WO1993024147A1 - Vaccins de virus vivants modifies contenant un adjuvant a base de lecithine - Google Patents

Vaccins de virus vivants modifies contenant un adjuvant a base de lecithine Download PDF

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Publication number
WO1993024147A1
WO1993024147A1 PCT/US1993/005088 US9305088W WO9324147A1 WO 1993024147 A1 WO1993024147 A1 WO 1993024147A1 US 9305088 W US9305088 W US 9305088W WO 9324147 A1 WO9324147 A1 WO 9324147A1
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WIPO (PCT)
Prior art keywords
vaccine
virus
lecithin
adjuvant
modified live
Prior art date
Application number
PCT/US1993/005088
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English (en)
Inventor
Jay Dean Gerber
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Smithkline Beecham Corporation
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Publication of WO1993024147A1 publication Critical patent/WO1993024147A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/245—Herpetoviridae, e.g. herpes simplex virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5254—Virus avirulent or attenuated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55544—Bacterial toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16711—Varicellovirus, e.g. human herpesvirus 3, Varicella Zoster, pseudorabies
    • C12N2710/16734—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • This invention relates to the field of modified live vaccines. More particularly, the invention relates to the field of modified live vaccines adjuvanted with lecithin in combination with a carrier which is selected from the group consisting of edible and non-edible oils.
  • Modified live viruses are known to be less immunogenic than the virulent virus from which they derive. The goal of modification or attenuation can be to remove the virulence or reduce it such that the virus can be safely administered as a vaccine.
  • modified live virus vaccines are generally freeze-dried for stability and reconstituted with water prior to administration.
  • U.S. Patent 4,650,677 teaches that the use of an oil-in-water emulsion as the solvent to rehydrate the modified live virus has the effect of improving the serological and immune response of the vaccinated animals.
  • U.S. Patent 4,650,677 teaches that the quantity of oil in the emulsion is usually between 15 and 50% by volume.
  • modified live vaccines which are adjuvanted to enhance virus neutralizing titer and to reduce the virus shed to noninfected animals yet contain minimum amounts of oil to reduce or eliminate tissue damage at the injection site that is commonly associated with oil adjuvants containing higher amounts of oil. See e.g., Straw et al., AVMA, Vol. 106, No. 4, February 15, 1990. Further, there is a need for modified live vaccines capable of circumventing the vaccine neutralizing effects of maternal antibodies in the vaccinated animal.
  • this invention provides a novel modified live virus vaccine in combination with an adjuvant diluent.
  • the adjuvant diluent comprises about 5.0% by weight to about 10% by weight of lecithin and from about 90% by volume to about 97% by volume of an oil carrier.
  • a novel method of immunizing animals with a modified live virus vaccine said animals having maternal antibody derived serum neutralizing titers to the virus, comprising vaccinating the animal with a vaccine of this invention.
  • FIG. 1 Override of maternal antibody following vaccination with an adjuvanted PR- Vac® (MLV) of this invention. Seropositive piglets were vaccinated at 4 weeks (Group 1, solid line), 7 weeks (Group 2, dashed line), 10 weeks (Group 3, dotted line), or not vaccinated (Group 4, long dashed line). Vaccinated animals were given an intravenous boost with nonadjuvanted inactivated antigen 3 weeks following vaccination (arrows).
  • MMV PR- Vac®
  • a modified live virus vaccine in combination with a lecithin adjuvant in a carrier which is selected from the group consisting of edible and non-edible oils.
  • the lecithin adjuvant and carrier are substantially as described in United States Patent Number 5,084,269 which patent is incorporated by reference as if fully set forth herein.
  • the lecithin adjuvant comprises 5.0% by weight to 10% by weight of lecithin and from 90% by weight to 95% by weight of an oil carrier.
  • the lecithin and oil carrier usually is from about 5% to about 50% by volume of the vaccine as taught in 5,0284,269.
  • the preferred lecithin adjuvant diluent comprises about 5.0% by weight to about 10% by weight of lecithin and from about 90% by volume to about 97% by volume of an oil carrier.
  • Lecithin is available from a variety of commercial sources such as Central Soya, Chemurgy Division, Fort Wayne, IN.
  • the adjuvant can be used at varying levels with different modified live viruses.
  • the amount of lecithin in an oil carrier can readily be determined by individual testing with each modified live virus. Additional adjuvants and additives can be added to the adjuvant diluent of the invention where necessary. For example, a final concentration of 12% by volume aluminum hydroxide has been added to the adjuvant diluent of the invention successfully.
  • the amounts of lecithin and oil remain as taught herein.
  • lecithin associated with an oil emulsion carrier works as an efficient means of delivering the vaccine antigen to cells of the immune system.
  • the lecithin may be layered on the surface of the oil droplets in the emulsion or occur as a lipid vesicle or liposomes in association with the oil carrier.
  • a suitable modified live virus is a pseudorabies virus (PrV) such as PrV based on the Bucharest strain.
  • PrV pseudorabies virus
  • Other suitable modified live viruses expected to be useful in this invention include bovine herpes virus, bovine respiratory syncytial virus, bovine viral diarrhea virus, parainfluenza virus type 3, porcine parvovirus, feline panleukopenia virus, feline herpes virus, feline calici virus, equine herpesvirus, canine distemper virus, infectious bronchitis virus and any other animal modified live virus vaccine.
  • the modified live virus is present in an amount sufficient to provide the desired immune response.
  • modified live viruses for use in the vaccine of this invention are commercially available such as Pr-Vac®.
  • a method of immunizing an animal comprising vaccinating the animal with an adjuvanted vaccine of this invention, whereby virus shed is reduced and virus neutralizing titer is increased over vaccination with a modified live virus vaccine administered with water.
  • a method of immunizing animals, such as swine, having maternal antibody derived serum neutralizing titers to the virus, such as pseudorabies virus is also provided by the invention.
  • swine having maternal antibodies to pseudorabies virus are vaccinated usually at about four to ten weeks of age with a vaccine comprising a modified live pseudorabies virus, e.g. based on the Bucharest strain, and an adjuvant comprising 10% by weight lecithin in a 90% by weight mineral oil carrier.
  • the adjuvant and carrier preferably comprise 5% of the vaccine by volume.
  • a modified live-killed combination vaccine contemplated by this invention might contain modified live pseudorabies virus and killed Actinobacillus pleuropneumoniae, Mycoplasma hyopneumoniae, Bordetella bronchiseptica, Haemophilus parasuis and Erysipelothrix rh siopathiae.
  • a stock emulsion is prepared in the following manner with composition per liter:
  • PBS Phosphate Buffered Saline
  • the lecithin mineral oil Solution is sterilized by filtration. Tween 80 and
  • Span 80 are each sterilized by autoclaving. Methyl-paraben, propylparaben, and butyl-paraben, at a total concentration not greater than 3.34 grams per liter of emulsion are added as preservative. These ingredients are mixed together using a valex mixer or equivalent for 16 to 24 hours at 37°C. The mixture is then cooled to between 25 and 30°C, and emulsified with the PBS, pH 7.2 ⁇ 0.2, in a Ross emulsifier (model ME401) or equivalent. Emulsification is continued by recirculation until all of the adjuvant is added into the saline. The emulsion is then passed once through a Gaulin homogenizer or equivalent. The emulsion may be stored at 4°C. Assembly of the adjuvant lecithin in combination with a carrier which is selected from the group consisting of edible and non-edible oils
  • adjuvant (a). vaccine
  • Serum neutralizations were run according to the procedure currently used by the state diagnostic laboratories, which includes use of the virulent Shope strain of PrV. This procedure results in lower titers than are obtained with the vaccine strain. Results
  • the serum neutralization titers obtained after first and second vaccination are shown in Table 1. Following the first vaccination, the only adjuvant groups that demonstrated a consistent neutralizing titer were the two groups (Groups 1 and 2) that received either adjuvant (a) or (b) (19 of 20 animals in these two groups had a measurable titer). Addition of endotoxin, adjuvant (b) did not increase the magnitude of the response. None of the pigs given PR- Vac® in water appeared to seroconvert following the first vaccination. Serum neutralization titers increased in all groups following a second vaccination, but the relative magnitude of the responses mirrored the results of first vaccination.
  • PR- Vac® rehydrated in adjuvant (a) gave the highest geometric mean titer (GMT) of 1:37.
  • PR- Vac® rehydrated in water and PR- Vac® rehydrated with aluminum hydroxide gave the lowest GMT of 1:6.
  • Example 2 Two pigs from some vaccine groups in Example 1 were picked at random and necropsied 21 days following the second vaccination. Injection sites were examined for possible lesions. Five additional pigs from each group were chosen at random for challenge. The groups were as follows: Group 1; PR- Vac® with adjuvant (a), Group 2; PR- Vac® rehydrated in water, and Group 3; nonvaccinated controls. Pigs were challenged with of virulent pseudorabies virus (ISU 4892 provided by the National Veterinary Service Laboratory, Ames, Iowa). The pigs were approximately 10 weeks old at the time of challenge. Body temperature and clinical signs of disease were monitored daily, nasal swabs were collected daily to monitor virus shed, and the pigs were weighed at 0, 7, and 14 days post challenge. RESULTS Injection site reactions
  • Virus shed Shed of virulent virus was monitored in nasal secretions (Table 4). All vaccinated animals shed virus from 1 day post challenge to 4 days post challenge. By 6 days post challenge, virus shed was not detected in any animals from Group 1 (adjuvant (a)), while two animals from Group 2 (water diluent) were still shedding detectable amounts of virus. All vaccinated animals were negative by day 8. In addition to shedding for a shorter period of time, pigs in Group 1 shed less virus.
  • Geometric mean virus titers of pigs in Group 1 were at least one and a half logs lower than those pigs in the water diluent group between days 1 and 4 post challenge. As expected, the control pigs shed much greater amounts of virus than either of the vaccinated groups. The mean titers on day 3 and day 4 post challenge were above 7 logs, and all pigs were still shedding large amounts of virus when they died. Discussion
  • the immune response of swine vaccinated with PR- Vac® was increased with the use of lecithin in combination with a carrier which is selected from the group consisting of edible and non-edible oils prepared as earlier described.
  • Adjuvant (a) was not viricidal when used in place of sterile water to rehydrate the lyophilized product. Serum neutralizing titers were consistently increased over those produced by the conventional vaccine following a single vaccination. The animals were given a second immunization to mimic field conditions. In most eradication plans, breeding animals are double vaccinated with a modified live product to maintain immunity at the highest possible level in an attempt to prevent virus spread.
  • the amount of virus shed from the nasal cavity of infected pigs was reduced by use of the adjuvant (a) diluent.
  • Pigs that received the vaccine adjuvanted with (a) shed an average of at least fifty-fold less virus than pigs vaccinated with the normal vaccine. This figure may have been even higher, since the titers from some animals in Group 2 (water diluent) did not reach an endpoint on days 3 and 4 (Table 4). This reduction in viral shed will be a key factor in controlling virus spread in an infected herd.
  • a swab of the nasal cavity was suspended in 2 ml of transport media (Hal's + 5% fetal bovine serum + high antibiotics) and stored frozen at -70°C until analysis. Results are expressed as the mean of two separate titrations.
  • Piglets born to sows vaccinated with two doses of PR-Vac®-Killed were divided into 3 groups. Each group consisted of 7 to 8 piglets, and groups were chosen so that the mean serum neutralization titer of each group would be approximately equal. Two additional piglets were used as sentinel controls. Animals were vaccinated with vaccine containing the minimum end of dating titer (10 3 -°TCID5 ⁇ /dose). fhe vaccination schedule was as follows: Group 1; vaccinated at 4 weeks of age, Group 2; vaccinated at 7 weeks of age, and Group 3; vaccinated at 10 weeks of age.
  • Seropositive piglets with maternal antibody derived SN titers that ranged from 1:64 to 1:16 were vaccinated at 4 weeks of age (Group 1, see Figure 1). These pigs did not exhibit a rise in titer following vaccination. Titers declined between 4 and 7 weeks of age in a fashion that was similar to nonvaccinated animals. However, the immune system of these pigs was primed by vaccination, as demonstrated by a sharp rise in titer following administration of non-adjuvanted inactivated PRV antigen at 7 weeks of age. In contrast, administration of the non- adjuvanted pseudorabies virus antigens in control animals did not elicit a rise in antibody titer. (Group 4)
  • the piglets in Group 2 were vaccinated at 7 weeks of age, when serum neutralization titers ranged from 1:23 to 1:6.
  • a small increase in SN titer was seen following vaccination, which resulted in titers that remained steady, in contrast to the declining titers seen in the nonvaccinated control pigs (Group 4).
  • PR- Vac® Current field use of PR- Vac® (MLV) usually involves vaccination at 8 to 12 weeks of age. Earlier vaccination has generally not been effective, and in many cases even vaccination at 8 to 12 weeks has failed to provide active immunity as measured by detection of an SN titer at market weight.
  • Administration of PR- Vac® in combination with adjuvant (a) to seropositive pigs at four weeks of age will actively prime the immune response to the virus. A second vaccination at seven to ten weeks of age would then result in the high levels of active immunity that are required to prevent clinical disease following exposure to virulent pseudorabies virus.

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Abstract

Vaccin de virus vivant modifié combiné à un adjuvant à base de lécithine. L'adjuvant comprend environ 5,0 % à environ 10 % en poids de lécithine et environ 90 % à environ 95 % en volume d'un support huileux.
PCT/US1993/005088 1992-05-29 1993-05-28 Vaccins de virus vivants modifies contenant un adjuvant a base de lecithine WO1993024147A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US89090392A 1992-05-29 1992-05-29
US07/890,903 1992-05-29
US95614592A 1992-10-05 1992-10-05
US07/956,145 1992-10-05

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WO1993024147A1 true WO1993024147A1 (fr) 1993-12-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1179349A1 (fr) * 2000-08-11 2002-02-13 Lohmann Animal Health GmbH & Co. KG E/H émulsion adjuvante destinée à des vaccins
US6676958B2 (en) * 2001-06-19 2004-01-13 Advanced Bioadjuvants, Llc Adjuvant composition for mucosal and injection delivered vaccines
WO2004087204A2 (fr) * 2003-04-04 2004-10-14 Pfizer Products Inc. Emulsions microfluidifiees d'huile dans l'eau et compositions de vaccins
EP0745388B2 (fr) † 1995-06-02 2006-08-30 Wyeth Composition de vaccin pour mammifères comprenant du squalène ou du squalane, un phospholipide et un agent tensio-actif comme adjuvant.

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4514497A (en) * 1983-12-30 1985-04-30 Novagene, Ltd. Modified live pseudorabies viruses
US4650677A (en) * 1983-06-06 1987-03-17 Duphar International Research B.V. Method of preparing adjuvanted live attenuated vaccines and adjuvanted live attenuated vaccines thus obtained
US4810634A (en) * 1985-07-29 1989-03-07 The Upjohn Company Pseudorabies virus mutants incapable of producing glycoprotein X
US5069901A (en) * 1988-02-03 1991-12-03 Jones Elaine V Preparation of a recombinant subunit vaccine against pseudorabies infection
US5084269A (en) * 1986-11-06 1992-01-28 Kullenberg Fred W Adjuvant for dose treatment with antigens

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4650677A (en) * 1983-06-06 1987-03-17 Duphar International Research B.V. Method of preparing adjuvanted live attenuated vaccines and adjuvanted live attenuated vaccines thus obtained
US4514497A (en) * 1983-12-30 1985-04-30 Novagene, Ltd. Modified live pseudorabies viruses
US4514497B1 (en) * 1983-12-30 1998-02-24 Novagene Inc Modified live pseudorabies viruses
US4810634A (en) * 1985-07-29 1989-03-07 The Upjohn Company Pseudorabies virus mutants incapable of producing glycoprotein X
US5084269A (en) * 1986-11-06 1992-01-28 Kullenberg Fred W Adjuvant for dose treatment with antigens
US5069901A (en) * 1988-02-03 1991-12-03 Jones Elaine V Preparation of a recombinant subunit vaccine against pseudorabies infection

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0745388B2 (fr) † 1995-06-02 2006-08-30 Wyeth Composition de vaccin pour mammifères comprenant du squalène ou du squalane, un phospholipide et un agent tensio-actif comme adjuvant.
EP1179349A1 (fr) * 2000-08-11 2002-02-13 Lohmann Animal Health GmbH & Co. KG E/H émulsion adjuvante destinée à des vaccins
WO2002013856A2 (fr) * 2000-08-11 2002-02-21 Lohmann Animal Health Gmbh & Co. Kg Compositions de materiaux et leurs applications
WO2002013856A3 (fr) * 2000-08-11 2002-07-18 Lohmann Animal Health Gmbh Compositions de materiaux et leurs applications
US6676958B2 (en) * 2001-06-19 2004-01-13 Advanced Bioadjuvants, Llc Adjuvant composition for mucosal and injection delivered vaccines
US7879333B2 (en) 2001-06-19 2011-02-01 Advanced Bioadjuvants, Llc Methods for preparing and delivering adjuvant compositions
US8501221B2 (en) 2001-06-19 2013-08-06 Advanced Bioadjuvants Llc Methods for preparing and delivering adjuvant compositions
WO2004087204A2 (fr) * 2003-04-04 2004-10-14 Pfizer Products Inc. Emulsions microfluidifiees d'huile dans l'eau et compositions de vaccins
WO2004087204A3 (fr) * 2003-04-04 2004-12-23 Pfizer Prod Inc Emulsions microfluidifiees d'huile dans l'eau et compositions de vaccins
AU2004226591B2 (en) * 2003-04-04 2009-06-04 Zoetis Services Llc Microfluidized oil-in-water emulsions and vaccine compositions
CN1767854B (zh) * 2003-04-04 2013-07-24 硕腾P有限责任公司 微流化水包油乳剂及疫苗组合物
US8771727B2 (en) 2003-04-04 2014-07-08 Zoetis Llc Microfluidized oil-in-water emulsions and vaccine compositions

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