Vaccine compositions and method for enhancing an immune response

• US 5,562,910 A
• Filed: 09/09/1993
• Issued: 10/08/1996
• Est. Priority Date: 09/25/1989
• Status: Expired due to Fees

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Araneo, Barbara A., Daynes, Raymond A.
• Primary Examiner(s): Housel, James C.
• Assistant Examiner(s): KRSEK STAPLES, JULIE
• Application Number:
  US08/123,843
• Time in Patent Office: 1,125 Days
• Field of Search: 424/88, 424/85.1, 424/278.1, 424/225.1, 424/209.1, 424/245.1, 424/247.1, 424/254.1, 424/212.1, 424/219.1, 424/217.1, 424/244.1, 424/231.1 , 424/211.1, 424/256.1, 424/230.1, 424/224.1, 424/184.1, 424/256.1, 424/230.1, 424/224.1, 424/184.1, 514/885, 514/167, 514/169, 514/178, 514/725, 514/885, 514/171
• US Class Current: 424/278.1
• CPC Class Codes: A61K 2039/5252 inactivated (killed)
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• 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 2039/6037 Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 39/02 Bacterial antigens
• CPC Class Codes: A61K 39/05 Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella, Corynebacterium; Propionibacterium Mycobacterium A61K39/04
• CPC Class Codes: A61K 39/08 Clostridium, e.g. Clostridium tetani
• CPC Class Codes: A61K 39/095 Neisseria
• CPC Class Codes: A61K 39/102 Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
• CPC Class Codes: A61K 39/118 Chlamydiaceae, e.g. Chlamydia trachomatis or Chlamydia psittaci
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/39 : characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C12N 2730/10134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2740/16134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/16134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/18534 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: G01N 33/6869 : Interleukin
• 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

The invention relates to a vaccine which comprises an antigen and an immune response augmenting agent. The immune response augmenting agent is capable of enhancing T cell lymphokine production. Suitable immune response augmenting agents include, but are not limited to, dehydroepiandrosterone (DHEA) and DHEA-derivatives. Examples of DHEA derivatives include DHEA-sulfate (DHEA-S), 16α-bromo-DHEA, 7-oxo-DHEA, 16α-bromo-DHEA-S and 7-oxo-DHEA-S.

The invention also relates to a method for enhancing a vaccine-induced humoral immune response which comprises administering a vaccine which comprises an antigen and an immunomodulator. The immunomodulator may be an immune response augmenting agent, a lymphoid organ modifying agent or a mixture of the immune response augmenting agent and lymphoid organ modifying agent. Suitable lymphoid organ modifying agents include, but are not limited to, 1,25-dihydroxy Vitamin D₃, biologically active Vitamin D₃ derivatives which are capable of activating the intracellular Vitamin D₃ receptor, all trans-retinoic acid, retinoic acid derivatives, retinol, retinol derivatives and glucocorticoid. Alternatively, the method for enhancing a vaccine-induced humoral immune response comprises separately administering the immunomodulator and a vaccine containing an antigen.

Claims

1. A method for enhancing an antigen-specific circulating antibody immune response which comprises administering to an individual a vaccine and an effective amount of an immunomodulator as a vaccine adjuvant, said immunomodulator selected from the group consisting of a lymphoid organ modifying agent and a mixture of all immune response augmenting agent and said lymphoid organ modifying agent, said immune response augmenting agent having the formula ##STR3## wherein R¹ is ═

O;

R² is H or halogen;

R³ is H with a 5-6 double bond;

R⁴ is OR⁵ ;

R⁵ is H, SO₂ OM, or PO₂ OM;

##STR4## R⁶ and R⁷ may be the same or different and may be a straight or branched C_1-14 alkyl, and said lymphoid organ modifying agent is selected from the group consisting of 1,25-dihydroxy Vitamin D₃ and all trans-retinoic acid.

2. The method of claim 1 wherein the immunomodulator is administered up to three hours prior to administration of said vaccine.

3. The method of claim 2 wherein said vaccine comprises an antigen which is capable of eliciting an immune response against viral hepatitis, influenza, diphtheria, tetanus, pertussis, measles, mumps, rubella, polio, pneumococcus, herpes, respiratory syncytial virus, haemophilus influenza type b, varicella-zoster virus or rabies.

4. The method of claim 1 wherein the immunomodulator and vaccine are administered contemporaneously.

5. The method of claim 4 wherein said vaccine comprises an antigen which is capable of eliciting an immune response against viral hepatitis, influenza, diphtheria, tetanus, pertussis, measles, mumps, rubella, polio, pneumococcus, herpes, respiratory syncytial virus, haemophilus influenza type b, varicella-zoster virus or rabies.

6. The method of claim 1 wherein the immunomodulator is administered in a vaccine.

7. The method of claim 6 wherein said vaccine comprises an antigen which is capable of eliciting an immune response against viral hepatitis, influenza, diphtheria, tetanus, pertussis, measles, mumps, rubella, polio, pneumococcus, herpes, respiratory syncytial virus, haemophilus influenza type b, varicella-zoster virus or rabies.

8. The method of claim 1 wherein wherein said immunomodulator is a lymphoid organ modifying agent.

9. The method of claim 8 wherein said lymphoid organ modifying agent is 1,25-dihydroxy Vitamin D₃.

10. The method of claim 8 wherein said lymphoid organ modifying agent is all trans-retinoic acid.

11. The method of claim 8 wherein the amount of said lymphoid organ modifying agent is 0.1-500 μ

g.

12. The method of claim 1 wherein wherein said immunomodulator is said mixture of an immune response augmenting agent and a lymphoid organ modifying agent.

13. The method of claim 12, R¹ is ═

O, R² is H, R³ is H with a 5-6 double bond, and R⁴ is OH.

14. The method of claim 13 wherein said lymphoid organ modifying agent is 1,25-dihydroxy Vitamin D₃.

15. The method of claim 13 wherein said lymphoid organ modifying agent is all trans-retinoic acid.

16. The method of claim 12, R¹ is ═

OH, R² is H, R³ is H with a 5-6 double bond, and R⁴ is OH.

17. The method of claim 16 wherein said lymphoid organ modifying agent is 1,25-dihydroxy Vitamin D₃.

18. The method of claim 16 wherein said lymphoid organ modifying agent is all trans-retinoic acid.

19. The method of claim 12, R¹ is ═

O, R² is H, R³ is H with a 5-6 double bond, and R⁴ is OH.

20. The method of claim 19 wherein said lymphoid organ modifying agent is 1,25-dihydroxy Vitamin D₃.

21. The method of claim 19 wherein said lymphoid organ modifying agent is all trans-retinoic acid.

22. The method of claim 12, R¹ is ═

O, R² is H, R³ is H with a 5-6 double bond, and R⁴ is OH.

23. The method of claim 22 wherein said lymphoid organ modifying agent is 1,25-dihydroxy Vitamin D₃.

24. The method of claim 22 wherein said lymphoid organ modifying agent is all trans-retinoic acid.

25. The method of claim 12 wherein said lymphoid organ modifying agent is 1,25-dihydroxy Vitamin D₃.

26. The method of claim 12 wherein said lymphoid organ modifying agent is all trans-retinoic acid.

27. The method of claim 12 wherein the amount of said immune response augmenting agent is 0.1-1,000 μ

g.

28. The method of claim 27 wherein the amount of said lymphoid organ modifying agent is 0.1-500 μ

g.

29. The method of claim 12 wherein the amount of said lymphoid organ modifying agent is 0.1-500 μ

g.

30. The method of claim 1 wherein said immunomodulator is administered epicutaneously.

31. The method of claim 1 wherein said immunomodulator is administered intramuscularly.

32. The method of claim 1 wherein said immunomodulator is administered intradermally.

33. The method of claim 1 wherein said immunomodulator is administered subcutaneously.

34. The method of claim 1 wherein the immunomodulator is administered up to three hours following administration of the vaccine.

35. The method of claim 34 wherein said vaccine comprises an antigen which is capable of eliciting an immune response against viral hepatitis, influenza, diphtheria, tetanus, pertussis, measles, mumps, rubella, polio, pneumococcus, herpes, respiratory syncytial virus, haemophilus influenza type b, varicella-zoster virus or rabies.

36. The method of claim 1 wherein said immunomodulator is administered topically.