Use of penetration enhancers and barrier disruption methods to enhance the immune response of antigen and adjuvant

• US 7,378,097 B2
• Filed: 03/03/2004
• Issued: 05/27/2008
• Est. Priority Date: 11/14/1996
• Status: Expired due to Fees

• Current Assignee: The United States Of America As Represented By The Secretary Of The Army
• Original Assignee: The United States Of America As Represented By The Secretary Of The Army
• Inventors: Glenn, Gregory M., Alving, Carl R.
• Primary Examiner(s): Chan; Christina
• Assistant Examiner(s): Kim; Yunsoo
• Application Number:
  US10/790,715
• Publication Number:
  US 20080063696A1
• Time in Patent Office: 1,546 Days
• Field of Search: 424/278.1, 424/184.1
• US Class Current: 424/184.1
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/55505 Inorganic adjuvants
• CPC Class Codes: A61K 2039/55511 Organic adjuvants
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/55533 IL-2
• CPC Class Codes: A61K 2039/55544 Bacterial toxins
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• CPC Class Codes: A61K 31/739 Lipopolysaccharides
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/008 Leishmania antigens
• CPC Class Codes: A61K 39/0258 Escherichia
• CPC Class Codes: A61K 39/05 Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella, Corynebacterium; Propionibacterium Mycobacterium A61K39/04
• CPC Class Codes: A61K 39/102 Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
• CPC Class Codes: A61K 39/107 Vibrio
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/145 : Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: A61K 39/205 : Rhabdoviridae, e.g. rabies virus
• CPC Class Codes: A61K 39/39 : characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 47/08 : containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• CPC Class Codes: A61K 47/10 : Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 : Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0014 : Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/06 : Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/08 : Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/107 : Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/127 : Liposomes
• CPC Class Codes: A61K 9/7023 : Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: C12N 2740/16234 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/16034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/20134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A transcutaneous immunization system where the topical application of an adjuvant and an antigen or nucleic acid encoding for an antigen, to intact skin induces a systemic or mucosol antibody response. The immune response so elicited can be enhanced by physical or chemical skin penetration enhancement.

Claims

1. A method for inducing an antigen-specific immune response in a subject comprising:

a) pretreating an area of the skin of the subject, wherein pretreating comprises applying means for enhancing penetration and/or barrier disruption of the skin; and

b) applying a formulation transcutaneously to the pretreated area to induce an antigen-specific immune response, wherein the formulation comprises;

1) an antigen in an amount effective to induce an antigen-specific immune response;

2) an adjuvant present in an amount effective to enhance the immune response to the antigen; and

,

3) a pharmaceutically acceptable carrier;

wherein pretreating enhances the immune response.

2. The method of claim 1, wherein pretreating comprises applying to the skin a chemical means, a physical means, a mechanical means, a hydration means, or a combination thereof.

3. The method of claim 1, wherein pretreating comprises applying a chemical to the skin.

4. The method of claim 3, wherein the chemical is an alcohol, an acetone, a detergent, a depilatory agent, a keratinolytic formulation, a cream, or a combination thereof.

5. The method of claim 1, wherein pretreating comprises applying a device.

6. The method of claim 5, wherein the device is selected from the group consisting of a propellant device, a device comprising tines, a device comprising microneedles, a device comprising a tine disk, a tape stripping device, a gas powered gun, a swab, an emery board, an abrasive pad, an electroporation device, an ultrasound device, and an iontophoresis device.

7. The method of claim 1, wherein the antigen is a nucleic acid encoding an antigen, carbohydrate, a glycolipid, a glycoprotein, a lipid, a lipoprotein, phospholipid, a polypeptide, a protein, a fusion protein, or chemical conjugate of a combination thereof.

8. The method of claim 1, wherein the antigen is derived from a pathogen.

9. The method of claim 8, wherein the pathogen is a virus, a bacterium, a parasite, or a fungus.

10. The method of claim 9, wherein the virus is an influenza virus or a rabies virus.

11. The method of claim 10, wherein the antigen is hemagglutinin A.

12. The method of claim 9, wherein the bacterium is E. coli or Bacillus anthracis.

13. The method of claim 12, wherein the antigen is E. coli heat-labile enterotoxin (LT).

14. The method of claim 12, wherein the antigen is a nucleic acid encoding E. coli heat-labile enterotoxin (LT).

15. The method of claim 1, wherein the antigen is a pathogen.

16. The method of claim 15, wherein the pathogen is a virus, a bacterium, a parasite, or a fungus.

17. The method of claim 16, wherein the virus is a whole virus, a live virus, an attenuated live virus, an inactivated virus, a detergent treated virus, or a combination thereof.

18. The method of claim 17, wherein the virus is an influenza virus or a rabies virus.

19. The method of claim 18, wherein the influenza virus comprises hemagglutinin A.

20. The method of claim 16, wherein the bacterium is E coli or Bacillus anthracis.

21. The method of claim 20, wherein the E. coli comprises E. coli heat-labile enterotoxin (LT).

22. The method of claim 1, wherein the antigen is a multivalent antigen.

23. The method of claim 1, wherein the adjuvant comprises a molecule selected from the group consisting of a bacterial ADP-ribosylating exotoxin (bARE), a binding B subunit of a bARE, a toxoid of a bARE, a genetically altered bARE, and a genetically detoxified mutant of a bARE.

24. The method of claim 23, wherein the antigen is an influenza antigen.

25. The method of claim 1, wherein the adjuvant is a nucleic acid encoding a molecule selected from the group consisting of a bacterial ADP-ribosylating exotoxin (bARE), a binding B subunit of a bARE, a toxoid of a bARE, a genetically altered bARE, and a genetically detoxified mutant of a bARE.

26. The method of claim 25, wherein the nucleic acid encodes E. coli heat labile enterotoxin (LT).

27. The method of claim 1, wherein the antigen and the adjuvant are the same molecule.

28. The method of claim 27, wherein the molecule is E. coli heat-labile enterotoxin (LT).

29. The method of claim 27, wherein the molecule is hemagglutinin A.

31. The method of claim 1, wherein the adjuvant is selected from the group consisting of nucleic acid encoding an adjuvant, bacterial exotoxin, cytokine, chemokine, lipopolysaccharide, a molecule containing unmethylated CpG motifs, a heat shock protein, a derivative of a heat shock protein, tumor necrosis factor, genetically detoxified toxin, and combinations thereof.

32. The method of claim 1, wherein the adjuvant is provided as a nucleic acid comprising a sequence encoding the adjuvant.

33. The method of claim 1, wherein the antigen or adjuvant activates an antigen presenting cell.

34. The method of claim 33, wherein the antigen presenting cell is a Langerhans cell or a dermal dendritic cell.

35. The method of claim 1, wherein the antigen is a whole microorganism, a whole cell, or a virion.

50. The method of claim 34, wherein the antigen is a pathogen.

51. The method of claim 50, wherein the pathogen is a virus, a bacterium, a parasite, or a fungus.

52. The method of claim 51, wherein the virus is a whole virus, a live virus, an attenuated live virus, an inactivated virus, a detergent treated virus, or a combination thereof.

53. The method of claim 52, wherein the virus is an influenza virus or a rabies virus.

54. The method of claim 53, wherein the influenza virus comprises hemagglutinin A.

55. The method of claim 51, wherein the bacterium is E coli or Bacillus anthracis.

56. The method of claim 55, wherein the E. coli comprises E. coli heat-labile enterotoxin (LT).

57. The method of claim 34, wherein the antigen is a multivalent antigen.

58. The method of claim 34, wherein the adjuvant comprises a molecule selected from the group consisting of a bacterial ADP-ribosylating exotoxin (bARE), a binding B subunit of a bARE, a toxoid of a bARE, a genetically altered bARE, and a genetically detoxified mutant of a bARE.

59. The method of claim 58, wherein the antigen is an influenza antigen.

60. The method of claim 34, wherein the adjuvant is a nucleic acid encoding a molecule selected from the group consisting of a bacterial ADP-ribosylating exotoxin (bARE), a binding B subunit of a bARE, a toxoid of a bARE, a genetically altered bARE, and a genetically detoxified mutant of a bARE.

61. The method of claim 60, wherein the nucleic acid encodes E. coli heat labile enterotoxin (LT).

104. The method of claim 7, wherein the nucleic acid is a DNA encoding an influenza protein.

107. The method of claim 28, wherein the LT is a genetically altered toxin.

30. The method of 1, wherein the formulation is applied using a patch.

36. A method for inducing an antigen-specific immune response in a subject comprising concurrently,

a) treating an area of the skin of the subject, wherein treating comprises applying means for enhancing penetration and/or barrier disruption of the skin;

and

b) applying a formulation transcutaneously to the treated area to induce an antigen-specific immune response, wherein the formulation comprises;

1) an antigen in an amount effective to induce an antigen-specific immune response;

2) an adjuvant present in an amount effective to enhance the immune response to the antigen; and

,

3) a pharmaceutically acceptable carrier;

wherein treating enhances the immune response.

37. The method of claim 36, wherein treating comprises applying to the skin a chemical means, a physical means, a mechanical means, a hydration means, or a combination thereof.

38. The method of claim 36, wherein treating comprises applying a chemical to the skin.

39. The method of claim 38, wherein the chemical is an alcohol, an acetone, a detergent, a depilatory agent, a keratinolytic formulation, a cream, or a combination thereof.

40. The method of claim 36, wherein treating comprises applying a device.

41. The method of claim 40, wherein the device is selected from the group consisting of a propellant device, a device comprising tines, a device comprising microneedles, a device comprising a tine disk, a tape stripping device, a gas powered gun, a swab, an emery board, an abrasive pad, an electroporation device, an ultrasound device, and an iontophoresis device.

42. The method of claim 36, wherein the antigen is a nucleic acid encoding an antigen, carbohydrate, a glycolipid, a glycoprotein, a lipid, a lipoprotein, phospholipid, a polypeptide, a protein, a fusion protein, or chemical conjugate of a combination thereof.

43. The method of claim 36, wherein the antigen is derived from a pathogen.

44. The method of claim 43, wherein the pathogen is a virus, a bacterium, a parasite, or a fungus.

45. The method of claim 44, wherein the virus is an influenza virus or a rabies virus.

46. The method of claim 45, wherein the antigen is hemagglutinin A.

47. The method of claim 44, wherein the bacterium is E. coli or Bacillus anthracis.

48. The method of claim 47, wherein the antigen is E. coli heat-labile enterotoxin (LT).

49. The method of claim 47, wherein the antigen is a nucleic acid encoding E. coli heat-labile enterotoxin (LT).

62. The method of claim 36, wherein the antigen and the adjuvant are the same molecule.

63. The method of claim 62, wherein the molecule is E. coli heat-labile enterotoxin (LT).

64. The method of claim 62, wherien the molecule is hemagglutinin A.

66. The method of claim 36, wherein the adjuvant is selected from the group consisting of nucleic acid encoding an adjuvant, bacterial exotoxin, cytokine, chemokine, lipopolysaccharide, a molecule containing unmethylated CpG motifs, a heat shock protein, a derivative of a heat shock protein, tumor necrosis factor, genetically detoxified toxin, and combinations thereof.

67. The method of claim 36, wherein the adjuvant is provided as a nucleic acid comprising a sequence encoding the adjuvant.

68. The method of claim 36, wherein the antigen or adjuvant activates an antigen presenting cell.

69. The method of claim 68, wherein the antigen presenting cell is a Langerhans cell or a dermal dendritic cell.

70. The method of claim 36, wherein the antigen is a whole microorganism, a whole cell, or a virion.

105. The method of claim 42, wherein the nucleic acid is a DNA encoding an influenza protein.

108. The method of claim 63, wherein the LT is a genetically altered toxin.

65. The method of 36, wherein the formulation is applied using a patch.

71. A method for inducing an antigen-specific immune response in a subject comprising:

a) delivering parenterally a first formulation comprising an antigen to a subject;

b) treating an area of the skin of the subject, wherein treating comprises applying means for enhancing penetration and/or barrier disruption of the skin to enhance the immune response; and

c) applying transcutaneously a second formulation comprising an adjuvant to the area of the skin, thereby inducing an antigen-specific immune response.

72. The method of claim 71, wherein treating comprises applying to the skin a chemical means, a physical means, a mechanical means, a hydration means, or a combination thereof.

73. The method of claim 71, wherein treating comprises applying a chemical to the area of the skin.

74. The method of claim 73, wherein the chemical is an acetone, a detergent, a depilatory agent, a keratinolytic formulation, or a combination thereof.

75. The method of claim 71, wherein treating comprises applying a device.

76. The method of claim 75, wherein the device is selected from the group consisting of a propellant device, a device comprising tines, a device comprising microneedles, a device comprising a tine disk, a tape stripping device, a gas powered gun, a swab, an emery board, an abrasive pad, an electroporation device, an ultrasound device, and an iontophoresis device.

77. The method of claim 71, wherein the antigen is a nucleic acid encoding an antigen, a carbohydrate, a glycolipid, a glycoprotein, a lipid, a lipoprotein, phospholipid, a polypeptide, a protein, a fusion protein, or chemical conjugate of a combination thereof.

78. The method of claim 71, wherein the antigen is derived from a pathogen.

79. The method of claim 78, wherein the pathogen is a virus, a bacterium, a parasite, or a fungus.

80. The method of claim 79, wherein the virus is an influenza virus or a rabies virus.

81. The method of claim 80, wherein the antigen is hemagglutinin A.

82. The method of claim 79, wherein the bacterium is E. coli or Bacillus anthracis.

83. The method of claim 82, wherein the antigen is E. coli heat-labile enterotoxin (LT).

84. The method of claim 81, wherein the antigen is a nucleic acid encoding E. coli heat-labile enterotoxin (LT).

85. The method of claim 71, wherein the antigen is a pathogen.

86. The method of claim 85, wherein the pathogen is a virus, a bacterium, a parasite, or a fungus.

87. The method of claim 86, wherein the virus is a whole virus, a live virus, an attenuated live virus, an inactivated virus, a detergent treated virus, or a combination thereof.

88. The method of claim 87, wherein the virus is an influenza virus or a rabies virus.

89. The method of claim 88, wherein the influenza virus comprises hemagglutinin A.

90. The method of claim 86, wherein the bacterium is E coli or Bacillus anthracis.

91. The method of claim 90, wherein the E. coli comprises E. coli heat-labile enterotoxin (LT).

92. The method of claim 71, wherein the antigen is a multivalent antigen.

93. The method of claim 71, wherein the adjuvant comprises a molecule selected from the group consisting of a bacterial ADP-ribosylating exotoxin (bARE), a binding B subunit of a bARE, a toxoid of a bARE, a genetically altered bARE, and a genetically detoxified mutant of a bARE.

94. The method of claim 93, wherein the antigen is an influenza antigen.

95. The method of claim 71, wherein the adjuvant is a nucleic acid encoding a molecule selected from the group consisting of a bacterial ADP-ribosylating exotoxin (bARE), a binding B subunit of a bARE, a toxoid of a bARE, a genetically altered bARE, and a genetically detoxified mutant of a bARE.

96. The method of claim 95, wherein the nucleic acid encodes E. coli heat labile enterotoxin (LT).

97. The method of claim 71, wherein the adjuvant is selected from the group consisting of nucleic acid encoding an adjuvant, bacterial exotoxin, cytokine, chemokine, lipopolysaccharide, a molecule containing umethylated CpG motifs, a heat shock protein, a derivative of a heat shock protein, tumor necrosis factor, genetically detoxified toxin, and combinations thereof.

98. The method of claim 71, wherein the adjuvant is provided as a nucleic acid comprising a sequence encoding the adjuvant.

99. The method of claim 71, wherein the antigen or adjuvant activates an antigen presenting cell.

100. The method of claim 99, wherein the antigen presenting cell is a Langerhans cell or a dermal dendritic cell.

101. The method of claim 71, wherein the antigen is a whole microorganism, a whole cell, or a virion.

102. The method of claim 71, wherein the first formulation is administered subcutaneously, intradermally, or intramuscularly.

103. The method of claim 71, wherein the second formulation is applied using a patch.

106. The method of claim 77, wherein the nucleic acid is a DNA encoding an influenza protein.