IMMUNOSTIMULATORY ADJUVANTS

Abstract

The present invention relates, in part, to vaccine compositions, adjuvants, chimeric proteins, or chimeric protein complexes and their use as vaccines or therapeutic agents. The present invention further relates to methods of vaccination or treatment of various diseases.

Description

Claims

1. A vaccine composition, comprising (a) an adjuvant, comprising a chimeric protein or chimeric protein complex, comprising: (i) a wildtype or mutant IL-1β,(ii) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to an antigen or receptor of interest; and(iii) a connector between (i) and (ii), the connector being: (1) an Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain that connects (i) and (ii) and/or(2) a flexible linker that connects (i) and (ii), wherein the mutant IL-1β is characterized by low affinity or activity at the IL-1 receptor; and(b) an antigen which is suitable for inducing an immune response.

2. The vaccine composition of claim 1, wherein the wildtype or mutant IL-1β is human IL-1β.

3. The vaccine composition of claim 1 or 2, wherein the low affinity or activity at the IL-1 receptor is restorable by attachment to one or more targeting moieties or upon inclusion in the chimeric protein complex.

4. The vaccine composition of any one of claims 1-3, wherein the mutant human IL-1β has an amino acid sequence of at least 95%, or 97% or 98% identity to SEQ ID NO: 1.

5. The vaccine composition of any one of claims 1-4, wherein the mutant IL-1β comprises one or more mutations selected from A117G/P118G, R120X, L122A, T125G/L126G, R127G, Q130X, Q131G, K132A, S137G/Q138Y, L145G, H146X, L145A/L147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209X, K209A/K210A, K219X, E221X, E221 S/N224A, N224S/K225S, E244K, and N245Q, wherein X is any change in amino acid, with respect to the amino acid sequence of SEQ ID NO: 1.

6. The vaccine composition of claim 5, wherein the mutant IL-1β comprises one or more mutations selected from R120A, R120G, Q130A, Q130W, H146A, H146G, H146E, H146N, H146R, Q148E, Q148G, Q148L, K209A, K209D, K219S, K219Q, E221S and E221K, with respect to the amino acid sequence of SEQ ID NO: 1.

7. The vaccine composition of claim 5, wherein the mutant IL-1β comprises any of the following with respect to the amino acid sequence of SEQ ID NO: 1: Q131G and Q148G;Q148G and K208E;R120G and Q131G;R120G and H146A;R120G and H146N;R120G and H146R;R120G and H146E;R120G and H146G;R120G and K208E; andR120G, F162A, and Q164E.

8. The vaccine composition of claim 5, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1.

9. The vaccine composition of any one of claims 1-8, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds an antigen or receptor on an endothelial cell, epithelial cell, mesenchymal cell, stromal cell, ECM and/or immune cell, organ cell, and/or tissue cell.

10. The vaccine composition of claim 9, wherein the immune cell is selected from a T cell, a B cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a monocyte, a red blood cell, myeloid cell, myeloid derived suppressor cell, a NKT cell, and a NK cell, or derivatives thereof.

11. The vaccine composition of claim 10, wherein the immune cell is a T cell.

12. The vaccine composition of any one of claims 1-11, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

13. The vaccine composition of any one of claims 1-12, wherein the targeting moiety comprises a recognition domain that is a full-length antibody or a fragment thereof, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a Humabody, a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′)2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.

14. The vaccine composition of any one of claims 1-13, wherein the chimeric protein or chimeric protein complex further comprises additional cytokines, optionally modified, optionally mutated.

15. The vaccine composition of any one of claims 1-14, wherein the chimeric protein or chimeric protein complex further comprises one or more additional targeting moieties.

16. The vaccine composition of any one of the above claims, wherein the chimeric protein or chimeric protein complex further comprises two signaling agents and/or two targeting moieties or two of both.

17. The vaccine composition of any one of the above claims, wherein the chimeric protein or chimeric protein complex further comprises three signaling agents and/or three targeting moieties or three of both.

18. The vaccine composition of any one of the above claims, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1 and the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

19. The vaccine composition of any one of the above claims, further comprising an aluminum gel or salt.

20. The vaccine composition of claim 19, wherein the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and aluminum sulfate.

21. The vaccine composition of any one of the above claims, wherein the vaccine further comprises an additional adjuvant selected from oil-in-water emulsion formulations, saponin adjuvants, Freunds Adjuvants, cytokines, toll like receptors ligands, and chitosans.

22. The vaccine composition of any one of the above claims, wherein the vaccine composition is suitable for preventing or mitigating a disease or disorder is an infectious disease.

23. The vaccine composition of claim 22, wherein the disease or disorder is an infectious disease.

24. The vaccine composition of claim 23, wherein the infectious disease is an infection with a pathogen, optionally selected from a bacterium, virus, fungus, or parasite.

25. The vaccine composition of claim 24, wherein the pathogen is a virus.

26. The vaccine composition of claim 25, wherein the virus is: (a) an influenza virus, optionally selected from Type A, Type B, Type C, and Type D influenza viruses, or(b) a member of the Coronaviridae family, optionally selected from (i) a betacoronavirus, optionally selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East Respiratory Syndrome-Corona Virus (MERS-CoV), HCoV-HKU1, and HCoV-OC43,(ii) an alphacoronavirus, optionally selected from HCoV-NL63 and HCoV-229E, or(iii) a member of Picornaviridae family, optionally selected from Rhinovirus A or Rhinovirus B.

27. The vaccine composition of claim 26, wherein the virus is SARS-CoV-2.

28. The vaccine composition of any one of the above claims, wherein the adjuvant is a nucleic acid encoding the chimeric protein or chimeric protein complex.

29. The vaccine composition of any one of claims 1-28, wherein the antigen is a protein or an antigenic fragment of a protein.

30. The vaccine composition of any one of claims 1-28, wherein the antigen is a nucleic acid encoding a protein or an antigenic fragment of a protein.

31. The vaccine composition of claim 28 or 30, wherein the nucleic acid is mRNA, optionally comprising one or more non-canonical nucleotides, optionally selected from pseudouridine and 5-methoxyuridine.

32. The vaccine composition of claim 30, wherein the nucleic acid is DNA, optionally selected from linear DNA, DNA fragments, or DNA plasmids.

33. The vaccine composition of claim 29, wherein the antigen is a 2019-nCoV protein, or an antigenic fragment thereof, optionally selected from spike surface glycoprotein, membrane glycoprotein M, envelope protein E, and nucleocapsid phosphoprotein N.

34. The vaccine composition of claim 33, wherein the spike surface glycoprotein is the S1 or S2 subunit, or an antigenic fragment thereof.

35. The vaccine composition of claim 34, wherein the spike surface glycoprotein comprises the amino acid sequence of SEQ ID NO: 31, membrane glycoprotein precursor M comprises the amino acid sequence of SEQ ID NO: 32, the envelope protein E comprises the amino acid sequence of SEQ ID NO: 33, and the nucleocapsid phosphoprotein N comprises the amino acid sequence of SEQ ID NO: 34, or an amino acid sequence at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity with any of the foregoing, or an antigenic fragment of any of the foregoing.

36. The vaccine composition of claim 26, wherein the virus is an influenza virus.

37. The vaccine composition of claim 36, wherein the antigen is an influenza viral antigen, optionally selected from hemagglutinin (HA) protein, matrix 2 (M2) protein, and neuraminidase, or an antigenic fragment thereof.

38. The vaccine composition of claim 23, wherein the disease or disorder is selected from diphtheria, tetanus, pertussis, influenza, pneumonia, hepatitis A, hepatitis B, polio, yellow fever, Human Papillomavirus (HPV) infection, anthrax, rabies, Japanese Encephalitis, meningitis, measles, mumps, rubella, gastroenteritis, smallpox, typhoid fever, varicella (chickenpox), rotavirus, and shingles.

39. The vaccine composition of claim 38, wherein the antigen is that of one or more of the following vaccines: DTP (diphtheria-tetanus-pertussis vaccine), DTaP (diphtheria-tetanus-acellular pertussis vaccine), Hib (Haemophilus influenzae type b) conjugate vaccines, Pneumococcal conjugate vaccine, Hepatitis A vaccines, Poliomyelitis vaccines, Yellow fever vaccines, Hepatitis B vaccines, combination DTaP, Tdap, Hib, Human Papillomavirus (HPV) vaccine, Anthrax vaccine, and Rabies vaccine.

40. The vaccine composition of any one of the above claims, wherein the connector between (i) and (ii) is a flexible linker.

41. The vaccine composition of claim 40, wherein the flexible linker is substantially comprised of glycine and serine residues, optionally wherein i) the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 8, or ii)the flexible linker comprises one or more of SEQ ID NOs: 556-571.

42. The vaccine composition of claim 41, wherein the flexible linker is substantially comprised of GGSGGSGGGGSGGGGS (SEQ ID NO: 10).

43. The vaccine composition of claim 40, wherein the flexible linker is substantially comprised of LE, GGGGS (SEQ ID NO:2), (GGGGS)n(n=1-4) (SEQ ID NO:2 -SEQ ID NO:5), (Gly)8 (SEQ ID NO:11), (Gly)6 (SEQ ID NO:12), (EAAAK)n (n=1-3) (SEQ ID NO:13 -SEQ ID NO:15), A(EAAAK)nA (n = 2-5) (SEQ ID NO:16 - SEQ ID NO:19), AEAAAKEAAAKA (SEQ ID NO:16), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:21), PAPAP (SEQ ID NO:22), KESGSVSSEQLAQFRSLD (SEQ ID NO:23), EGKSSGSGSESKST (SEQ ID NO:24), GSAGSAAGSGEF (SEQ ID NO:25), and (XP)n, with X designating any amino acid, e.g., Ala, Lys, or Glu.

44. The vaccine composition of any one of the above claims, wherein the wherein the Fc domain is from IgG, IgA, IgD, IgM or IgE.

45. The vaccine composition of claim 44, wherein the IgG is selected from IgG1, IgG2, IgG3, or IgG4.

46. The vaccine composition of claim 44, wherein the Fc domain is from human IgG, IgA, IgD, IgM or IgE.

47. The vaccine composition of claim 46, wherein the human IgG is selected from human IgG1, IgG2, IgG3, or IgG4.

48. The vaccine composition of any one of the above claims, wherein the Fc chain pairing is promoted by ionic pairing and/or a knob-in-hole pairing.

49. The vaccine composition of claim 48, wherein the one or more mutations to the Fc domain results in an ionic pairing between the Fc chains in the Fc domain.

50. The vaccine composition of claim 48, wherein the one or more mutations to the Fc domain results in a knob-in-hole pairing in the Fc domain.

51. The vaccine composition of any one of the above claims, wherein the one or more mutations to the Fc domain results in the reduction or elimination of the effector function of the Fc domain.

52. The vaccine composition of any one of the above claims, wherein the chimeric protein complex is a heterodimer and has a trans orientation.

53. The vaccine composition of any one of the above claims, wherein the chimeric protein-complex is a heterodimer and has a cis orientation.

54. The vaccine composition of any one of the above claims, wherein the Fc domain comprises L234A, L235A, and K322Q substitutions in human IgG1 (according to EU numbering).

55. The vaccine composition of claim 54, wherein the Fc domain is human IgG1, and optionally contains one or more of L234, L235, K322, D265, P329, and P331 (according to EU numbering).

56. The vaccine composition of any one of the above claims, wherein the chimeric protein complex has an orientation and/or configuration of any one of FIGs. 1A-19F.

57. The vaccine composition of any one of the above claims, wherein the vaccine composition is formulated for administration intravenously.

58. The vaccine composition of any one of the above claims, wherein the vaccine composition is formulated for administration to the lung.

59. The vaccine composition of any one of the above claims, wherein the vaccine composition is formulated for administration by inhalation.

60. The vaccine composition of any one of the above claims, wherein the vaccine composition is formulated for administration via aerosol or nebulizer.

61. The vaccine composition of any one of the above claims, wherein the vaccine composition is formulated for administration liquid nebulization, dry powder dispersion and meter-dose administration.

62. The vaccine composition of any one of the above claims, wherein the adjuvant or vaccine composition has (a) low toxicity;(b) an ability to stimulate a long-lasting immune response against the antigen;(c) substantial stability;(d) an ability to elicit a humoral immune response and/or a cell-mediated immunity to the antigen;(e) a capability of selectively interacting with populations of antigen presenting cells;(f) an ability to specifically elicit TH1 and/or TH2 cell-specific immune responses to the antigen; and/or(g) an ability to selectively increase appropriate antibody isotype levels against antigens, the isotype optionally being IgA,when administered to a patient.

63. The vaccine composition of any one of the above claims, wherein the adjuvant or vaccine composition stimulates a CD8+ T cell response to the antigen, when administered to a patient.

64. The vaccine composition of any one of the above claims, wherein the adjuvant or vaccine composition stimulates activation of the IL-1R, when administered to a patient.

65. The vaccine composition of any one of the above claims, wherein the adjuvant or vaccine composition does not substantially cause one or more of fever, neutrophilia and the release of acute phase proteins when administered to a patient.

66. A method for vaccinating a subject against an infectious disease, comprising administering: (a) an adjuvant comprising a chimeric protein or chimeric protein complex, comprising: (i) a wildtype or mutant IL-1β,(ii) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to an antigen or receptor of interest; and(iii) a connector between (i) and (ii), the connector being: (1) an Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain that connects (i) and (ii) and/or(2) a flexible linker that connects (i) and (ii); wherein the mutant IL-1β is characterized by low affinity or activity at the IL-1 receptor; and(b) an antigen which is suitable for inducing an immune response.

67. The method of claim 66, wherein the adjuvant and antigen are administered concurrently.

68. The method of claim 66, wherein the adjuvant complex and antigen are co-formulated.

69. The method of claim 66, wherein the adjuvant and antigen are administered sequentially.

70. The method of claim 66, wherein the adjuvant and antigen are administered in multiple doses.

71. The method of claim 66, wherein the adjuvant is administered in multiple booster doses and the antigen is administered once.

72. The method of any one of claims 66-71, wherein the wildtype or mutant IL-1β is human IL-1β.

73. The method of any one of claims 66-72, wherein the low affinity or activity at the IL-1receptor is restorable by attachment to one or more targeting moieties or upon inclusion in the chimeric protein complex.

74. The method of any one of claims 66-73, wherein the mutant human IL-1β has an amino acid sequence of at least 95%, or 97% or 98% identity to SEQ ID NO: 1.

75. The method of any one of claims 66-74, wherein the mutant IL-1β comprises one or more mutations selected from A117G/P118G, R120X, L122A, T125G/L126G, R127G, Q130X, Q131G, K132A, S137G/Q138Y, L145G, H146X, L145A/L147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209X, K209A/K210A, K219X, E221X, E221 S/N224A, N224S/K225S, E244K, and N245Q, wherein X is any change in amino acid, with respect to the amino acid sequence of SEQ ID NO: 1.

76. The method of claim 75, wherein the mutant IL-1β comprises one or more mutations selected from R120A, R120G, Q130A, Q130W, H146A, H146G, H146E, H146N, H146R, Q148E, Q148G, Q148L, K209A, K209D, K219S, K219Q, E221S and E221K, with respect to the amino acid sequence of SEQ ID NO: 1.

77. The method of claim 75, wherein the mutant IL-1β comprises any of the following with respect to the amino acid sequence of SEQ ID NO: 1: Q131G and Q148G;Q148G and K208E;R120G and Q131G;R120G and H146A;R120G and H146N;R120G and H146R;R120G and H146E;R120G and H146G;R120G and K208E; andR120G, F162A, and Q164E.

78. The method of claim 75, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1.

79. The method of any one of claims 66-78, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds an antigen or receptor on an endothelial cell, epithelial cell, mesenchymal cell, stromal cell, ECM and/or immune cell, organ cell, and/or tissue cell.

80. The method of claim 79, wherein the immune cell is selected from a T cell, a B cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a monocyte, a red blood cell, myeloid cell, myeloid derived suppressor cell, a NKT cell, and a NK cell, or derivatives thereof.

81. The method of claim 80, wherein the immune cell is a T cell.

82. The method of any one of claims 66-81, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

83. The method of any one of claims 66-81, wherein the targeting moiety comprises a recognition domain that is a full-length antibody or a fragment thereof, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a Humabody, a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′)2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.

84. The method of any one of claims 66-83, wherein the chimeric protein or chimeric protein complex further comprises additional cytokines, optionally modified, optionally mutated.

85. The method of any one of claims 66-84, wherein the chimeric protein or chimeric protein complex further comprises one or more additional targeting moieties.

86. The method of any one of claims 66-85, wherein the chimeric protein or chimeric protein complex further comprises two signaling agents and/or two targeting moieties or two of both.

87. The method of any one of claims 66-86, wherein the chimeric protein or chimeric protein complex further comprises three signaling agents and/or three targeting moieties or three of both.

88. The method of any one of claims 66-87, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1 and the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

89. The method of any one of claims 66-88, further comprising an aluminum gel or salt.

90. The method of claim 89, wherein the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and aluminum sulfate.

91. The method of any one of claims 66-90, wherein the vaccine further comprises an additional adjuvant selected from oil-in-water emulsion formulations, saponin adjuvants, Freunds Adjuvants, cytokines, toll like receptors ligands, and chitosans.

92. The method of claim 91, wherein the infectious disease is an infection with a pathogen, optionally selected from a bacterium, virus, fungus, or parasite.

93. The method of claim 91, wherein the pathogen is a virus.

94. The method of claim 93, wherein the virus is: (a) an influenza virus, optionally selected from Type A, Type B, Type C, and Type D influenza viruses, or(b) a member of the Coronaviridae family, optionally selected from (i) a betacoronavirus, optionally selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East Respiratory Syndrome-Corona Virus (MERS-CoV), HCoV-HKU1, and HCoV-OC43,(ii) alphacoronavirus, optionally selected from HCoV-NL63 and HCoV-229E, or(iii) a member of Picornaviridae family, optionally selected from Rhinovirus A or Rhinovirus B.

95. The method of claim 94, wherein the virus is SARS-CoV-2.

96. The method of any one of claims 66-95, wherein the adjuvant is a nucleic acid encoding the chimeric protein or chimeric protein complex.

97. The method of any one of claims 66-96, wherein the antigen is a protein or an antigenic fragment of a protein.

98. The method of any one of claims 66-97, wherein the antigen is a nucleic acid encoding a protein or an antigenic fragment of a protein.

99. The method of claim 98, wherein the nucleic acid is mRNA, optionally comprising one or more non-canonical nucleotides, optionally selected from pseudouridine and 5-methoxyuridine.

100. The method of claim 98, wherein the nucleic acid is DNA, optionally selected from linear DNA, DNA fragments, or DNA plasmids.

101. The method of claim 97 or 98, wherein the antigen is a 2019-nCoV protein, or an antigenic fragment thereof, optionally selected from spike surface glycoprotein, membrane glycoprotein M, envelope protein E, and nucleocapsid phosphoprotein N.

102. The method of claim 101, wherein the spike surface glycoprotein is the S1 or S2 subunit, or an antigenic fragment thereof.

103. The method of claim 102, wherein the spike surface glycoprotein comprises the amino acid sequence of SEQ ID NO: 31, membrane glycoprotein precursor M comprises the amino acid sequence of SEQ ID NO: 32, the envelope protein E comprises the amino acid sequence of SEQ ID NO: 33, and the nucleocapsid phosphoprotein N comprises the amino acid sequence of SEQ ID NO: 34, or an amino acid sequence at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity with any of the foregoing, or an antigenic fragment of any of the foregoing.

104. The method of claim 94, wherein the virus is an influenza virus.

105. The method of claim 104, wherein the antigen is an influenza viral antigen, optionally selected from hemagglutinin (HA) protein, matrix 2 (M2) protein, and neuraminidase, or an antigenic fragment thereof.

106. The method of any one of claims 66-105, wherein the connector between (i) and (ii) is a flexible linker.

107. The method of claim 106, wherein the flexible linker is substantially comprised of glycine and serine residues, optionally wherein i) the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 8, or ii) the flexible linker comprises one or more of SEQ ID NOs: 556-571.

108. The method of claim 107, wherein the flexible linker is substantially comprised of GGSGGSGGGGSGGGGS (SEQ ID NO: 10).

109. The method of claim 106, wherein the flexible linker is substantially comprised of LE, GGGGS (SEQ ID NO:2), (GGGGS)n(n=1-4) (SEQ ID NO:2-SEQ ID NO:5),(Gly)8 (SEQ ID NO:11), (Gly)6 (SEQ ID NO:12), (EAAAK)n (n=1-3) (SEQ ID NO:13 -SEQ ID NO:15), A(EAAAK)nA (n = 2-5) (SEQ ID NO:16 - SEQ ID NO:19), AEAAAKEAAAKA (SEQ ID NO:16), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:21), PAPAP (SEQ ID NO:22), KESGSVSSEQLAQFRSLD (SEQ ID NO:23), EGKSSGSGSESKST (SEQ ID NO:24), GSAGSAAGSGEF (SEQ ID NO:25), and (XP)n, with X designating any amino acid, e.g., Ala, Lys, or Glu.

110. The method of any one of claims 66-109, wherein the wherein the Fc domain is from IgG, IgA, IgD, IgM or IgE.

111. The method of claim 110, wherein the IgG is selected from IgG1, IgG2, IgG3, or IgG4.

112. The method of claim 110, wherein the Fc domain is from human IgG, IgA, IgD, IgM or IgE.

113. The method of claim 112, wherein the human IgG is selected from human IgG1, IgG2, IgG3, or IgG4.

114. The method of any one of claims 66-113, wherein the Fc chain pairing is promoted by ionic pairing and/or a knob-in-hole pairing.

115. The method of claim 114, wherein the one or more mutations to the Fc domain results in an ionic pairing between the Fc chains in the Fc domain.

116. The method of claim 114, wherein the one or more mutations to the Fc domain results in a knob-in-hole pairing in the Fc domain.

117. The method of any one of claims 66-116, wherein the one or more mutations to the Fc domain results in the reduction or elimination of the effector function of the Fc domain.

118. The method of any one of claims 66-117, wherein the Fc-based chimeric protein complex is a heterodimer and has a trans orientation.

119. The method of any one of claims 66-118, wherein the Fc-based chimeric protein-complex is a heterodimer and has a cis orientation.

120. The method of any one of claims 66-119, wherein the Fc comprises L234A, L235A, and K322Q substitutions in human IgG1 (according to EU numbering).

121. The method of claim 120, wherein the Fc is human IgG1, and optionally contains one or more of L234, L235, K322, D265, P329, and P331 (according to EU numbering).

122. The method of any one of claims 66-121, wherein the Fc-based chimeric protein complex has an orientation and/or configuration of any one of FIGs. 1A-19F.

123. The method of any one of claims 66-122, wherein the adjuvant and/or the antigen are formulated for administration intravenously.

124. The method of any one of claims 66-122, wherein the adjuvant and/or the antigen are formulated for administration to the lung.

125. The method of any one of claims 66-122, wherein the adjuvant and/or the antigen are formulated for administration by inhalation.

126. The method of any one of claims 66-122, wherein the adjuvant and/or the antigen are formulated for administration via aerosol or nebulizer.

127. The method of any one of claims 66-122, wherein the adjuvant and/or the antigen are formulated for administration liquid nebulization, dry powder dispersion and meter-dose administration.

128. The method of any one of claims 66-127, wherein the adjuvant has (a) low toxicity;(b) an ability to stimulate a long-lasting immune response against the antigen;(c) substantial stability;(d) an ability to elicit a humoral immune response and/or a cell-mediated immunity to the antigen;(e) a capability of selectively interacting with populations of antigen presenting cells;(f) an ability to specifically elicit TH1 and/or TH2 cell-specific immune responses to the antigen; and/or(g) an ability to selectively increase appropriate antibody isotype levels against antigens, the isotype optionally being IgA,when administered to a patient.

129. The method of any one of claims 66-128, wherein the adjuvant stimulates a CD8+ T cell response to the antigen, when administered to a patient.

130. The method of any one of claims 66-129, wherein the adjuvant or vaccine composition stimulates activation of the IL-1R, when administered to a patient.

131. The method of any one of claims 66-130, wherein the adjuvant does not substantially cause one or more of fever, neutrophilia and the release of acute phase proteins when administered to a patient.

132. A method for vaccinating a subject against an influenza infection, comprising administering: (a) an adjuvant comprising a chimeric protein or chimeric protein complex, comprising: (i) a wildtype or mutant IL-1β,(ii) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to an antigen or receptor of interest; and(iii) a connector between (i) and (ii), the connector being: (1) an Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain that connects (i) and (ii) and/or(2) a flexible linker that connects (i) and (ii); wherein the mutant IL-1β is characterized by low affinity or activity at the IL-1 receptor; and(b) an influenza antigen which is suitable for inducing an immune response.

133. The vaccine composition of claim 132, wherein the mutant IL-1β is human IL-1β.

134. The method of claim 132 or 133, wherein the low affinity or activity at the IL-1 receptor is restorable by attachment to one or more targeting moieties or upon inclusion in the chimeric protein complex.

135. The method of any one of claims 132-134, wherein the mutant human IL-1β has an amino acid sequence of at least 95%, or 97% or 98% identity to SEQ ID NO: 1.

136. The method of any one of claims 132-135, wherein the mutant IL-1β comprises one or more mutations selected from A117G/P118G, R120X, L122A, T125G/L126G, R127G, Q130X, Q131G, K132A, S137G/Q138Y, L145G, H146X, L145A/L147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209X, K209A/K210A, K219X, E221X, E221 S/N224A, N224S/K225S, E244K, and N245Q, wherein X is any change in amino acid, with respect to the amino acid sequence of SEQ ID NO: 1.

137. The method of claim 136, wherein the mutant IL-1β comprises one or more mutations selected from R120A, R120G, Q130A, Q130W, H146A, H146G, H146E, H146N, H146R, Q148E, Q148G, Q148L, K209A, K209D, K219S, K219Q, E221S and E221K, with respect to the amino acid sequence of SEQ ID NO: 1.

138. The method of claim 136, wherein the mutant IL-1β comprises any of the following with respect to the amino acid sequence of SEQ ID NO: 1: Q131G and Q148G;Q148G and K208E;R120G and Q131G;R120G and H146A;R120G and H146N;R120G and H146R;R120G and H146E;R120G and H146G;R120G and K208E; andR120G, F162A, and Q164E.

139. The method of claim 136, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1.

140. The method of any one of claims 132-139, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds an antigen or receptor on an endothelial cell, epithelial cell, mesenchymal cell, stromal cell, ECM and/or immune cell, organ cell, and/or tissue cell.

141. The method of claim 140, wherein the immune cell is selected from a T cell, a B cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a monocyte, a red blood cell, myeloid cell, myeloid derived suppressor cell, a NKT cell, and a NK cell, or derivatives thereof.

142. The method of claim 141, wherein the immune cell is a T cell.

143. The method of any one of claims 132-142, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

144. The method of any one of claims 132-143, wherein the targeting moiety comprises a recognition domain that is a full-length antibody or a fragment thereof, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a Humabody, a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′)2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.

145. The method of any one of claims 132-144, wherein the chimeric protein or chimeric protein complex further comprises additional cytokines, optionally modified, optionally mutated.

146. The method of any one of claims 132-145, wherein the chimeric protein or chimeric protein complex further comprises one or more additional targeting moieties.

147. The method of any one of claims 132-146, wherein the chimeric protein or chimeric protein complex further comprises two signaling agents and/or two targeting moieties or two of both.

148. The method of any one of claims 132-147, wherein the chimeric protein or chimeric protein complex further comprises three signaling agents and/or three targeting moieties or three of both.

149. The method of any one of claims 132-148, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1 and the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

150. The method of any one of claims 132-149, further comprising an aluminum gel or salt.

151. The method of claim 150, wherein the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and aluminum sulfate.

152. The method of any one of claims 132-151, wherein the vaccine further comprises an additional adjuvant selected from oil-in-water emulsion formulations, saponin adjuvants, Freunds Adjuvants, cytokines, toll like receptors ligands, and chitosans.

153. The method of any one of claims 132-152, wherein the adjuvant is a nucleic acid encoding the chimeric protein or chimeric protein complex.

154. The method of any one of claims 132-153, wherein the antigen is a protein or an antigenic fragment of a protein.

155. The method of any one of claims 132-153, wherein the antigen is a nucleic acid encoding a protein or an antigenic fragment of a protein.

156. The method of claim 155, wherein the nucleic acid is mRNA, optionally comprising one or more non-canonical nucleotides, optionally selected from pseudouridine and 5-methoxyuridine.

157. The method of claim 155, wherein the nucleic acid is DNA, optionally selected from linear DNA, DNA fragments, or DNA plasmids.

158. The method of claim 154, wherein the influenza viral antigen is selected from hemagglutinin (HA) protein, matrix 2 (M2) protein, and neuraminidase, or an antigenic fragment thereof.

159. The method of any one of claims 132-158, wherein the connector between (i) and (ii) is a flexible linker.

160. The method of claim 159, wherein the flexible linker is substantially comprised of glycine and serine residues, optionally wherein i) the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 8, or ii) the flexible linker comprises one or more of SEQ ID NOs: 556-571.

161. The method of claim 160, wherein the flexible linker is substantially comprised of GGSGGSGGGGSGGGGS (SEQ ID NO: 10).

162. The method of claim 159, wherein the flexible linker is substantially comprised of LE, GGGGS (SEQ ID NO:2), (GGGGS)n(n=1-4) (SEQ ID NO:2-SEQ ID NO:5), (Gly)8(SEQ ID NO:11), (Gly)6 (SEQ ID NO:12), (EAAAK)n (n=1-3) (SEQ ID NO:13 -SEQ ID NO:15), A(EAAAK)nA (n = 2-5) (SEQ ID NO:16 - SEQ ID NO:19), AEAAAKEAAAKA (SEQ ID NO:16), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:21), PAPAP (SEQ ID NO:22), KESGSVSSEQLAQFRSLD (SEQ ID NO:23), EGKSSGSGSESKST (SEQ ID NO:24), GSAGSAAGSGEF (SEQ ID NO:25), and (XP)n, with X designating any amino acid, e.g., Ala, Lys, or Glu.

163. The method of any one of claims 132-162, wherein the wherein the Fc domain is from IgG, IgA, IgD, IgM or IgE.

164. The method of claim 163, wherein the IgG is selected from IgG1, IgG2, IgG3, or IgG4.

165. The method of claim 163, wherein the Fc domain is from human IgG, IgA, IgD, IgM or IgE.

166. The method of claim 165, wherein the human IgG is selected from human IgG1, IgG2, IgG3, or IgG4.

167. The method of any one of claims 132-166, wherein the Fc chain pairing is promoted by ionic pairing and/or a knob-in-hole pairing.

168. The method of claim 167, wherein the one or more mutations to the Fc domain results in an ionic pairing between the Fc chains in the Fc domain.

169. The method of claim 167, wherein the one or more mutations to the Fc domain results in a knob-in-hole pairing in the Fc domain.

170. The method of claim 167, wherein the one or more mutations to the Fc domain results in the reduction or elimination of the effector function of the Fc domain.

171. The method of any one of claims 132-170, wherein the Fc-based chimeric protein complex is a heterodimer and has a trans orientation.

172. The method of any one of claims 132-170, wherein the Fc-based chimeric protein-complex is a heterodimer and has a cis orientation.

173. The method of any one of claims 132-172, wherein the Fc comprises L234A, L235A, and K322Q substitutions in human IgG1 (according to EU numbering).

174. The method of claim 173, wherein the Fc is human IgG1, and optionally contains one or more of L234, L235, K322, D265, P329, and P331 (according to EU numbering).

175. The method of any one of claims 132-174, wherein the Fc-based chimeric protein complex has an orientation and/or configuration of any one of FIGs. 1A-19F.

176. The method of any one of claims 132-175, wherein the adjuvant and/or the antigen are formulated for administration intravenously.

177. The method of any one of claims 132-175, wherein the adjuvant and/or the antigen are formulated for administration to the lung.

178. The method of any one of claims 132-175, wherein the adjuvant and/or the antigen are formulated for administration by inhalation.

179. The method of any one of claims 132-175, wherein the adjuvant and/or the antigen are formulated for administration via aerosol or nebulizer.

180. The method of any one of claims 132-175, wherein the adjuvant and/or the antigen are formulated for administration liquid nebulization, dry powder dispersion and meter-dose administration.

181. The method of any one of claims 132-180, wherein the adjuvant has (a) low toxicity;(b) an ability to stimulate a long-lasting immune response against the antigen;(c) substantial stability;(d) an ability to elicit a humoral immune response and/or a cell-mediated immunity to the antigen;(e) a capability of selectively interacting with populations of antigen presenting cells;(f) an ability to specifically elicit TH1 and/or TH2 cell-specific immune responses to the antigen; and/or(g) an ability to selectively increase appropriate antibody isotype levels against antigens, the isotype optionally being IgA,when administered to a patient.

182. The method of any one of claims 132-181, wherein the adjuvant stimulates a CD8+ T cell response to the antigen, when administered to a patient.

183. The method of any one of claims 132-182, wherein the adjuvant or vaccine composition stimulates activation of the IL-1R, when administered to a patient.

184. The method of any one of claims 132-183, wherein the adjuvant does not substantially cause one or more of fever, neutrophilia and the release of acute phase proteins when administered to a patient.

185. A method for vaccinating a subject against a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection comprising administering: (a) an adjuvant comprising a chimeric protein or chimeric protein complex, comprising: (i) a wildtype or mutant IL-1β,(ii) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to an antigen or receptor of interest; and(iii) a connector between (i) and (ii), the connector being: (1) an Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain that connects (i) and (ii) and/or(2) a flexible linker that connects (i) and (ii); wherein the mutant IL-1β is characterized by low affinity or activity at the IL-1 receptor; and(b) a SARS-CoV-2 antigen which is suitable for inducing an immune response.

186. The method of claim 185, wherein the wildtype or mutant IL-1β is human IL-1β.

187. The method of any one of claims 185-186, wherein the low affinity or activity at the IL-1 receptor is restorable by attachment to one or more targeting moieties or upon inclusion in the chimeric protein complex.

188. The method of any one of claims 185-187, wherein the mutant human IL-1β has an amino acid sequence of at least 95%, or 97% or 98% identity to SEQ ID NO: 1.

189. The method of any one of claims 185-188, wherein the mutant IL-1β comprises one or more mutations selected from A117G/P118G, R120X, L122A, T125G/L126G, R127G, Q130X, Q131G, K132A, S137G/Q138Y, L145G, H146X, L145A/L147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209X, K209A/K210A, K219X, E221X, E221 S/N224A, N224S/K225S, E244K, and N245Q, wherein X is any change in amino acid, with respect to the amino acid sequence of SEQ ID NO: 1.

190. The method of claim 189, wherein the mutant IL-1β comprises one or more mutations selected from R120A, R120G, Q130A, Q130W, H146A, H146G, H146E, H146N, H146R, Q148E, Q148G, Q148L, K209A, K209D, K219S, K219Q, E221S and E221K, with respect to the amino acid sequence of SEQ ID NO: 1.

191. The method of claim 189, wherein the mutant IL-1β comprises any of the following with respect to the amino acid sequence of SEQ ID NO: 1: Q131G and Q148G;Q148G and K208E;R120G and Q131G;R120G and H146A;R120G and H146N;R120G and H146R;R120G and H146E;R120G and H146G;R120G and K208E; andR120G, F162A, and Q164E.

192. The method of claim 189, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1.

193. The method of any one of claims 185-192, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds an antigen or receptor on an endothelial cell, epithelial cell, mesenchymal cell, stromal cell, ECM and/or immune cell, organ cell, and/or tissue cell.

194. The method of claim 193, wherein the immune cell is selected from a T cell, a B cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a monocyte, a red blood cell, myeloid cell, myeloid derived suppressor cell, a NKT cell, and a NK cell, or derivatives thereof.

195. The method of claim 194, wherein the immune cell is a T cell.

196. The method of any one of claims 185-195, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

197. The method of any one of claims 185-196, wherein the targeting moiety comprises a recognition domain that is a full-length antibody or a fragment thereof, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a Humabody, a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′)2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.

198. The method of any one of claims 185-197, wherein the chimeric protein or chimeric protein complex further comprises additional cytokines, optionally modified, optionally mutated.

199. The method of any one of claims 185-198, wherein the chimeric protein or chimeric protein complex further comprises one or more additional targeting moieties.

200. The method of any one of claims 185-199, wherein the chimeric protein or chimeric protein complex further comprises two signaling agents and/or two targeting moieties or two of both.

201. The method of any one of claims 185-200, wherein the chimeric protein or chimeric protein complex further comprises three signaling agents and/or three targeting moieties or three of both.

202. The method of any one of claims 185-201, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1 and the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

203. The method of any one of claims 185-202, further comprising an aluminum gel or salt.

204. The method of claim 203, wherein the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and aluminum sulfate.

205. The method of any one of claims 185-204, wherein the vaccine further comprises an additional adjuvant selected from oil-in-water emulsion formulations, saponin adjuvants, Freunds Adjuvants, cytokines, toll like receptors ligands, and chitosans.

206. The method of any one of claims 185-205, wherein the adjuvant is a nucleic acid encoding the chimeric protein or chimeric protein complex.

207. The method of any one of claims 185-206, wherein the antigen is a protein or an antigenic fragment of a protein.

208. The method of any one of claims 185-206, wherein the antigen is a nucleic acid encoding a protein or an antigenic fragment of a protein.

209. The method of claim 208, wherein the nucleic acid is mRNA, optionally comprising one or more non-canonical nucleotides, optionally selected from pseudouridine and 5-methoxyuridine.

210. The method of claim 208, wherein the nucleic acid is DNA, optionally selected from linear DNA, DNA fragments, or DNA plasmids.

211. The method of claim 207, wherein the SARS-CoV-2 antigen is a 2019-nCoV protein, or an antigenic fragment thereof, selected from spike surface glycoprotein, membrane glycoprotein M, envelope protein E, and nucleocapsid phosphoprotein N.

212. The method of claim 211, wherein the spike surface glycoprotein is the S1 or S2 subunit, or an antigenic fragment thereof.

213. The method of claim 212, wherein the spike surface glycoprotein comprises the amino acid sequence of SEQ ID NO: 31, membrane glycoprotein precursor M comprises the amino acid sequence of SEQ ID NO: 32, the envelope protein E comprises the amino acid sequence of SEQ ID NO: 33, and the nucleocapsid phosphoprotein N comprises the amino acid sequence of SEQ ID NO: 34, or an amino acid sequence at least about 90%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity with any of the foregoing, or an antigenic fragment of any of the foregoing.

214. The method of any one of claims 185-213, wherein the connector between (i) and (ii) is a flexible linker.

215. The method of claim 214, wherein the flexible linker is substantially comprised of glycine and serine residues, optionally wherein i) the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 8, or ii) the flexible linker comprises one or more of SEQ ID NOs: 556-571.

216. The method of claim 215, wherein the flexible linker is substantially comprised of GGSGGSGGGGSGGGGS (SEQ ID NO: 10).

217. The method of claim 214, wherein the flexible linker is substantially comprised of LE, GGGGS (SEQ ID NO:2), (GGGGS)n(n=1-4) (SEQ ID NO:2-SEQ ID NO:5),(Gly)8(SEQ ID NO:11), (Gly)6 (SEQ ID NO:12), (EAAAK)n (n=1-3) (SEQ ID NO:13 -SEQ ID NO:15), A(EAAAK)nA (n = 2-5) (SEQ ID NO:16 - SEQ ID NO:19), AEAAAKEAAAKA (SEQ ID NO:16), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:21), PAPAP (SEQ ID NO:22), KESGSVSSEQLAQFRSLD (SEQ ID NO:23), EGKSSGSGSESKST (SEQ ID NO:24), GSAGSAAGSGEF (SEQ ID NO:25), and (XP)n, with X designating any amino acid, e.g., Ala, Lys, or Glu.

218. The method of any one of claims 185-217, wherein the wherein the Fc domain is from IgG, IgA, IgD, IgM or IgE.

219. The method of claim 218, wherein the IgG is selected from IgG1, IgG2, IgG3, or IgG4.

220. The method of claim 218, wherein the Fc domain is from human IgG, IgA, IgD, IgM or IgE.

221. The method of claim 220, wherein the human IgG is selected from human IgG1, IgG2, IgG3, or IgG4.

222. The method of any one of claims 185-221, wherein the Fc chain pairing is promoted by ionic pairing and/or a knob-in-hole pairing.

223. The method of claim 222, wherein the one or more mutations to the Fc domain results in an ionic pairing between the Fc chains in the Fc domain.

224. The method of claim 222, wherein the one or more mutations to the Fc domain results in a knob-in-hole pairing in the Fc domain.

225. The method of any one of claims 185-224, wherein the one or more mutations to the Fc domain results in the reduction or elimination of the effector function of the Fc domain.

226. The method of any one of claims 185-225, wherein the Fc-based chimeric protein complex is a heterodimer and has a trans orientation.

227. The method of any one of claims 185-225, wherein the Fc-based chimeric protein-complex is a heterodimer and has a cis orientation.

228. The method of any one of claims 185-227, wherein the Fc comprises L234A, L235A, and K322Q substitutions in human IgG1 (according to EU numbering).

229. The method of claim 228, wherein the Fc is human IgG1, and optionally contains one or more of L234, L235, K322, D265, P329, and P331 (according to EU numbering).

230. The method of any one of claims 185-229, wherein the Fc-based chimeric protein complex has an orientation and/or configuration of any one of FIGs. 1A-19F.

231. The method of any one of claims 185-230, wherein the adjuvant and/or the antigen are formulated for administration intravenously.

232. The method of any one of claims 185-230, wherein the adjuvant and/or the antigen are formulated for administration to the lung.

233. The method of any one of claims 185-230, wherein the adjuvant and/or the antigen are formulated for administration by inhalation.

234. The method of any one of claims 185-230, wherein the adjuvant and/or the antigen are formulated for administration via aerosol or nebulizer.

235. The method of any one of claims 185-230, wherein the adjuvant and/or the antigen are formulated for administration liquid nebulization, dry powder dispersion and meter-dose administration.

236. The method of any one of claims 185-235, wherein the adjuvant has (a) low toxicity;(b) an ability to stimulate a long-lasting immune response against the antigen;(c) substantial stability;(d) an ability to elicit a humoral immune response and/or a cell-mediated immunity to the antigen;(e) a capability of selectively interacting with populations of antigen presenting cells;(f) an ability to specifically elicit TH1 and/or TH2 cell-specific immune responses to the antigen; and/or(g) an ability to selectively increase appropriate antibody isotype levels against antigens, the isotype optionally being IgA,when administered to a patient.

237. The method of any one of claims 185-236, wherein the adjuvant stimulates a CD8+ T cell response to the antigen, when administered to a patient.

238. The method of any one of claims 185-237, wherein the adjuvant or vaccine composition stimulates activation of the IL-1R, when administered to a patient.

239. The method of any one of claims 185-238, wherein the adjuvant does not substantially cause one or more of fever, neutrophilia and the release of acute phase proteins when administered to a patient.

240. A method for treating a subject afflicted with an infectious disease, comprising administering a chimeric protein or chimeric protein complex, comprising: (i) a wild type or mutant IL-1β,(ii) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to an antigen or receptor of interest; and(iii) a connector between (i) and (ii), the connector being: (1) an Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain that connects (i) and (ii) and/or(2) a flexible linker that connects (i) and (ii); wherein the mutant IL-1β is characterized by low affinity or activity at the IL-1 receptor.

241. The method of claim 240, wherein the wildtype or mutant IL-1β is human IL-1β.

242. The method of any one of claims 240-241, wherein the low affinity or activity at the IL-1 receptor is restorable by attachment to one or more targeting moieties or upon inclusion in the chimeric protein complex.

243. The method of any one of claims 240-242, wherein the mutant human IL-1β has an amino acid sequence of at least 95%, or 97% or 98% identity to SEQ ID NO: 1.

244. The method of any one of claims 240-243, wherein the mutant IL-1β comprises one or more mutations selected from A117G/P118G, R120X, L122A, T125G/L126G, R127G, Q130X, Q131G, K132A, S137G/Q138Y, L145G, H146X, L145A/L147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209X, K209A/K210A, K219X, E221X, E221 S/N224A, N224S/K225S, E244K, and N245Q, wherein X is any change in amino acid, with respect to the amino acid sequence of SEQ ID NO: 1.

245. The method of claim 244, wherein the mutant IL-1β comprises one or more mutations selected from R120A, R120G, Q130A, Q130W, H146A, H146G, H146E, H146N, H146R, Q148E, Q148G, Q148L, K209A, K209D, K219S, K219Q, E221S and E221K, with respect to the amino acid sequence of SEQ ID NO: 1.

246. The method of claim 244, wherein the mutant IL-1β comprises any of the following with respect to the amino acid sequence of SEQ ID NO: 1: Q131G and Q148G;Q148G and K208E;R120G and Q131G;R120G and H146A;R120G and H146N;R120G and H146R;R120G and H146E;R120G and H146G;R120G and K208E; andR120G, F162A, and Q164E.

247. The method of claim 244, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1.

248. The method of any one of claims 240-247, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds an antigen or receptor on a an endothelial cell, epithelial cell, mesenchymal cell, stromal cell, ECM and/or immune cell, organ cell, and/or tissue cell.

249. The method of claim 248, wherein the immune cell is selected from a T cell, a B cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a monocyte, a red blood cell, myeloid cell, myeloid derived suppressor cell, a NKT cell, and a NK cell, or derivatives thereof.

250. The method of claim 249, wherein the immune cell is a T cell.

251. The method of any one of claims 240-250, wherein the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

252. The method of any one of claims 240-250, wherein the targeting moiety comprises a recognition domain that is a full-length antibody or a fragment thereof, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a Humabody, a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′)2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.

253. The method of any one of claims 240-252, wherein the chimeric protein or chimeric protein complex further comprises additional cytokines, optionally modified, optionally mutated.

254. The method of any one of claims 240-253, wherein the chimeric protein or chimeric protein complex further comprises one or more additional targeting moieties.

255. The method of any one of claims 240-254, wherein the chimeric protein or chimeric protein complex further comprises two signaling agents and/or two targeting moieties or two of both.

256. The method of any one of claims 240-255, wherein the chimeric protein or chimeric protein complex further comprises three signaling agents and/or three targeting moieties or three of both.

257. The method of any one of claims 240-256, wherein the mutant IL-1β comprises Q148G, with respect to the amino acid sequence of SEQ ID NO: 1 and the targeting moiety comprises a recognition domain that recognizes and/or binds CD8 or CD4.

258. The method of any one of claims 240-257, further comprising an aluminum gel or salt.

259. The method of claim 258, wherein the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and aluminum sulfate.

260. The method of any one of claims 240-259, wherein the vaccine further comprises an additional adjuvant selected from oil-in-water emulsion formulations, saponin adjuvants, Freunds Adjuvants, cytokines, toll like receptors ligands, and chitosans.

261. The method of claim 260, wherein the infectious disease is an infection with a pathogen, optionally selected from a bacterium, virus, fungus, or parasite.

262. The method of claim 260, wherein the pathogen is a virus.

263. The method of claim 262, wherein the virus is: (a) an influenza virus, optionally selected from Type A, Type B, Type C, and Type D influenza viruses, or(b) a member of the Coronaviridae family, optionally selected from (i) a betacoronavirus, optionally selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East Respiratory Syndrome-Corona Virus (MERS-CoV), HCoV-HKU1, and HCoV-OC43 or(ii) an alphacoronavirus, optionally selected from HCoV-NL63 and HCoV-229E, or(iii) a member of Picornaviridae family, optionally selected from Rhinovirus A or Rhinovirus B.

264. The method of claim 263, wherein the virus is SARS-CoV-2.

265. The method of claim 263, wherein the virus is an influenza virus.

266. The method of any one of claims 240-265, wherein the connector between (i) and (ii) is a flexible linker.

267. The method of claim 266, wherein the flexible linker is substantially comprised of glycine and serine residues, optionally wherein i) the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 8, or ii) the flexible linker comprises one or more of SEQ ID NOs: 556-571.

268. The method of claim 267, wherein the flexible linker is substantially comprised of GGSGGSGGGGSGGGGS (SEQ ID NO: 10).

269. The method of claim 266, wherein the flexible linker is substantially comprised of LE, GGGGS (SEQ ID NO:2), (GGGGS)n(n=1-4) (SEQ ID NO:2-SEQ ID NO:5), (Gly)8(SEQ ID NO:11), (Gly)6 (SEQ ID NO:12), (EAAAK)n (n=1-3) (SEQ ID NO:13 -SEQ ID NO:15), A(EAAAK)nA (n = 2-5) (SEQ ID NO:16 - SEQ ID NO:19), AEAAAKEAAAKA (SEQ ID NO:16), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:21), PAPAP (SEQ ID NO:22), KESGSVSSEQLAQFRSLD (SEQ ID NO:23), EGKSSGSGSESKST (SEQ ID NO:24), GSAGSAAGSGEF (SEQ ID NO:25), and (XP)n, with X designating any amino acid, e.g., Ala, Lys, or Glu.

270. The method of any one of claims 240-269, wherein the wherein the Fc domain is from IgG, IgA, IgD, IgM or IgE.

271. The method of claim 270, wherein the IgG is selected from IgG1, IgG2, IgG3, or IgG4.

272. The method of claim 270, wherein the Fc domain is from human IgG, IgA, IgD, IgM or IgE.

273. The method of claim 272, wherein the human IgG is selected from human IgG1, IgG2, IgG3, or IgG4.

274. The method of any one of claims 240-273, wherein the Fc chain pairing is promoted by ionic pairing and/or a knob-in-hole pairing.

275. The method of claim 274, wherein the one or more mutations to the Fc domain results in an ionic pairing between the Fc chains in the Fc domain.

276. The method of claim 274, wherein the one or more mutations to the Fc domain results in a knob-in-hole pairing in the Fc domain.

277. The method of any one of claims 240-276, wherein the one or more mutations to the Fc domain results in the reduction or elimination of the effector function of the Fc domain.

278. The method of any one of claims 240-277, wherein the Fc-based chimeric protein complex is a heterodimer and has a trans orientation.

279. The method of any one of claims 240-278, wherein the Fc-based chimeric protein-complex is a heterodimer and has a cis orientation.

280. The method of any one of claims 240-279, wherein the Fc comprises L234A, L235A, and K322Q substitutions in human IgG1 (according to EU numbering).

281. The method of claim 280, wherein the Fc is human IgG1, and optionally contains one or more of L234, L235, K322, D265, P329, and P331 (according to EU numbering).

282. The method of any one of claims 240-281, wherein the Fc-based chimeric protein complex has an orientation and/or configuration of any one of FIGs. 1A-19F.

283. The method of any one of claims 240-282, wherein the chimeric protein or chimeric protein complex stimulates a CD8+ T cell response to the antigen, when administered to a patient.

284. The method of any one of claims 240-283, wherein the adjuvant or vaccine composition stimulates activation of the IL-1R, when administered to a patient.

285. The method of any one of claims 240-284, wherein the chimeric protein or chimeric protein complex does not substantially cause one or more of fever, neutrophilia and the release of acute phase proteins when administered to a patient.