VLP stabilized vaccine compositions
The invention is directed to compositions and methods for the stabilization of viral and bacterial vaccines. Vaccines of the invention are contained in VLPs with stabilizing agents such as, for example, sugar alcohols (e.g., sorbitol) and degraded gelatins. Preferably the gelatin has an average molecular weight of 10,000 kilodaltons or less. These vaccines have a substantially improved thermostability as well as long term stability. The invention is also directed to the manufacture of a vaccine or the invention and methods for the administration of a vaccine of the invention to patients.
1. A process for the manufacture of a liquid composition comprising virus-like particles (VLPs), an immunogenic component, and a stabilizing agent comprising:
providing VLPs;
providing an immunogenic portion of a bacterium as the immunogenic component;
providing one or more degraded gelatins as the stabilizing agent, wherein the one or more gelatins are degraded to an average molecular weight of twenty kilodaltons or less;
combining the VLPs, the immunogenic component, and the stabilizing agent; and
forming the liquid composition, wherein the composition has not been maintained in a non-liquid state and is maintained as a liquid prior to administration.
2. The process of claim 1 , wherein the VLPs are obtained from hepatitis virus particles.
3. The process of claim 1 , wherein the VLPs are obtained from papilloma virus particles.
4. The process of claim 1 , wherein the bacterium is selected from the group consisting of a bacterial infectious agent, chlamydia, clostridium, diphtheria, tetanus, meningococcal, streptococcal, staphylococcal, pneumococcal, and combinations thereof.
5. The process of claim 1 , wherein the stabilizing agent further comprises one or more amino acids, or one or more sugar alcohols, or a combination thereof.
6. The process of claim 1 , wherein the one or more degraded gelatins are degraded to an average molecular weight of eight kilodaltons or less.
7. The process of claim 1 , wherein the one or more gelatins are degraded chemically.
8. The process of claim 1 , wherein the one or more gelatins are degraded mechanically.
9. The process of claim 1 , wherein the stabilizing agent includes a sugar alcohol.
10. The process of claim 9 , wherein the sugar alcohol comprises sorbitol.
11. The process of claim 1 , wherein the stabilizing agent is at a concentration of from about 1 mM to about 50 mM of the liquid composition.
12. The process of claim 1 , wherein the immunogenic component and the stabilizing agent are combined at approximately equimolar amounts.
13. The process of claim 1 , wherein the immunogenic component and the stabilizing agent are combined as an aqueous mixture.
14. The process of claim 1 , wherein the immunogenic component and the stabilizing agent are combined before forming the liquid composition.
15. The process of claim 1 , wherein the liquid composition does not contain an aluminum compound.
16. The process of claim 1 , wherein the VLPs comprise structural components of a hepatitis virus, the immunogenic component comprises a bacterial antigen component, and the stabilizing agent further comprises a sugar alcohol, and the process does not contain an aluminum compound.
17. The process of claim 1 , which further contains a pharmaceutically acceptable carrier selected from the group consisting of water, alcohol, oil, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, mineral oils, liquid petrolatum, isopropylpalmitate, polyethylene ethanol, polyoxyethylene monolauriater, sodium lauryl sulfate, an anti-oxidant, a humectant, a viscosity stabilizer or modifier, a colorant, a flavoring agent, and combinations thereof.
18. The process of claim 1 , wherein the liquid composition is a vaccine.
19. The process of claim 1 , wherein the liquid composition is stored for at least one month at ambient temperature or less without significant loss of immunogenic activity.
20. The process of claim 19 , wherein storage is for at least two months.
21. The process of claim 19 , wherein storage is for at least six months.
22. The process of claim 19 , wherein storage is at 4° C. or less.
23. The process of claim 1 , wherein, upon administration to a patient, the liquid composition does not generate an inflammatory response at the site of administration.
24. A method for the manufacture of a composition comprised of VLPs, an immunogenic component, and a stabilizing agent, comprising:
generating VLPs comprising structural components of hepatitis virus particles;
providing an immunogenic portion of a bacterium as the immunogenic component;
providing a stabilizing agent comprised of degraded gelatin;
mixing the VLPs, the immunogenic component and the stabilizing agent, wherein structural components, the immunogenic component and the stabilizing agent are mixed at approximately equimolar amounts;
and
forming an aqueous composition of the mixture, wherein the composition has not been maintained in a non-liquid state and is maintained as a liquid prior to administration.
25. The method of claim 24 , wherein the bacterium is selected from the group consisting of a bacterial infectious agent, chlamydia, clostridium, diphtheria, tetanus, meningococcal, streptococcal, staphylococcal, pneumococcal, and combinations thereof.
26. The method of claim 24 , wherein the stabilizing agent further comprises one or more amino acids, or one or more sugar alcohols, or a combination thereof.
27. The method of claim 24 , wherein the one or more degraded gelatins are degraded to an average molecular weight of eight kilodaltons or less.
28. The method of claim 24 , wherein the stabilizing agent includes a sugar alcohol.
29. The method of claim 28 , wherein the sugar alcohol comprises sorbitol.
30. The method of claim 24 , wherein the aqueous composition is stored for at least one month at ambient temperature or less without significant loss of immunogenic activity.
31. The method of claim 30 , wherein storage is for at least two months.
32. The method of claim 30 , wherein storage is for at least six months.
33. The method of claim 30 , wherein storage is at 4° C. or less.
34. The method of claim 24 , wherein, upon administration to a patient, the liquid composition does not generate an inflammatory response at the site of administration.
35. The method of claim 24 , wherein the aqueous composition is a vaccine.
36. A method for the manufacture of a composition comprised of VLPs, an immunogenic component, and a stabilizing agent, comprising:
generating VLPs comprising structural components of papilloma virus particles;
providing an immunogenic portion of a bacterium as the immunogenic component;
providing a stabilizing agent comprised of degraded gelatin;
mixing the VLPs, the immunogenic component and the stabilizing agent, wherein structural components, the immunogenic component and the stabilizing agent are mixed at approximately equimolar amounts;
and
forming an aqueous composition of the mixture, wherein the composition has not been maintained in a non-liquid state and is maintained as a liquid prior to administration.
37. The method of claim 36 , wherein the bacterium is selected from the group consisting of a bacterial infectious agent, chlamydia, clostridium, diphtheria, tetanus, meningococcal, streptococcal, staphylococcal, pneumococcal, and combinations thereof.
38. The method of claim 36 , wherein the stabilizing agent further comprises one or more amino acids, or one or more sugar alcohols, or a combination thereof.
39. The method of claim 36 , wherein the one or more degraded gelatins are degraded to an average molecular weight of eight kilodaltons or less.
40. The method of claim 36 , wherein the stabilizing agent includes a sugar alcohol.
41. The method of claim 40 , wherein the sugar alcohol comprises sorbitol.
42. The method of claim 36 , wherein the aqueous composition is stored for at least one month at ambient temperature or less without significant loss of immunogenic activity.
43. The method of claim 42 , wherein storage is for at least two months.
44. The method of claim 42 , wherein storage is for at least six months.
45. The method of claim 42 , wherein storage is at 4° C. or less.
46. The method of claim 36 , wherein, upon administration to a patient, the liquid composition does not generate an inflammatory response at the site of administration.
47. The method of claim 36 , wherein the aqueous composition is a vaccine.