Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Separation or purification
Reexamination Certificate
1998-07-27
2002-11-05
Graser, Jennifer E. (Department: 1641)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Separation or purification
C530S412000, C530S350000, C424S197110, C424S203100, C424S234100, C424S249100, C435S243000, C435S101000, C536S123100
Reexamination Certificate
active
06476201
ABSTRACT:
1. FIELD OF THE INVENTION
This invention concerns methods of production and compositions for non-covalently complexed multivalent proteosome vaccines for mucosal and parenteral administration.
2. BACKGROUND OF THE INVENTION
In order for multivalent sub-unit vaccines to stimulate optimal immune responses to each of the components, the proper components should be appropriately associated and each be available to the immune system so that they may be efficiently recognized and processed by cells of the immune system. Prime examples of such non-covalently complexed vaccines include proteosome vaccines which can consist of neisserial outer membrane protein proteosomes non-covalently complexed to a wide variety of antigens including peptides, lipopeptides, transmembrane or toxoided proteins, polysaccharides or lipopolysaccharides (LPS) (patent application Ser. No. 07/065,440 filed Jun. 23, 1987 “Immunogenic peptide vaccines and methods of preparation”; Ser. No. 07/336,952 filed Apr. 12, 1989 Immunopotentiaing system for large proteins and polypeptides”; Ser. No. 07-958,426 filed Oct. 8, 1992 “Oral or Intranasal Vaccines Using Hydrophobic Complexes Having Proteosomes and Lipopolysaccharides”; Ser. No. 08/029,666 filed Mar. 11, 1993 “Immunopotentiating Systems for Preparation of Immunogenic Materials”; Ser. No. 08/143,365 filed Oct. 29, 1993 “Immunopotentiating Systems for Preparation of Immunogenic Materials”; Ser. No. 93/10,402 filed Oct. 29, 1993 “Submicron Emulsions as Vaccine Adjuvants”; Ser. No. 08/063,613 filed May 18, 1994 Solid Fat Nanoemulsions as Vehicles for Vaccine Delivery” and publications Orr, N., Robin, G., Cohen, D., Arnon, R. and Lowell, G. H. (1993). Immunogenicity and Efficacy of Oral or Intranasal Shigella flexneri 2a and
Shigella sonnei
Proteosome-Lipopolysaccharide Vaccines in Animal Models. Infect. Immun. 61:2390; Mallett, C. P., T. L. Hale, R. Kaminski, T. Larsen, N. Orr, D. Cohen, and G. H. Lowell. 1995. Intranasal or intragastric immunization with proteosome-Shigella lipopolysaccharide vaccines protect against lethal pneumonia in a murine model of shigellosis. Infect. Immun. 63:2382-2386.; Lowell G H, Kaminski R W, Grate S et al. (1996) Intranasal and intramuscular proteosome-staphylococcal enterotoxin B (SEB) toxoid vaccines: immunogenicity and efficacy against lethal SEB intoxication in mice. Infec. Immun. 64:1706-1713.; Lowell, G. H. (1990) Proteosomes, Hydrophobic Anchors, Iscoms and Liposomes for Improved Presentation of Peptide and Protein Vaccines. in
New Generation Vaccines
: G. C. Woodrow and M. M. Levine, eds. (Marcel Dekker, NY). Chapter 12 (pp. 141-160) and Lowell, G. H., W. R. Ballou, L. F. Smith, R. A. Wirtz, W. D. Zollinger and W. T. Hockmeyer. 1988. Proteosome-lipopeptide vaccines: enhancement of immunogenicity for malaria CS peptides. Science 240:800.)
The contents of all the documents cited herein are expressly incorporated by reference.
For practical application in administering vaccines to protect against disease, it is frequently necessary to deliver several such antigens at the same time usually due to the fact that individuals are susceptible to the contraction of diseases caused by a variety of organisms. Moreover, several organisms, whether or not they are related to one another, often are endemic in the same location and therefore individuals requiring protection may need vaccination with several types of vaccines.
In the past, the production of vaccines that require non-covalent complexing of components has been accomplished using simple dialysis in which components are placed in dialysis tubing in the presence of dialyzable detergent and the mixture is dialyzed for 7-10 days to attempt to remove the detergent. The practical disadvantages of this system tend to severely preclude the advanced development and commercialization of this technology for several reasons including 1) Time: Length of time of the procedure: The need to use GMP resources for weeks while the vaccine is dialyzing is impractical both due to the excess costs involved and the increased opportunity for breakdown or contamination of mechanical or biological components during this extended period of time; 2) Contamination: Increased opportunity for contamination: dialysis tubing is difficult to sterilize, dialysis tubing requires manually opening and closing the system thereby exposing the components to contamination during both the loading and unloading process. Since many days transpire between loading and unloading the tubing, the risk of a small contamination in the initial days of the process may readily be magnified during the many days of dialysis to render this method useless for practical vaccine manufacture. The risk of puncturing the bag can result in loss of product. 3) Temperature: Necessity to perform the dialysis at 40° C. due to the extensive time involved; 4) Volume of dialyzing fluids: In order to manufacture vaccine for scale-up of the process, the use of massive amounts of dialysis fluid would be necessary since a 200:1 ratio of liquid outside to the dialysis tubing to inside the tubing is typically required. Therefore, for example, the production of a pilot lot of two liters of vaccine would require 400 liters of fluid outside the tubing per day—4,000 liters per 10 days—and the production of a production lot of 20-200 liters would require 40,000-4,000,000 liters. These amounts are wasteful and impractical compared to the method used in the instant invention; Dialysis tubing is not scalable since large amounts of product is problematic and 5) Inability to readily measure completeness of removal of the detergent so as to maximize vaccine effectiveness. Since the dialysis bag is placed in a container with 200 volumes of buffer, the ongoing measurement of detergent removal is neither practical nor feasible and 6) In addition, no method has been described for the measurement of the presence of the detergent used in the preferred embodiment, Empigen BB.
The second problem solved in this invention is the demonstration of the method of producing and delivering multivalent vaccines. Components can either be made together or produced separately and mixed together prior to administration. The instant invention demonstrates the optimal way of preparing such multivalent vaccines.
3. SUMMARY OF THE INVENTION
The subject of the instant invention broadly relates to the production and manufacture of proteosome-amphiphilic determinant vaccines designed for either parenteral or especially for mucosal administration including , but not limited to, respiratory (e.g. including intranasal, intrapharyngeaeal and intrapulmonary), gastro-intestinal (e.g. including oral or rectal) or topical (e.g. conjunctival or otic) administration to induce both systemic (serum) and mucosal (including respiratory and intestinal) antibody responses. An amphiphilic determinant is a molecule having hydrophobic and hydrophilic regions which, when appropriately formulated with proteosomes, align with the proteosomes to for a complex which elicits an immunologic response in a subject. Typical amphiphilic determinants include glycolipids, liposaccharides (including detoxified lipopolysaccharides), lipopeptides, transmembrane, envelope or toxoided proteins, or proteins or peptides with intrinsic hydrophobic amino acid anchors. These determinant materials can be obtained from gram negative bacteria including eschefichia, klebsiella, pseudomonas,
hemophilus brucella
, shigella and neisseria. More specifically, the invention relates to proteosome vaccines in which meningococcal outer membrane protein proteosome preparations (prepared from any strain of
N. meningiditis
or
N. gonorrhea
or other neisserial species) are non-covalently complexed to native or detoxified shigella or neisserial lipopolysaccharides or lipooligosaccharides to form vaccines designed to protect against diseases caused by gram negative organisms that contain any of the component parts of the complex including meningococci or shigellae. More specifically, the invention relates to proteosome vaccines that contain LPS t
Lowell George H.
Wood James F.
Zollinger Wendell D.
Graser Jennifer E.
ID Biomedical Corporation of Quebec
Morrison & Foerster / LLP
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