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Acellular pertussis vaccines and methods of preparation thereof

a cell pertussis and vaccine technology, applied in the field of acellular pertussis vaccines and methods of preparation thereof, can solve the problems of reversion to toxicity of formalin-inactivated pt, fha alone does not protect the potency of intracerebral challenge mice, and current commercially available acellular pertussis vaccines may not contain appropriate immunogenic formulations of appropriate antigens

Inactive Publication Date: 2001-07-26
AVENTIS PASTUER LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] The present invention is directed towards acellular pertussis vaccine preparations, components thereof, methods of preparation of such vaccines and their components, and methods of use thereof.

Problems solved by technology

However, alone FHA does not protect in the mouse intracerebral challenge potency assay (ref.
However, there was evidence for reversion to toxicity of formalin-inactivated PT in these vaccines.
Thus, current commercially-available acellular pertussis vaccines may not contain appropriate formulations of appropriate antigens in appropriate immunogenic forms to achieve a desired level of efficacy in a pertussis-susceptible human population.
Some of these adjuvants are toxic, however, and can cause undesirable side-effects, making them unsuitable for use in humans and many animals.
While the usefulness of alum is well established for some applications, it has limitations.
For example, alum is ineffective for influenza vaccination and inconsistently elicits a cell mediated immune response.
The antibodies elicited by alum-adjuvanted antigens are mainly of the IgGl isotype in the mouse, which may not be optimal for protection by some vaccinal agents.
Although FCA is an excellent adjuvant and widely used in research, it is not licensed for use in human or veterinary vaccines because of its toxicity.

Method used

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  • Acellular pertussis vaccines and methods of preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0091] This Example describes the growth of Bordetella pertussis.

Master Seed

[0092] Master seed cultures of a Bordetella pertussis strain were held as freeze-dried seed lots, at 2.degree. C. to 8.degree. C.

Working Seed

[0093] The freeze-dried culture was recovered in Hornibrook medium and used to seed Bordet-Gengou Agar (BGA) plates. Hornibrook medium has the following composition:

5 Component for 1 liter Casein hydrolysate (charcoal treated) 10.0 g Nicotinic acid 0.001 g Calcium chloride 0.002 g Sodium chloride 5.0 g Magnesium chloride hexahydrate 0.025 g Potassium chloride 0.200 g Potassium phosphate dibasic 0.250 g Starch 1.0 g Distilled water to 1.0 liter

[0094] The pH is adjusted to 6.9.+-.0.1 with lo sodium carbonate solution. The medium is dispensed into tubes and sterilized by steaming in the autoclave for 20 minutes and autoclaving for 20 minutes at 121.degree. C. to 124.degree. C. The seed was subcultured twice, firstly on BGA plates then on Component Pertussis Agar (CPA). Com...

example 2

[0100] This Example describes the purification of antigens from the Bordetella pertussis cell culture.

Production of Broth and Cell Concentrates

[0101] Bacterial suspension was grown in two production fermenters, at 34.degree. C. to 37.degree..degree.C. for 35 to 50 hours. The fermenters were sampled for media sterility testing. The suspension was fed to a continuous-flow disk-stack centrifuge (12,000.times.g) to separate cells from the broth. Cells were collected to await extraction of fimbriae component. The clarified liquor was passed through .ltoreq. 0.22 .mu.m membrane filter. The filtered liquor was concentrated by ultra filtration using a 10 to 30 kDa nominal molecular weight limit (NMWL) membrane. The concentrate was stored to await separation and purification of the Pertussis Toxin (PT), Filamentous haemagglutonin (FHA) and 69 kDa (pertactin) components.

Separation of the Broth Components

[0102] The broth components (69 kDa, PT and FHA) were separated and purified by perlite ch...

example 3

[0113] This Example describes the toxoiding of the purified Bordetella pertussis antigens, PT and FHA.

[0114] PT, prepared in pure form as described in Example 2, was toxoided by adjusting the glutaraldehyde concentration in the PT solution to 0.5% .+-.0.1% and incubating at 37.degree. C..+-.3.degree. C. for 4 hours. The reaction was stopped by adding L-aspartate to 0.21.+-.0.02M. The mixture was then held at room temperature for 1.+-.0.1 hours and then at 2.degree. C. to 8.degree. C. for 1 to 7 days.

[0115] The resulting mixture was diafiltered against 10 mM potassium phosphate / 0.15M NaCl / 5% glycerol buffer on a 30 kDa NMWL membrane filter and then sterilized by passage through a .ltoreq.0.22 .mu.m membrane filter. This sterile bulk was stored at 2.degree. C. to 8.degree. C. and adsorption performed within three months.

[0116] The FHA fraction, prepared in pure form as described in Example 2, was toxoided by adjusting the L-lysine and formaldehyde concentration to 47.+-.5 mM and 0.24....

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Abstract

Acellular pertussis vaccines comprise purified toxin or toxoid thereof, filamentous haemagglutinin, pertactin and fimbrial agglutinogens formulated to confer protection to at least 70% of members of an at-risk population. The fimbrial agglutinogens may be prepared from a Bordetella strain, particularly a B. pertussis strain, by a multiple step procedure involving extraction of the fimbrial agglutinogens from cell paste and concentrating and purifying the extracted material.

Description

REFERENCE TO RELATED APPLICATION[0001] This application is a continuation-in-part of copending U.S. patent application Ser. No. 08 / 501,743 filed Jul. 12, 1995, which itself is a continuation-in-part of copending U.S. patent application Ser. No. 08 / 433,646 filed May 4, 1995.[0002] The present invention relates to acellular pertussis vaccines, components thereof, and their preparation.BACKGROUND TO THE INVENTION[0003] Whooping cough or pertussis is a severe, highly contagious upper respiratory tract infection caused by Bordetella pertussis. The World Health Organization estimates that there are 60 million cases of pertussis per year and 0.5 to 1 million associated deaths (ref. 1. Throughout this specification., various references are referred to in parenthesis to more fully describe the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately following the claims. The disclosures of these ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A61K39/10A61K39/116A61K39/155A61P31/04A61P37/00C07K14/235
CPCA61K39/00A61K39/099A61K2039/545A61K2039/55505A61K2039/55544C07K14/235A61P31/04A61P37/00Y02A50/30
Inventor VOSE, JOHN RFAHIM, RAAFAT E FJACKSON, GAIL E DTAN, LARRY U LHERBERT, ANDREWBOUX, LESLIEBARRETO, LUISTHIPPHAWONG, JOHNKLEIN, MICHEL H
Owner AVENTIS PASTUER LTD
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