WO2007002470A2 - Inactivated chimeric vaccines and related methods of use - Google Patents
Inactivated chimeric vaccines and related methods of use Download PDFInfo
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- WO2007002470A2 WO2007002470A2 PCT/US2006/024584 US2006024584W WO2007002470A2 WO 2007002470 A2 WO2007002470 A2 WO 2007002470A2 US 2006024584 W US2006024584 W US 2006024584W WO 2007002470 A2 WO2007002470 A2 WO 2007002470A2
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- A61P31/12—Antivirals
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- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
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- 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
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- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
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- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24111—Flavivirus, e.g. yellow fever virus, dengue, JEV
- C12N2770/24122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24111—Flavivirus, e.g. yellow fever virus, dengue, JEV
- C12N2770/24134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24111—Flavivirus, e.g. yellow fever virus, dengue, JEV
- C12N2770/24161—Methods of inactivation or attenuation
Definitions
- This invention is directed to new and improved methods of preventing and treating flavivirus and other closely related viral infection in animals.
- Flaviviruses are small, enveloped, positive-strand RNA viruses that are of concern in many medical and veterinary settings throughout the world.
- West Nile virus WN, or WNV
- WNV West Nile virus
- the virus has been found in Africa, western Asia, the Middle East, the Mediterranean region of Europe, and, recently, in the United States.
- Mosquitoes become infected with the virus after feeding on infected wild birds, and then transmit the virus through bites to humans, birds, and animals, such as horses, sheep, cattle, and pigs.
- West Nile virus is an emerging infectious disease. West Nile virus was first isolated in Kenya in 1937. Today it is most commonly found in Africa, West Asia, Europe, and the Middle East. However, it made its first recognized appearance in the United States in 1999. By 2004, the virus had been found in birds and mosquitoes in every state except Alaska and Hawaii. Other well-known diseases caused by flaviviruses include yellow fever, Japanese encephalitis, Dengue, and Saint Louis encephalitis. Flavivirus infections are commonly transmitted by ticks and/or mosquitoes.
- the primary hosts for West Nile are only mosquitoes and birds.
- Other animal species, such as humans, and animals, such as horses, sheep, cattle, and pigs, and the like are thought only to be incidental hosts that become infected when an infected female mosquito bites the incidental host.
- West Nile virus People who contract West Nile virus usually experience only mild symptoms including fever, headache, body aches, skin rash, and swollen lymph glands. If West Nile virus enters the brain, however, it can cause life-threatening encephalitis or meningitis. Life-threatening cases primarily occur in the elderly. Recent studies have shown that West Nile virus can be transmitted through blood transfusions and organ transplants. Some health experts also believe it is possible for West Nile virus to be transmitted from a mother to her unborn child, and through breast milk.
- Flavivirus proteins are produced by translation of a single, long open reading frame to generate a polyprotein, which undergoes a complex series of post-translational proteolytic cleavages by a combination of host and viral proteases to generate mature viral proteins.
- the virus structural proteins are arranged in the polyprotein in the order C-prM-E, where "C” is capsid, “prM” is a precursor of the viral envelope-bound M (membrane) protein, and "E” is the envelope protein.
- proteins are present in the N-terminal region of the polyprotein, while the non-structural proteins (NSl, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are located in the C-terminal region of the polypeptide.
- One Acambis live, attenuated vaccine contains genes from two different viruses, yellow fever and West Nile, and is an example of a chimeric virus.
- This Acambis live, attenuated vaccine comprises a Yellow Fever virus with a few genes replaced with genes for surface proteins of West Nile virus.
- live, attenuated vaccines have proven successful and trials continue.
- certain risks may accompany the use of a live, attenuated virus vaccine. These risks are even more pronounced for immunocompromised subjects, the elderly subjects, pregnant subjects, and other subjects with a weakened or stressed immune system.
- live, attenuated virus vaccines have been demonstrated to be either under-attenuated (cause disease) or over-attenuated (fail to immunize). It is also possible for an optimally-attenuated live virus vaccine to revert to a virulent (disease- causing) form through mutation.
- the YF-WN from Acambis has shown no indication of reversion to virulence.
- a vaccine is needed in the art for safely treating and/or preventing flavivirus infections, such as West Nile, in subjects with these or other similar risks. Particularly for those who are immune compromised or other subjects most at risk.
- Various embodiments of the present invention comprise a vaccine or immunogenic composition for the treatment or prevention of flavivirus infection in an animal.
- the invention also provides methods for preventing or treating flavivirus infections in susceptible animals, which involve administering to the subjects inactivated chimeric flaviviruses.
- the invention also provides the use of inactivated chimeric flaviviruses in the preparation of medicaments for use in such methods and vaccines and/or immunogenic compositions.
- the inactivated chimeric flaviviruses can include, for example, the capsid and non-structural proteins of a first flavivirus, and the prM and envelope proteins of a second flavivirus.
- the present invention is directed to an inactivated chimeric flavivirus, comprising a first flavivirus in which the nucleotide sequences encoding the pre-membrane and envelope proteins are replaced with nucleotide sequences encoding pre-membrane and envelope proteins of a second flavivirus.
- the first flavivirus can be yellow fever virus, including yellow fever virus derived from the 17D strain.
- the chimeric virus can comprise a signal sequence at the amino acid terminus of the pre- membrane protein, and the signal sequence can be that of yellow fever virus.
- the second flavivirus can be West Nile virus.
- the present invention is directed to an immunogenic composition
- an inactivated chimeric flavivirus comprising a first flavivirus in which the nucleotide sequences encoding the pre-membrane and envelope proteins are replaced with nucleotide sequences encoding pre-membrane and envelope proteins of a second flavivirus.
- the present invention is directed to a vaccine comprising an inactivated chimeric flavivirus, comprising a first flavivirus in which the nucleotide sequences encoding the pre-membrane and envelope proteins are replaced with nucleotide sequences encoding pre-membrane and envelope proteins of a second flavivirus.
- the vaccine can further comprise i) one or more modified live viruses; ii)one or more inactive viruses; or iii) one or more bacterial antigens.
- the vaccine can further comprise one or more of inactive Eastern encephalomyelitis virus, inactive Western encephalomyelitis virus, inactive Venezuelan encephalomyelitis virus, inactive equine herpes virus type 1, inactive equine herpes virus type 4, inactive equine influenza virus strain Kentucky 1993/A2, inactive equine influenza virus strain Kentucky 2002/A2, inactive equine influenza virus strain New Market/2/93/A2 and a tetanus toxoid fraction.
- inactive Eastern encephalomyelitis virus inactive Western encephalomyelitis virus, inactive Venezuelan encephalomyelitis virus, inactive equine herpes virus type 1, inactive equine herpes virus type 4, inactive equine influenza virus strain Kentucky 1993/A2, inactive equine influenza virus strain Kentucky 2002/A2, inactive equine influenza virus strain New Market/2/93/A2 and a tetanus toxoid fraction.
- the present invention is directed to a method of preventing or treating a flavivirus infection in an animal, the method comprising administering to the animal an inactivated chimeric flavivirus (or immunogenic composition or vaccine thereof) comprising a first flavivirus in which the nucleotide sequences encoding the pre- membrane and envelope proteins are replaced with nucleotide sequences encoding pre- membrane and envelope proteins of a second flavivirus.
- the first flavivirus can be yellow fever virus.
- the yellow fever virus can be derived from the 17D strain.
- the second flavivirus can be West Nile virus.
- the inactivated chimeric virus can be present in a concentration ranging between 10 2 and 10 8 plaque-forming units (pfu).
- the chimeric flavivirus can be administered at a dose ranging between 10 6 and 10 7 pfu.
- the chimeric flavivirus can be administered at a dose ranging between 1-10 relative antigen dose units.
- the inactivated chimeric virus can be administered by a subcutaneous, intramuscular, submucosal, mucosal, or intradermal route. In an embodiment of the present invention, the inactivated chimeric flavivirus is orally administered.
- vaccine(s) means and refers to a product, the administration of which is intended to elicit an immune response(s) that can prevent and/or lessen the severity of one or more infectious diseases.
- Vaccines can include one or more of the following: a live attenuated or inactivated preparation of bacteria, viruses or parasites, inactivated (killed) whole organisms, living irradiated cells, crude fractions or purified rmmunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as plasmid DNA vaccines), living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen.
- chimeric virus refers to a virus having a genome containing sequences from two or more different viruses, including different viral strains. Unless otherwise stated, “chimera” refers to a chimeric virus.
- a non-limiting example of a chimeric virus is the YFAVN chimera, which is a chimeric flavivirus.
- chimeric flavivirus refers to a virus having a genome containing sequences from two or more different flaviviruses, including different flavivirus strains. As described above, a non-limiting example of a chimeric flavivirus is the YFAVN chimera.
- West Nile chimeric virus As used herein, “West Nile chimeric virus”, “West Nile chimera”, “YFAVN virus” and “YFAVN chimera” refer to a chimeric live, attenuated virus, comprising the 17D vaccine strain of yellow fever virus (YFV) in which the nucleotide sequences encoding the pre-membrane (prM) and envelope (E) proteins are replaced by the nucleotide sequences encoding the prM and E proteins of West Nile Virus (WNV), so that the prM and E proteins of West Nile virus are expressed, and the capsid protein of the chimeric virus is from the yellow fever virus.
- YFV yellow fever virus
- prM pre-membrane
- E envelope
- WNV West Nile Virus
- West Nile chimeric virus (or, YFAVN virus) can be inactivated using techniques well known to the skilled artisan.
- West Nile chimeric virus (or, YFAVN virus) can be inactivated with chemical inactivating agents or other physical means such as heat.
- chemical inactivating agents include binary ethylenimine (BEI) or formalin (a 37% solution of formaldehyde).
- BEI binary ethylenimine
- formalin a 37% solution of formaldehyde
- Live virus can be inactivated using BEI by first mixing binary ethyleneamine (BEA) powder with a sodium hydroxide solution. After BEI is generated in the basic environment, the BEI solution is added to a solution containing live virus to give a final BEI concentration of 0.5 mM to 10 mM. This solution can then be incubated from 4 - 37 0 C for 24-96 hours. Sodium thiosulphate can then be added after the virus is inactivated to neutralize any remaining BEL
- Live virus can also be inactivated with formalin (37% solution of formaldehyde).
- formalin is added to a solution containing live virus to give a final formalin concentration of 0.05 - 2% v:v (formalin:live viral solution). This solution can then be incubated from 4 - 37 0 C for 24-96 hours.
- the term "antigen” means and refers to a virus, a bacteria, parts of a virus or bacteria or a foreign protein that acts to stimulate the immune system in an animal.
- the immune system can be stimulated to cause the white blood cells to attack and destroy the antigen or to produce a protein molecule, which attaches to the antigen and either kills the antigen or makes it inactive.
- antibody means and refers to a protein-containing molecule that an animal's immune system makes that reacts with an antigen to make it inactive.
- animal means and refers to both human and non-human animals.
- vaccine strain means and refers to a viral strain suitable for use in an immunogenic composition or vaccine.
- a “vaccine strain” can comprise, but is not necessarily limited to, a non-pathogenic strain or relatively non-pathogenic strain, a killed strain, and/or an attenuated strain.
- the term "lyophilize,” and conjugations thereof, means and refers to freeze drying.
- the term “animal origin” means and refers to originating from animals.
- non-animal origin means and refers to not originating directly or indirectly from animals.
- stabilize means and refers to make or hold stable, firm, steadfast and to maintain at about a given or substantially unfluctuating level, about a given or substantially unfluctuating quality and about a given or substantially unfluctuating quantity.
- level, quality, and/or quantity of the stabilized composition may be encountered.
- Embodiments of the present invention are intended to encompass stabilizers that allow such fluctuations.
- stabilizers include dry stabilizers, bulk stabilizers, cryoprotectants, thermo-stabilizers, osmoprotectants, desiccation protectants, and the like. Such terms are specifically meant to be included within the stabilizers of the present invention.
- protein means and refers to a molecular chain of amino acids.
- a protein is not of a specific length and can, if required, be modified in vivo or in vitro, by, e.g. glycosylation, amidation, carboxylation or phosphorylation.
- peptides, oligopeptides and polypeptides are included within the definition of protein.
- a protein or peptide can be of biologic and/or synthetic origin.
- nucleic acid means and refers to a molecular chain of ribonucleic acids or deoxyribonucleic acids.
- a nucleic acid is not of a specific length, therefore polynucleotides, genes, open reading frames (ORF 's), probes, primers, linkers, spacers and adaptors are included within the definition.
- a nucleic acid can be of biologic and/or synthetic origin.
- the nucleic acid may be in single stranded or double stranded form. The single strand may be in sense or anti-sense orientation. Also included within the definition are modified RNAs or DNAs.
- a pharmaceutically acceptable carrier is understood to be a compound that does not adversely affect the health of the animal or organism to be vaccinated, at least not to the extent that the adverse effect is worse than the effects seen when the animal is not vaccinated.
- pharmaceutically acceptable carriers include sterile water or a sterile physiological salt solution. In a more complex form the carrier can be a buffer.
- carbohydrate means and refers to mono- , di-, oligo-, and poly-saccharides.
- feline means and refers to any animal of or pertaining to the genus FeKs, or family Felidae, cat family, such as, but not limited to, a cat, a lion, a tiger, a mountain lion, a puma, a jaguar, a bobcat, an ocelot and the like.
- canine means and refers to any animal of or pertaining to the genus Canis, dog family, such as, but not limited to, a dog, wolf, and the like.
- the term "equine” means and refers to any animal of or pertaining to the genus Equis, or family Equidae, horse family, such as, but not limited to, a horse, mule, donkey, zebra, and the like.
- the present invention generally relates to compositions for and methods of preventing and treating flavivirus infection in animals.
- the methods of the invention involve vaccination of animals that are at risk of developing or have flavivirus infection with an inactivated chimeric flavivirus.
- Other aspects of the invention are directed to methods of preparing a vaccine or immunogenic composition comprising an inactivated chimeric flavivirus for the treatment or prevention of flavivirus infection in animals.
- the invention is also directed to inactivated chimeric viruses for treating or preventing diseases or illnesses associated with or caused by viruses of the family Flaviviridae or Togaviridae.
- Non-limiting examples of genuses of viruses falling within these families include viruses belonging to the Flavivirus, Pestivirus, Hepacivirus or Alphavirus genuses.
- Non-limiting examples of viruses or diseases caused by viruses belonging to these families or genuses include encephalitis viruses, Eastern Equine Encephalitis, Western Equine Encephalitis, Venezuela Equine Encephalitis, Kunjin, Murray Valley encephalitis, Louping ill viruses, Japanese encephalitis, Dengue (serotypes 1-4), Yellow Fever, Murray Valley encephalitis, St.
- Additional viruses that can be treated or prevented using inactivated chimeric viruses of the present invention include those belonging to the Pestivirus genus (e.g., Bovine diarrhea virus), and other viruses, such as Lassa, Ebola, and Marburg viruses or other RNA viruses with a genomic construction that would be compatible with incorporation into the chimera.
- Pestivirus genus e.g., Bovine diarrhea virus
- other viruses such as Lassa, Ebola, and Marburg viruses or other RNA viruses with a genomic construction that would be compatible with incorporation into the chimera.
- Infection by any of the above described viruses can be prevented or treated with the inactivated chimeric viruses described herein.
- inactivated chimeric viruses that comprise a first virus in which one or more structural protein (or proteins) of the first virus has been replaced with a corresponding structural protein (or proteins) of a second virus against which protection or treatment is sought.
- a preferred aspect of the invention is directed to inactivated chimeric flaviviruses, methods of making inactivated chimeric flaviviruses, -vaccines comprising inactivated chimeric flaviviruses, and methods of using such vaccines.
- This aspect of the invention is directed to inactivated chimeric flaviviruses that comprise a flavivirus in which one or more structural proteins of a first flavivirus have been replaced with one or more corresponding structural proteins of a second flavivirus, to which immunity is sought.
- the chimeras consist of the backbone of a first flavivirus in which the prM and E proteins have been replaced with the prM and E proteins of a second flavivirus.
- the inactivated chimeric viruses that are used in the invention can consist of any combination of viruses, provided that, as is mentioned above, the virus to which immunity is desired is the source of the inserted structural protein(s).
- a chimeric flavivirus consisting of a flavivirus backbone, such as that of yellow fever (YF) virus, into which West Nile virus structural proteins, such as prM and E proteins, are inserted can be used.
- YF yellow fever
- prM and E proteins West Nile virus structural proteins
- the prM and E proteins of JE virus can be inserted into a backbone flavivirus, such as a yellow fever virus, in place of the corresponding backbone proteins.
- a backbone flavivirus such as a yellow fever virus
- Other flaviviruses that cause disease in horses, and for which chimeric viruses can be used for inducing protection include Kunjin, Murray Valley encephalitis, and Louping ill viruses.
- the chimeric virus is then inactivated.
- animals that can be vaccinated and/or treated with the inactivated chimeric viruses of the present invention comprise humans, horses, pigs, sheep, cattle, domestic animals, such as cats and dogs, and domestic birds. However, in general any animal susceptible to infection from the flavivirus for which protection is sought may be vaccinated.
- flaviviruses that can be used in the invention, as sources of backbone virus or structural protein inserts, include mosquito-borne flaviviruses, such as Japanese encephalitis, Dengue (serotypes 1-4), Yellow Fever, Murray Valley encephalitis, St.
- encephalitis Louis encephalitis, West Nile, Kunjin, Rocio encephalitis, Wesselsbron, and Ilheus viruses
- tick-borne flaviviruses such as Central European encephalitis, Siberian encephalitis, Russian Spring-Summer encephalitis, Kyasanur Forest Disease, Omsk Hemorrhagic fever, Louping ill, Powassan, Negishi, Absettarov, Hansalova, acea, and Hypr viruses
- viruses from the Hepacivirus genus e.g., Hepatitis C virus.
- Additional viruses that can be used as the source of inserted structural proteins include viruses from the Pestivirus genus (e.g., Bovine diarrhea virus), and other viruses, such as Lassa, Ebola, and Marburg viruses.
- such methods entail replacing genes encoding two structural proteins [prM and E] of yellow fever 17D vaccine virus with the corresponding genes of West Nile virus and inactivating the chimeric virus.
- the resulting inactivated virion has the envelope of West Nile, containing structures involved in virus-cell attachment and virus internalization, all antigenic determinants for neutralization, and epitope(s) for cytotoxic T lymphocytes.
- the nucleocapsid (C) protein, nonstructural proteins, and non-translated termini responsible for virus replication remain those of the original yellow fever 17D virus.
- One preferred embodiment of the present invention is directed to an inactivated chimeric vaccine and/or immunogenic composition for the treatment or prevention of West Nile infection, in an animal susceptible to West Nile infection.
- Details of making chimeric viruses including a WN/YF chimeric virus that can then be inactivated and used in various embodiments of the invention are provided, for example, in U.S. Patent Nos. 6,962,708 and 6,696,281 and Chambers et al, J. Virol. 73:3095-3101, 1999, which are all hereby incorporated by reference in their entirety.
- U.S. Patent Nos. 6,962,708 and 6,696,281 are limited, however, to live attenuated chimeric viruses, vaccines and related methods of use.
- Vaccine and immunogenic compositions can be prepared and/or marketed in the form of a liquid, frozen suspension or in a lyophilized form.
- vaccines and/or immunogenic compositions prepared according to the present invention contain a pharmaceutically acceptable carrier or diluent customarily used for such compositions.
- Carriers include, but are not limited to, stabilizers, preservatives and buffers. Suitable stabilizers are, for example SPGA, Tween compositions (such as are available from A.G.
- Suitable buffers include alkali metal phosphates. Suitable preservatives are thimerosal, merthiolate and gentamicin.
- Diluents include water, aqueous buffer (such as buffered saline), alcohols and polyols (such as glycerol).
- the inactivated vaccines according to the invention may contain an adjuvant.
- Suitable compounds or compositions for this purpose include HAVLOGEN ® (an acrylic acid polymer-based adjuvant, Intervet Inc., Millsboro, DE), polyacrylic acids, aluminium hydroxide, -phosphate or -oxide, oil-in-water or water-in-oil emulsion based on, for example a mineral oil, such as BAYOLTM or MARCOLTM (Esso Imperial Oil Limited, Canada), or a vegetable oil such as vitamin E acetate, and saponins.
- HAVLOGEN ® an acrylic acid polymer-based adjuvant, Intervet Inc., Millsboro, DE
- polyacrylic acids aluminium hydroxide
- -phosphate or -oxide oil-in-water or water-in-oil emulsion
- oil-in-water or water-in-oil emulsion based on, for example a mineral oil, such as BAYOLTM or MAR
- the vaccine may be administered subcutaneously, intradermally, submucosally, or intramuscularly in an effective amount to prevent infection from the flavivirus of interest and/or treat an infection from the flavivirus.
- An effective amount is defined as an amount of immunizing inactivated chimeric material that will induce immunity in the vaccinated animals, against challenge by a virulent virus. In various other embodiments, an effective amount will induce immunity in the vaccinated animals or their progeny, against challenge by a virulent virus.
- Immunity is defined herein as the induction of a significant higher level of protection in a population of the animal after vaccination compared to an unvaccinated group.
- suitable excipients, stabilizers and the like may be added.
- the inactivated chimeric virus can be formulated as a sterile aqueous solution containing between 10 2 and 10 12 infectious units (as determined prior to inactivation).
- the inactivated chimeric virus can be formulated as a sterile aqueous solution containing between 10 7 and 10 10 infectious units (as determined prior to inactivation). Infectious units include plaque-forming units (pfu) or tissue culture infectious doses (tcid).
- the inactivated chimeric virus can be formulated as a sterile aqueous solution containing between 1-10 relative antigen dose units.
- the formulated inactivated chimeric virus can be provided in a dose volume of 0.1 to 1.0 ml, to be administered by, for example, subcutaneous, intramuscular, submucosal or intradermal routes. Further embodiments may be administered by a mucosal route, such as an oral route. Selection of an appropriate amount of chimera to administer can be determined by those of skill in this art, and this amount can vary due to numerous factors, including without limitation the size, type, and general health of the animal to which the chimera is to be administered.
- PRESTIGE ® V+VEE vaccine contains inactivated Eastern Encephalomyelitis virus, inactivated Western Encephalomyelitis virus, inactivated Venezuelan Encephalomyelitis virus, inactivated Equine Herpes virus types 1 and 4 (Rhinopneumonitis), inactivated Influenza virus (Kentucky strain 1993, Kentucky strain 2002, and New Market-2-93), and tetanus toxoid fractions.
- the YF-WN live attenuated chimera was obtained from Acambis in Cambridge, MA, and inactivated with binary ethyleneimine (BEI). Inactivation was accomplished by first mixing binary ethyleneamine (BEA) powder with a sodium hydroxide solution. Upon mixing, the BEA converts to BEL This BEI liquid solution is added to a solution of live chimeric virus to give a final BEI concentration of 2 niM. The BEI/chimera solution was incubated at about 18 -25 0 C for about 3 days.
- BEI binary ethyleneamine
- PRESTIGE ® V+VEE vaccine available from Intervet Inc, Millsboro, DE
- YF- WN formalin-inactivated Yellow Fever- West Nile
- the YF-WN live attenuated chimera was obtained from Acambis in Cambridge, MA, and inactivated with formalin (37% solution of formaldehyde). Inactivation was accomplished by mixing formalin solution to a solution of live chimeric virus to give a final formalin concentration of 0.1 % v:v with respect to the solution of live chimeric virus. The formalin/chimera solution was incubated at about 18 -25 0 C for about 3 days.
- WNV West Nile Virus
- VN Virus neutralizing antibody titers to WNV in horses vaccinated with two dose of inactivated YF-WN or one dose of live YF-WN chimera (from Acambis, Cambrid e, MA)
- a Titer values are the number-fold dilution representing the greatest dilution of serum at which 50 % plaque reduction is observed relative to control. "Negative” indicates no plaque reduction observed; “80” represents an 80-fold dilution; “160” represents a 160- fold dilution, etc.; “N/A” is indicated where no second vaccination was administered; “Dead” refers to the horses.
- b BEI or formalin inactivated YF-WN chimera was in combination with PRESTIGE ® V+VEE vaccine.
- Example #1 The serological results from Example #1 illustrate the unexpected results of the inactivated West Nile chimera vaccine of the present invention.
- live viruses such as Acambis' live attenuated YF-WN chimera
- humoral responses antibody response
- inactivated viruses only produce humoral responses.
- the inactivated YF-WN produces a high humoral response, as is evident from the serological data.
- the inactivated YF-WN performs as well as the live YF-WN at eliciting a humoral response.
- the advantages of the inactivated vaccines of the present invention are unexpected.
- Example 2 Experimental design:
- PRESTIGE ® V+VEE vaccine contains inactivated Eastern Encephalomyelitis virus, inactivated Western Encephalomyelitis virus, inactivated Venezuelan Encephalomyelitis virus, inactivated Equine Herpes virus types 1 and 4 (Rhinopneumonitis), inactivated Influenza virus (Kentucky strain 1993, Kentucky strain 2002, and New Market-2-93), and tetanus toxoid fractions.
- the YF-WN live attenuated chimera was obtained from Acambis in Cambridge, MA.
- the chimeric virus was inactivated with BEI and added to the PRESTIGE ® V+VEE vaccine as described above in Example 1.
- the purpose of this experiment was to establish the immunogenicity of the inactivated West Nile chimeric virus contained in a combination vaccine comprising the antigenic components of PRESTIGE ® V+VEE vaccine (available from Intervet Inc, Millsboro, DE; i.e., inactivated Eastern Encephalomyelitis virus, inactivated Western Encephalomyelitis virus, inactivated Venezuelan Encephalomyelitis virus, inactivated Equine Herpes virus types 1 and 4 (Rhinopneumonitis), inactivated Influenza virus (Kentucky strain 1993, Kentucky strain 2002, and New Market-2-93 strain), and Tetanus toxoid), all combined with a polyacrylic acid adjuvant.
- PRESTIGE ® V+VEE vaccine available from Intervet Inc, Millsboro, DE; i.e., inactivated Eastern Encephalomyelitis virus, inactivated Western Encephalomyelitis virus, inactivated Venezuelan Encephalomyelitis virus, inactivated
- IM intramuscular
- vaccinated and unvaccinated control horses were challenged by the intrathecal (IT) route with virulent WNV.
- IT intrathecal
- Two separate groups of 10 vaccinate and 5 control horses were sequentially vaccinated and challenged.
- Blood samples for serological evaluation were collected before vaccination, after vaccination and after challenge and tested for virus neutralization (VN) antibody titers to WNV.
- Blood samples were collected post-challenge for isolation of WNV. Neural tissues were collected at the time of necropsy for histological examination.
- VN virus neutralization
- the vaccine contained YFAVN chimera in combination with Eastern encephalomyelitis (EE) virus, Western encephalomyelitis (WE) virus, Venezuelan encephalomyelitis (VE) virus, equine herpes virus type 1 (EHV-I), equine herpes virus type 4 (EHV-4), equine influenza virus (EIV) strain Kentucky 1993/A2, EIV strain Kentucky 2002/A2, and EIV strain New Market/2/93/A2, and tetanus toxoid fractions.
- the vaccine contained a polyacrylic acid adjuvant.
- Two vaccines were used to demonstrate non-interference.
- One vaccine contained a minimum immunizing dose of inactivated YFAVN chimera and a standard release dose of the remaining inactivated viruses or tetanus toxoid fractions.
- the other vaccine contained a standard release dose of inactivated YF/WN chimera and a minimum immunizing dose of the remaining inactivated viruses or tetanus toxoid fractions.
- the component(s) present at the standard release dose did not interfere with the component(s) present at the minimum immunizing dose level.
- Horses were 6 to 9 months of age at the time of the first vaccination. Horses were randomized into groups by use of a random number generator and acclimatized for a minimum of seven days. Twenty horses were vaccinated IM in the neck with two 1 ml doses of the vaccine at three weeks apart. Ten horses were used as unvaccinated controls. Two groups of horses (each containing 10 vaccinates and 5 controls) were sequentially vaccinated.
- Rectal body temperatures were taken and injection site reactions were observed on days -1 through 10 post-vaccination. Body temperatures of ⁇ l02.5 o F are considered to be an elevated temperature. Injection site reactions were scored according to a scoring method. Any systemic reactions or observations of abnormal health were recorded. Blood for serum was collected on days 0, 7, and 21 day post-first vaccination and at 21 days post-second vaccination. Neutralization antibody titers to WNV in serum samples from horses were determined by the use of a 50% plaque reduction neutralization test. G. Challenge of Horses with Virulent WNV
- horses were challenged by IT administration of 1 ml containing virulent WNV strain NY99.
- Results of five replicate titrations of the challenge material were 5.0, 5.1, 5.1, 5.0, and 5.0 for a mean of 5.0 and 5.1, 5.1, 5.0, 5.0, and 5.1 for a mean of 5.1 logio PFU/ml dose, for challenge groups 1 and 2, respectively.
- Rectal body temperatures were recorded on days -1 through 21 post-challenge.
- Challenge of unvaccinated control horses with WNV by the IT route resulted in clinical signs of disease that are observed in horses naturally infected with WNV under field conditions.
- Body temperatures of 2102.5 0 F were recorded for one day post-first vaccination for three vaccinate horses and for two days for one control horse. Body temperatures of >102.5 o F were not recorded for any vaccinate or control horse after the second vaccination. All horses were in good general health at the start of the study. Vaccination site reactions were evaluated according to a scoring method (0 (no reaction) to 5 (systemic reaction)). Post-first vaccination, mild injection site reactions, of scores of 2 or less, were recorded on one or two days for three horses. Another vaccinate horse had a mild reaction that persisted through 10 days post-first vaccination but did not cause any pain or result in reluctance to move.
- Vaccinate Group Plaque reduction neutralization antibody titers 50% (PRNT50%) to WNV post-l st and 2 nd vaccination and post-challenge.
- Titer values are the number-fold dilution representing the greatest dilution of serum at which 50 % plaque reduction is observed relative to control.
- b Day 21 is day of 2 nd vaccination
- c Day 42 is 21 days post-2 nd vaccination and day of challenge
- Control Group Plaque reduction neutralization antibody titers 50% (PRNT50%) to WNV post-l st and 2 nd vaccination and post-challenge.
- Titer values are the number-fold dilution representing the greatest dilution of serum at which 50 % plaque reduction is observed relative to control.
- AU vaccinate and control horses were seronegative to WNV at the time of vaccination and at 7 days post-first vaccination.
- Plaque reduction virus neutralizing antibody titers to WNV were detected in one vaccinate post- first vaccination and were detected in 14 of 20 vaccinates at 21 days post-second vaccination. All unvaccinated control horses remained seronegative throughout the first and second vaccination period.
- the case definition of infection with WNV and primary outcome for demonstration of disease caused by WNV was defined as horses having moderate or severe signs of disease for two or more consecutive days in any of the categories of: Changes in mentation, paresis, fasciculations, and ataxia/recumbency or any animal in which euthanasia was required due to overall severe health condition of the animal as a result of WNV infection. These criteria had to be satisfied in order for the primary outcome to be a failure; otherwise, the horse was considered a success.
- neural tissue from the pons, medulla, and hypothalamus/thalamus were collected and analyzed for histopathology due to viral encephalitis. In general, there was reduced histopathology in vaccinates compared to controls but there was not a statistically significant difference.
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CN101222936A (en) | 2008-07-16 |
EP1896069B1 (en) | 2013-03-13 |
MX2007016083A (en) | 2008-03-10 |
NZ564375A (en) | 2010-02-26 |
JP5193856B2 (en) | 2013-05-08 |
US20070009548A1 (en) | 2007-01-11 |
CA2612047A1 (en) | 2007-01-04 |
ZA200710974B (en) | 2008-10-29 |
AU2006261943A1 (en) | 2007-01-04 |
JP2008546416A (en) | 2008-12-25 |
US8133712B2 (en) | 2012-03-13 |
RU2436591C2 (en) | 2011-12-20 |
WO2007002470A3 (en) | 2007-11-01 |
RU2008102654A (en) | 2009-07-27 |
AU2006261943B2 (en) | 2010-12-02 |
BRPI0611581B1 (en) | 2021-08-03 |
US8048429B2 (en) | 2011-11-01 |
EP1896069A4 (en) | 2010-01-27 |
US20110212126A1 (en) | 2011-09-01 |
EP1896069A2 (en) | 2008-03-12 |
CA2612047C (en) | 2015-05-12 |
US20090246223A1 (en) | 2009-10-01 |
BRPI0611581A2 (en) | 2011-02-22 |
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