284), Pol 325-355 (RT 158-188), circumsporozoite protein (CSP) central repeat region, and E protein Domain III.
3. The method of claim 1 , wherein the vaccine antigen comprises a cancer antigen selected from SEQ ID NOs. 135-141 or a viral antigen selected from SEQ ID NOs: 128-134.
4. The method of claim 1 , wherein the encoded TCR comprises an α chain selected from SEQ ID NOs: 1, 4, 18, 21, 23, 25, 27, 29-32, 34, and 36.
5. The method of claim 1 , wherein the encoded TCR comprises a β chain selected from SEQ ID NOs: 2, 3, 19, 22, 24, 26, 28, 33, 35, and 37.
6. The method of claim 1 , wherein the encoded TCR comprises a sequence selected from SEQ ID NOs: 5-12, 15, 16, and 39.
7. The method of claim 1 , comprising administering an adjuvant.
8. The method of claim 7 , wherein the vaccine adjuvant is selected from CpG, Cpg-28, Polyriboinosinic polyribocytidylic acid (Poly(I:C)), α-galactoceramide, monophosphoryl lipid A (MPLA), a toll-like receptor agonist, Amino-1-isobutyl-1H-imidazo(4,5-c)quinoline, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, and/or a stimulator of interferon genes (STING) agonist selected from c-diGMP, c-diAMP, c-GAMP, c-AIMP, (3′,2′)c-AIMP, (2′,2′)c-AIMP, (2′,3′)c-AIMP, c-AIMP(S), c-(dAMP-dIMP), c-(dAMP-2′FdIMP), c-(2′FdAMP-2′FdIMP), (2′,3′)c-(AMP-2′FdIMP), c-[2′FdAMP(S)-2′FdIMP(S)], c-[2′FdAMP(S)-2′FdIMP(S)](POM) 2 , and/or dimethylxanthone acetic acid (DMXAA).
9. The method of claim 1 , wherein the polynucleotide is encapsulated within a positively-charged polymer matrix.
10. The method of claim 9 , wherein the positively-charged polymer matrix comprises poly-β-amino ester (PBAE).
11. The method of claim 9 , wherein the positively-charged polymer matrix is surrounded by a negatively-charged coating.
12. The method of claim 11 , wherein the negatively-charged coating comprises polyglutamic acid (PGA).
13. The method of claim 1 , wherein the binding fragment comprises a sequence selected from SEQ ID NOs: 41-58.
14. The method of claim 1 , wherein the nanoparticle comprises an iPB7 transposase comprising SEQ ID NO: 142.
15. The method of claim 1 , wherein the subject has a low T cell count.
16. The method of claim 1 , wherein the method improves the efficacy of the vaccination as compared to administration of the vaccine antigen alone.
17. A kit for practicing the method of claim 1 comprising:
a vaccine antigen;
a positively-charged polymer;
a negatively-charged polymer covalently linked to a binding fragment of an anti-CD4 or anti-CD8 antibody; and
a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen.
18. The kit of claim 17 , wherein the vaccine antigen comprises a cancer antigen selected from prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), mesothelin, CD19, CD20), receptor tyrosine kinase-like orphan receptor 1 (ROR1), and Wilms' tumor gene 1 (WT1) or a fragment of PSMA, PSCA, mesothelin, CD19, CD20, ROR1, and WT1 or a viral antigen selected from Nef (66-97), Nef (116-145), Gag p17 (17-35), Gag p17-p24 (253-284), Pol 325-355 (RT 158-188), circumsporozoite protein (CSP) central repeat region, and E protein Domain III.
19. A composition, comprising:
a vaccine antigen; and
an effective amount of a nanoparticle,
wherein the nanoparticle comprises
(i) a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen; and
(ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on the surface of the nanoparticle.
20. The composition of claim 19 , wherein the vaccine antigen comprises a cancer antigen selected from prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), mesothelin, CD19, CD20, receptor tyrosine kinase-like orphan receptor 1 (ROR1), and Wilms' tumor gene 1 (WT1) or a fragment of PSMA, PSCA, mesothelin, CD19, CD20, ROR1, and WT1 or a viral antigen selected from Nef (66-97), Nef (116-145), Gag p17 (17-35), Gag p17-p24 (253-284), Pol 325-355 (RT 158-188), circumsporozoite protein (CSP) central repeat region, and E protein Domain III.
21. The composition of claim 19 , comprising an adjuvant.
22. The composition of claim 19 , wherein the polynucleotide is encapsulated within a positively-charged polymer matrix.
23. The composition of claim 22 , wherein the positively-charged polymer matrix comprises poly-β-amino ester (PBAE).
24. The composition of claim 22 , wherein the positively-charged polymer matrix is surrounded by a negatively-charged coating.
25. The composition of claim 24 , wherein the negatively-charged coating comprises polyglutamic acid (PGA).
26. A method, comprising:
administering an effective amount of a nanoparticle to a subject vaccinated with a vaccine antigen; wherein the nanoparticle comprises:
(i) a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen; and
(ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on the surface of the nanoparticle.
27. The method of claim 7 , wherein the vaccine adjuvant is selected from CpG, Cpg-28, Polyriboinosinic polyribocytidylic acid (Poly(I:C)), α-galactoceramide, monophosphoryl lipid A (MPLA), 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, and/or a stimulator of interferon genes (STING) agonist selected from c-diGMP, c-diAMP, c-GAMP, c-AIMP, (3′,2′)c-AIMP, (2′,2′)c-AIMP, (2′,3′)c-AIMP, c-AIMP(S), c-(dAMP-dIMP), c-(dAMP-2′FdIMP), c-(2′FdAMP-2′FdIMP), (2′,3′)c-(AMP-2′FdIMP), c-[2′FdAMP(S)-2′FdIMP(S)], c-[2′FdAMP(S)-2′FdIMP(S)](POM) 2 , and/or dimethylxanthenone acetic acid (DMXAA).
28. The method of claim 1 , wherein the vaccine antigen comprises mesothelin.