Systems and methods to improve vaccine efficacy

Abstract

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 - 80 . (canceled) 
     
     
         81 . A method of genetically modifying a cell to express a T cell receptor (TCR) that binds a vaccine antigen, wherein the method comprises:
 administering an effective amount of a nanoparticle to a subject within a clinically relevant time from which the subject received the vaccine antigen, wherein the nanoparticle comprises:   (i) a polynucleotide encoding the TCR; and   (ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on a surface of the nanoparticle,   whereby the nanoparticle genetically modifies the cell after the administering.   
     
     
         82 . The method of  claim 81 , wherein the subject receives the vaccine antigen before or after the administering. 
     
     
         83 . The method of  claim 81 , wherein the subject receives the vaccine antigen after the administering. 
     
     
         84 . The method of  claim 81 , wherein the subject receives the vaccine antigen before the administering. 
     
     
         85 . The method of  claim 81 , wherein the subject is in need of treatment for an infection or a cancer. 
     
     
         86 . The method of  claim 85 , wherein the subject in need of has, or is prone to have the infection or the cancer. 
     
     
         87 . The method of  claim 81 , 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. 
     
     
         88 . The method of  claim 81 , 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. 
     
     
         89 . The method of  claim 81 , 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. 
     
     
         90 . The method of  claim 81 , wherein the encoded TCR comprises a β chain selected from SEQ ID NOs: 2, 3, 19, 22, 24, 26, 28, 33, 35, and 37. 
     
     
         91 . The method of  claim 81 , wherein the encoded TCR comprises a sequence selected from SEQ ID NOs: 5-12, 15, 16, and 39. 
     
     
         92 . The method of  claim 81 , further comprising administering a vaccine adjuvant to the subject. 
     
     
         93 . The method of  claim 92 , 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, 4-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) agonistselected 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). 
     
     
         94 . The method of  claim 81 , wherein the polynucleotide is encapsulated within a positively-charged polymer matrix. 
     
     
         95 . The method of  claim 94 , wherein the positively-charged polymer matrix comprises poly-β-amino ester (PBAE). 
     
     
         96 . The method of  claim 94 , wherein the positively-charged polymer matrix is surrounded by a negatively-charged coating. 
     
     
         97 . The method of  claim 96 , wherein the negatively-charged coating comprises polyglutamic acid (PGA). 
     
     
         98 . The method of  claim 81 , wherein the binding fragment comprises a sequence selected from SEQ ID NOs: 41-58. 
     
     
         99 . The method of  claim 81 , wherein the nanoparticle comprises an iPB7 transposase comprising SEQ ID NO: 142. 
     
     
         100 . The method of  claim 81 , wherein the subject has a low T cell count.