WO2009120306A1 - Vecteur de vaccin multivalent dans le traitement et l’inhibition d’infection virale - Google Patents

Vecteur de vaccin multivalent dans le traitement et l’inhibition d’infection virale Download PDF

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Publication number
WO2009120306A1
WO2009120306A1 PCT/US2009/001821 US2009001821W WO2009120306A1 WO 2009120306 A1 WO2009120306 A1 WO 2009120306A1 US 2009001821 W US2009001821 W US 2009001821W WO 2009120306 A1 WO2009120306 A1 WO 2009120306A1
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virus
viruses
vector
pharmaceutical composition
human
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PCT/US2009/001821
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English (en)
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Thomas William Geisbert
John Hazard Connor
Hideki Ebihara
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Trustees Of Boston University
Boston Medical Center Corporation
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Publication of WO2009120306A1 publication Critical patent/WO2009120306A1/fr

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5256—Virus expressing foreign proteins
    • 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
    • A61K2039/70—Multivalent vaccine
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/14011—Filoviridae
    • C12N2760/14111—Ebolavirus, e.g. Zaire ebolavirus
    • C12N2760/14134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/20011—Rhabdoviridae
    • C12N2760/20211—Vesiculovirus, e.g. vesicular stomatitis Indiana virus
    • C12N2760/20241—Use of virus, viral particle or viral elements as a vector
    • C12N2760/20243—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • Viral infections in particular infections associated with hemorrhagic fever viruses, may cause severe symptoms in humans and nonhuman primates that can be fatal. With the exception of a vaccine for Junin virus, there are currently no vaccines or treatments targeting hemorrhagic fever viruses licensed for human use. Because of the multitude of strains and species of pathogenic hemorrhagic fever viruses, protection against hemorrhagic fever viruses may require multiple different vaccination regimens. However, interference between the vaccines may occur upon administration, potentially disrupting the efficacy of the vaccinations. Therefore, there is a need in the art for a single vaccine that could provide broad protection against a number of different viruses or different strains of the same virus.
  • the present invention features compositions and methods for the treatment or inhibition of one or more viruses using a recombinant viral vector that encodes and expresses all or part of multiple viral proteins (e.g., two, three, or four viral proteins) from one or more viruses.
  • the viral genes contained within the recombinant viral vector may be gene sequences from different viruses, gene sequences from different strains of the same virus, or combinations thereof.
  • the invention features a recombinant viral vector that includes all or a portion of at least one gene that is not endogenous to the vector from three or more (e.g., four) different viruses or different viral strains.
  • the vector may contain all or a portion of at least two genes from one of three or more different viruses or different viral strains.
  • the gene(s) of the viral vector encode viral glycoproteins, capsid proteins, tegument proteins, or non-structural proteins, or fragments thereof.
  • the vector is a vesicular stomatitis virus (VSV) vector that does not encode the VSV glycoprotein.
  • VSV vesicular stomatitis virus
  • the vector may contain a VSV matrix protein having one or more mutations that decrease cytopathogenicity of the vector.
  • the vector is included in a pharmaceutical composition (e.g., a vaccine).
  • the vaccine treats, reduces, or inhibits infection by at least one of two or more different viruses.
  • the vaccine alleviates one or more symptoms associated with viral infection (e.g., hemorrhagic fever viral infection).
  • the composition includes a pharmaceutically acceptable diluent, excipient, carrier, or adjuvant.
  • the pharmaceutical composition is suitable for administration to a human that has been infected with or exposed to at least one of two or more different viruses (e.g., hemorrhagic fever viruses).
  • the pharmaceutical composition contains between 1 x 10 1 and 1 x 10 8 pfu of the viral vector, more preferably at least 1 x 10 3 pfu of the viral vector.
  • the invention features a method of inhibiting or treating infection by three or more different viruses (e.g., hemorrhagic fever viruses) or different strains of the same virus in a subject by administering to the subject the vector described herein in an amount sufficient to inhibit or treat the infection.
  • the vector is included in a pharmaceutical composition that inhibits or treats infection by at least one, preferably two, three, or four viruses.
  • the pharmaceutical composition is administered to the subject prior to exposure to the viruses.
  • the composition is administered following exposure of the subject to the viruses.
  • the composition is administered to a human by, e.g., injection.
  • the invention features a method of inducing an immune response against infection by three or more different viruses in a subject by administering to the subject the vector described herein in an amount sufficient to inhibit or treat the infection.
  • the viruses of the invention are hemorrhagic fever viruses, such as arenaviruses (e.g., Lassa virus (e.g., the Josiah, LP, or GA391 strain), Junin virus, or Machupo virus), filoviruses (e.g., Ebola virus (e.g., the Zaire species, Sudan species, Ivory Coast species, Kenya species, or a new strain or species of Ebola virus) or Marburg virus (e.g., the Angola, Ci67, Musoke, Popp, or Ravn strain)), bunyaviruses, or flaviviruses.
  • arenaviruses e.g., Lassa virus (e.g., the Josiah, LP, or GA391 strain), Junin virus, or Machupo virus
  • filoviruses e.g., Ebola virus (e.g., the Zaire species, Sudan species, Ivory Coast species, Kenya species, or a new strain or species of
  • the virus of the invention may be, for example, hepatitis C virus, respiratory syncytial virus, Sindbis virus, poliovirus, hepatitis B virus, human papilloma virus, Epstein-Barr virus, adeno-associated virus, Venezuela encephalitis virus, rubella, coxsackievirus, enterovirus, hepatitis A virus, astrovirus, rabies virus, influenza virus A, influenza virus B, measles, mumps, La Crosse virus, California encephalitis virus, Eastern equine encephalitis virus, JC virus, BK virus, herpes simplex virus (type 1), herpes simplex virus (type two), human herpes simplex virus (type six), human herpes virus (type seven), human herpes virus (type eight), human adenovirus, human cytomegalovirus, smallpox virus, Norwalk virus, coronavirus, parainfluenza, rotavirus, Varicella-Zoster
  • administering is meant a method of giving a dosage of a pharmaceutical composition to a subject.
  • the compositions utilized in the methods described herein can be administered by a route selected from, e.g., parenteral, dermal, transdermal, ocular, inhalation, buccal, sublingual, periungual, nasal, rectal, topical, and oral.
  • Parenteral administration includes intra-arterial, intravenous, intraperitoneal, subcutaneous, and intramuscular administration.
  • the preferred method of administration can vary depending on various factors (e.g., the components of the composition being administered and the severity of the condition being treated).
  • an amount sufficient to treat is meant the amount of a composition administered to improve, inhibit, or ameliorate a condition of a subject, or a symptom of a disorder, in a clinically relevant manner (e.g., improve, inhibit, or ameliorate infection by one or more viruses or viral strains or one or more symptoms that occur following infection). Any improvement in the subject is considered sufficient to achieve treatment.
  • an amount sufficient to treat is an amount that reduces, inhibits, or prevents the occurrence or one or more symptoms of a viral infection (e.g., symptoms that result from infection by at least one and preferably two or more viruses or viral strains) or is an amount that reduces the severity of, or the length of time during which a subject suffers from, one or more symptoms of the infection (e.g., by at least 10%, 20%, or 30%, more preferably by at least 50%, 60%, or 70%, and most preferably by at least 80%, 90%, 95%, 99%, or more, relative to a control subject that is not treated with a composition of the invention).
  • a viral infection e.g., symptoms that result from infection by at least one and preferably two or more viruses or viral strains
  • an amount that reduces the severity of, or the length of time during which a subject suffers from, one or more symptoms of the infection e.g., by at least 10%, 20%, or 30%, more preferably by at least 50%, 60%, or 70%, and most
  • a sufficient amount of the pharmaceutical composition used to practice the methods described herein varies depending upon the manner of administration and the age, body weight, and general health of the subject being treated. A physician or researcher can decide the appropriate amount and dosage regimen.
  • genes refers to a nucleic acid molecule that either directly or indirectly encodes all or a portion of a nucleic acid or protein product that has a defined biological activity.
  • exemplary genes contained in the recombinant viral vector of the present invention include, e.g., genes that encode viral glycoproteins, capsid proteins, tegument proteins, and non-structural proteins, or fragments thereof.
  • glycoprotein is meant a glycoprotein polypeptide, in secreted or transmembrane -bound form, that is encoded by a virus, or any fragment or mutation of the glycoprotein polypeptide, so long as it has the ability to induce or enhance an immune response that confers a protective or therapeutic benefit to the subject, e.g., against a virus (e.g., a hemorrhagic fever virus).
  • a virus e.g., a hemorrhagic fever virus
  • the glycoprotein may also include any polypeptide or fragment thereof that is substantially identical (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or even 100% identical) to the viral glycoprotein over at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 or more contiguous residues.
  • inducing an immune response is meant eliciting a humoral response (e.g., the production of antibodies) or a cellular response (e.g., the activation of T cells) directed against two or more viruses or viral strains (e.g., two, three, four, or more viruses or viral strains) in a subject to which the pharmaceutical composition (e.g., a vaccine) has been administered.
  • a humoral response e.g., the production of antibodies
  • a cellular response e.g., the activation of T cells
  • composition any composition that contains a therapeutically or biologically active agent (e.g., at least one nucleic acid molecule that encodes all or part of two or more viral proteins (e.g., glycoproteins, capsid proteins, tegument proteins, or non- structural proteins) or all or a portion of at least two viral proteins (e.g., glycoproteins, capsid proteins, tegument proteins, or nonstructural proteins), either incorporated into a viral vector or independent of a viral vector) that is suitable for administration to a subject and that is capable of inducing an immune response against at least two different viruses (e.g., two, three, four, or more viruses).
  • a therapeutically or biologically active agent e.g., at least one nucleic acid molecule that encodes all or part of two or more viral proteins (e.g., glycoproteins, capsid proteins, tegument proteins, or non- structural proteins) or all or a portion of at least two viral proteins (e.g., glycoproteins
  • compositions suitable for delivering a therapeutic or biologically active agent can include, e.g., tablets, gelcaps, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels, hydrogels, oral gels, pastes, eye drops, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. Any of these formulations can be prepared by well-known and accepted methods of art. See, for example, Remington: The Science and Practice of Pharmacy (21 st ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2005, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick, Informa Healthcare, 2006, each of which is hereby incorporated by reference.
  • pharmaceutically acceptable diluent, excipient, carrier, or adjuvant is meant a diluent, excipient, carrier, or adjuvant which is physiologically acceptable to the subject while retaining the therapeutic properties of the pharmaceutical composition with which it is administered.
  • a pharmaceutically acceptable carrier is physiological saline.
  • physiologically acceptable diluents, excipients, carriers, or adjuvants and their formulations are known to one skilled in the art.
  • recombinant with respect to a viral vector, is meant a vector that includes all or a portion of a viral genome that has been incorporated into one or more delivery vehicles and that has been manipulated in vitro, e.g., using recombinant nucleic acid techniques to introduce changes to the viral genome (e.g., to include two or more heterologous viral nucleic acid sequences).
  • An example of a recombinant viral vector of the invention is a vector that includes all or part of the VSV genome and that includes a nucleic acid sequence that encodes all or part of, e.g., two or more heterologous viral gene products, such as glycoproteins of at least two different viruses or viral strains (e.g., the glycoproteins of at least two different hemorrhagic fever viruses) that are not endogenous to the viral genome of the viral vector.
  • subject is meant any animal, e.g., a mammal (e.g., a human).
  • a subject to be treated according to the methods described herein may be one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means. A subject in whom the development of an infection is being prevented may or may not have received such a diagnosis.
  • a subject to be treated according to the present invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors (e.g., exposure to at least two different viruses or viral strains).
  • one or more risk factors e.g., exposure to at least two different viruses or viral strains.
  • treating is meant administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • Prophylactic treatment may be administered, for example, to a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disorder, e.g., infection with at least two (and preferably three, four, or more) different viruses or viral strains (e.g., at least two different hemorrhagic fever viruses or viral strains).
  • Therapeutic treatment may be administered, for example, to a subject already suffering from a disorder in order to improve or stabilize the subject's condition (e.g., a subject already infected with at least one virus).
  • treating is the administration to a subject either for therapeutic or prophylactic purposes.
  • treatment may ameliorate a disorder or a symptom thereof by, e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • treating can result in the inhibition of viral infection by at least two (and preferably three, four, or more) different viruses or viral strains, the treatment of the infection(s), and/or the amelioration of symptoms (e.g., hemorrhagic fever) of the infection(s).
  • Confirmation of treatment can be assessed by detecting an improvement in the treated subject (e.g., the absence of symptoms in the subject), or by the inability to detect the presence of one or more viruses (e.g., one or more hemorrhagic fever viruses) in the treated subject.
  • an improvement in the treated subject e.g., the absence of symptoms in the subject
  • one or more viruses e.g., one or more hemorrhagic fever viruses
  • vacun is defined as material used to provoke an immune response and confer immunity after administration of the vaccine to a subject.
  • a "viral vector” is a composition that includes all or a portion of two or more (e.g., three, four, or more) viral genes from two or more different viruses or viral strains that is able to transmit the genetic information to a host or subject so that the host or subject can mount an immune response against the protein product of viral genes or against the nucleic acid encoding the viral genes.
  • the nucleic acid material of the viral vector may be encapsulated, e.g., in a lipid membrane or by structural proteins (e.g., capsid proteins) that may include one or more viral polypeptides (e.g., a glycoprotein).
  • the viral genes of the viral vector may include, e.g., a nucleic acid that encodes one or more polypeptides (e.g., glycoproteins, capsid proteins, tegument proteins, or non-structural proteins, or fragments thereof) of at least two (and preferably three, four, or more) different viruses or viral strains.
  • the viral vector can be used to infect cells of a subject, which, in turn, promotes the translation into a protein product of the viral genes of the viral vector (e.g., a glycoprotein).
  • the viral vector may also be, e.g., a pseudotyped virus that includes one or more of the polypeptides encoded by the genome of the virus.
  • the viral vector itself can be used to stimulate an immune response that is protective against infection by the virus(es) (e.g., two or more hemorrhagic fever viruses) or that treats infection by the virus(es).
  • the viral vector can be administered to a subject so that it infects one or more cells of the subject, which then promotes expression of the one or more viral genes of the viral vector and stimulates an immune response that is protective against infection by the virus(es) or that treats infection by the virus(es).
  • the term "virus,” as used herein, is defined as any virus that infects humans and any viral strains thereof.
  • Fig. 1 is a schematic diagram of the cloning sites in the pATX VSV ⁇ G4 vector.
  • Fig. 2 is a photograph of Vero E6 cells transfected with the pATX VSV ⁇ G4 vector. The figure shows Vero E6 cell cultures after blind passage of supernatant from primary transfected Vero E6 cells to fresh Vero E6 cells.
  • Figure 2A is a negative control.
  • Figure 2B is the positive rescue of the pATX VSV ⁇ G4 vector.
  • Fig. 3 is graph showing the results of a luciferase assay.
  • L luciferase gene
  • G VSV glycoprotein G gene
  • 1 to 4 exogenous gene position in pATX VSV ⁇ G4 vector
  • the invention described herein features compositions and methods for the treatment or inhibition of at least one virus (and preferably two or more (e.g., three, four, or more) different viruses or viral strains) using a recombinant viral vector that encodes and expresses all or a portion of one or more viral genes from two or more different viruses or viral strains.
  • the viral genes contained within the recombinant vector may be gene sequences (or fragments thereof) from different viruses or may be gene sequences (or fragments thereof) from different strains of the same virus.
  • Formulation of the vector as a vaccine would result in the production of multiple antigens, which would allow for broader protection against different viruses or different viral strains using a single vaccination approach.
  • compositions and methods of the invention may be used to treat or inhibit infection by two or more different viruses or viral strains.
  • exemplary human viruses include, e.g., hepatitis C virus, respiratory syncytial virus, Sindbis virus, poliovirus, hepatitis B virus, human papilloma virus, Epstein-Barr virus, adeno-associated virus, Venezuela encephalitis virus, Eastern equine encephalitis virus, smallpox virus, Norwalk virus, coronavirus, parainfluenza, rotavirus, rubella, coxsackevirus, enterovirus, hepatitis A virus, astrovirus, rabies virus, influenza virus A, influenza virus B, measles, mumps, La Crosse virus, California encephalitis virus, JC virus, BK virus, herpes simplex virus (type 1), herpes simplex virus (type two), human herpes simplex virus (type six), human herpes virus (type seven), human herpes virus
  • the compositions and methods are used to treat and inhibit infection by two or more different hemorrhagic fever viruses or viral strains.
  • Hemorrhagic fever viruses include, e.g., arenaviruses, filoviruses, bunyaviruses, and flaviviruses.
  • Exemplary arenaviruses include Lassa virus (e.g., Josiah, LP, and G A391 strains), Ippy virus, lymphocytic choriomeningitis virus,
  • Mobala virus Mopeia virus, Amapari virus, Flexal virus, Guanarito virus, Junin virus, Latino virus, Machupo virus, Oliveros virus, Parana virus, Pichinde virus, Pirital virus, Sabia virus, Tacaribe virus, Tamiami virus, and Whitewater Arroyo virus.
  • Exemplary filoviruses include Marburg virus (e.g., Angola, Ci67, Musoke, Popp, and Ravn strains) and Ebola virus (e.g., Ivory Coast, Reston, Sudan, Kenya, and Zaire strains).
  • Exemplary bunyaviruses include Hanta virus, Crimean-Congo hemorrhagic fever virus, Nairovirus (e.g., Dugbe virus), Orthobunyavirus (e.g., Bunyamwera virus), and Phlebovirus (e.g.. Rift Valley fever virus).
  • Exemplary flaviviruses include, e.g., Gadgets Gully virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus, tick- borne encephalitis virus, Louping ill virus, Meaban virus, Saumarez Reef virus, Tyuleniy virus, Aroa virus, Dengue virus, Kedougou virus, Cacipacore virus, Koutango virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St.
  • Louis encephalitis virus Usutu virus, West Nile virus, Yaounde virus, Kokobera virus, Bagaza virus, Ilheus virus, Israel turkey meningoencephalo-myelitis virus, Ntaya virus, Tembusu virus, Zika virus, Banzi virus, Bouboui virus, Edge Hill virus, Jugra virus, Saboya virus, Sepik virus, Kenya S virus, Wesselsbron virus, yellow fever virus, Entebbe bat virus, Yokose virus, acea virus, Cowbone Ridge virus, Jutiapa virus, Modoc virus, Sal Vieja virus, San Perlita virus, Bukalasa bat virus, Carey Island virus, Dakar bat virus, Montana myotis leukoencephalitis virus, Phnom Penh bat virus, and Rio Bravo virus.
  • compositions and methods described herein utilize viral genes or proteins to confer protection against pathogenic species of viruses.
  • the gene(s) present in the viral vector of the invention may encode or contain, e.g., one or more of a glycoprotein gene, capsid protein gene, tegument protein gene, or nonstructural protein gene, or a fragment thereof.
  • the viral proteins have the ability to induce or enhance an immune response that confers a protective or therapeutic benefit to the subject.
  • the gene or protein product may have a mutation or deletion (e.g., an internal deletion, truncation of the amino- or carboxy-terminal, or a point mutation), so long as the mutation or deletion does not interfere with the immune response elicited by the viral protein(s) upon administration of the viral vector.
  • the polypeptide or fragment encoded by the vector that is capable of eliciting an immune response may have 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 300, 400, 500, 600 or more amino acid residues.
  • Multiple genes e.g., genes not endogenous to the viral vector may be encoded by the viral vector of the present invention.
  • the vector may encode, e.g., two, three, four, or more genes (e.g., glycoprotein genes) from one or more different viruses (e.g., hemorrhagic fever viruses) or viral strains.
  • the vector may include two or more genes encoding different proteins from the same virus, from different viruses, or from different strains of the same virus.
  • the viral gene sequences expressed by the vector may be obtained by any suitable means, including, e.g., application of genetic engineering techniques to a viral source, chemical synthesis techniques, recombinant production, or any combination thereof.
  • the sequences of many viral genomes are published and nucleic acid sequences encoding viral proteins are available from a variety of sources, including, e.g., GenBank and PubMed (e.g., GenBank No. AF272001 for the ZEBOV Mayinga strain or GenBank No. Z12132 for the MARV Musoke strain).
  • GenBank accession numbers for exemplary viral sequences are listed in Table 1.
  • the invention described herein relates to a multivalent viral vector that expresses multiple viral genes (e.g., genes from at least two (and preferably three, four, or more) different hemorrhagic fever viruses or viral strains) for the inhibition or treatment of an infection caused by one or more viruses (e.g., different viruses, different strains of the same virus, or combinations thereof).
  • multiple viral genes e.g., genes from at least two (and preferably three, four, or more) different hemorrhagic fever viruses or viral strains
  • viruses e.g., different viruses, different strains of the same virus, or combinations thereof.
  • any suitable viral vector system can be used to construct the vector of the invention including, e.g., an adenovirus vector, a lentivirus vector, a rhabdovirus vector (e.g., vesicular stomatitis virus), or a poxvirus vector.
  • the viral vector contains at least two genes (and preferably three, four, or more genes) from at least two (and preferably three, four, or more) different viruses or viral strains that are not endogenous to the viral vector chosen as the delivery vehicle. These genes may encode, for example, glycoproteins, capsid proteins, tegument proteins, or nonstructural proteins or combinations or fragments thereof.
  • Expression of the viral genes is under the control of regulatory sequences that direct the expression of the genes in a cell (e.g., a host cell).
  • a cell e.g., a host cell.
  • Methods of constructing the viral vector and delivering the vector to a cell are known to one of skill in the art.
  • the sequence of the viral vector may be modified to decrease the cytopathogenicity (e.g., neurovirulence) of the vector upon its administration to a subject (e.g., in the form of a pharmaceutical composition).
  • the viral vector may contain a deletion of one or more gene sequences that are associated with cytopathogenicity (e.g., a glycoprotein or matrix protein) upon its expression.
  • the gene sequences encoding cytopathogenic viral proteins may contain mutations (e.g., substitutions, insertions, or deletions) that decrease the cytopathogenicity of one or more proteins encoded by the vector gene sequence.
  • Non-viral approaches can also be employed for the introduction of therapeutic nucleic acid molecules or proteins into cells to treat or prevent viral infection.
  • a glycoprotein, or nucleic acid molecule encoding the same, from a virus can be introduced into a cell by lipofection (see, e.g., Feigner et al., Proc. Natl. Acad. ScL USA 84:7413, 1987; Ono et al., Neuroscience Letters 17:259, 1990; Brigham et al., Am. J. Med.
  • Gene transfer can also be achieved by the use of calcium phosphate, DEAE dextran, electroporation, and protoplast fusion.
  • Liposomes, microparticles, or nanoparticles can also be potentially beneficial for delivery of a nucleic acid molecule or a protein (e.g., a gene that encodes a viral glycoprotein or the glycoprotein encoded thereby) into a cell or into a subject in order to stimulate an immune response against the nucleic acid molecule or polypeptide.
  • Treatment may be performed alone or in conjunction with another therapy, and may be provided, e.g., at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the therapy depends on the age and condition of the subject, the severity of the subject's infection, and how the subject responds to the treatment.
  • compositions utilized in the methods described herein can be administered by a route selected from, e.g., parenteral, dermal, transdermal, ocular, inhalation, buccal, sublingual, periungual, nasal, topical, and oral.
  • the preferred method of administration can vary depending on various factors (e.g., the components of the composition being administered and the severity of the condition being treated).
  • Formulations suitable for oral administration may consist of liquid solutions, such as an effective amount of the composition dissolved in a diluent (e.g., water, saline, or PEG-400), capsules, sachets or tablets, each containing a predetermined amount of the vaccine.
  • a diluent e.g., water, saline, or PEG-400
  • the pharmaceutical composition may also be an aerosol formulation for inhalation, e.g., to the bronchial passageways.
  • Aerosol formulations may be mixed with pressurized, pharmaceutically acceptable propellants (e.g., dichlorodifluoromethane, propane, or nitrogen).
  • compositions according to the invention described herein may be formulated to release the composition immediately upon administration (e.g., targeted delivery of the viral vector) or at any predetermined time period after administration using controlled or extended release formulations that will release the viral vector over time.
  • Administration of the pharmaceutical compositions (e.g., vaccines) of the present invention can be by any of the routes known to one of skill in the art. Administration may be by, e.g., intramuscular injection.
  • the compositions utilized in the methods described herein can also be administered by a route selected from, e.g., parenteral, dermal, transdermal, ocular, inhalation, buccal, sublingual, periungual, nasal, rectal, topical administration, and oral administration.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, and intramuscular administration.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the composition being administered and the severity of the condition being treated.
  • the composition may be administered as a vaccine (e.g., to inhibit, reduce, or prevent infection by one or more (e.g., two, three, four, or more) different viruses or viral strains) or after a subject has been exposed to a virus.
  • the composition may be administered, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 35, 40, 45, 50, 55, or 60 minutes post-exposure, or may be administered to the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 20, 24, 48, 72 hours, or longer after being exposed to a virus.
  • compositions of the invention are administered in such an amount as will be therapeutically effective, immunogenic, and/or protective against a pathogenic strain of a virus (e.g., at least 1 x 10 3 pfus/dose or between 1 x 10 1 and 1 x 10 8 pfus/dose).
  • the dosage administered depends on the subject to be treated (e.g., the manner of administration and the age, body weight, capacity of the immune system, and general health of the subject being treated).
  • the composition is administered in an amount to provide a sufficient level of expression that elicits an immune response without undue adverse physiological effects. A physician or researcher can decide the appropriate amount and dosage regimen.
  • compositions of the present invention may be given to a subject (e.g., one administration or administration two or more times).
  • subjects who are particularly susceptible to a viral infection may require multiple treatments to establish and/or maintain protection against the virus.
  • Levels of induced immunity provided by the pharmaceutical compositions described herein can be monitored by, e.g., measuring amounts of neutralizing secretory and serum antibodies. The dosages may then be adjusted or repeated as necessary to maintain desired levels of protection against viral infection.
  • an additional therapeutic agent may be administered with the pharmaceutical compositions described herein at concentrations known to be effective for such therapeutic agents.
  • Particularly useful therapeutic agents include, e.g., antiviral agents, immunostimulatory agents, and other immunization vaccines.
  • Additional therapeutic agents may be delivered separately or may be admixed into a single formulation together with the pharmaceutical composition.
  • agents may be present in different pharmaceutical compositions, different routes of administration may be employed.
  • the pharmaceutical composition and additional therapeutic agents are administered at least one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, fourteen days, or one month apart.
  • the dosage and frequency of administration of each component can be controlled independently.
  • the additional therapeutic agents described herein may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions of the present invention to a subject.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds, described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey.
  • a slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • the additional therapeutic regimen may involve other therapies, including modification to the lifestyle of the subject being treated.
  • Antiviral agents may be used as an additional therapeutic agent, either in combination with the vaccine or in a separate administration.
  • Exemplary antiviral agents are abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, atripla, brivudine, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, famciclovir, fixed dose combinations, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors, ganciclovir, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor
  • Immunostimulatory Agents may be significantly improved if the composition of the present invention is co-administered with an immunostimulatory agent or adjuvant.
  • immunostimulatory agents include aluminum phosphate, aluminum hydroxide, QS21, Quil A (and derivatives and components thereof), calcium phosphate, calcium hydroxide, zinc hydroxide, glycolipid analogs, octodecyl esters of an amino acid, muramyl dipeptides, polyphosphazene, lipoproteins, ISCOM matrix, DC-Choi, DDA, cytokines, and other adjuvants and derivatives thereof.
  • compositions of the present invention can be administered simultaneously, separately, or sequentially with other immunization vaccines, such as those for, e.g., influenza, malaria, tuberculosis, smallpox, measles, rubella, mumps, or any other vaccines known in the art.
  • immunization vaccines such as those for, e.g., influenza, malaria, tuberculosis, smallpox, measles, rubella, mumps, or any other vaccines known in the art.
  • a recombinant vesicular stomatitis virus (rVSV) vector lacking the glycoprotein (G) gene was constructed with two cloning sites (restriction sites for MIu 1 /Bin 1 and Xhol/Nhel) for foreign genes positioned between the matrix protein (M) gene and the polymerase (L) gene (see, e.g., Garbutt et al., J Virol. 78: 5458-65, 2004, and Jones et al., Nat Med. 1 1 : 786-90, 2005).
  • MCS matrix protein
  • N nucleoprotein
  • the MCS encoded restriction sites for two different restriction enzyme combinations (Acc651/Xmal and BsiWI/BstEII).
  • This vector (pATX VSV ⁇ G4) accommodated the insertion of four additional genes into the rVSV vector ( Figure 1).
  • Example 2 Evaluating gene expression of the pATX VSV ⁇ G4 vector
  • two genes at different positions within the vector were expressed, including the luciferase gene (as a simple and quantifiable assay of gene expression) and the VSV glycoprotein (VSVG) gene. Expression of VSVG allowed for the production of infectious viral particles. The rescue of the recombinant VSV particles was performed as previously described (see, e.g., Garbutt et al., J Virol. 78: 5458-5465, 2004). Following transfection of Vero E6 cells with the pATX VSV ⁇ G4 vector, cell cultures were screened for the appearance of a VSV-specific cytopathic effect ( Figure 2).
  • the rescued recombinant VSV vectors expressing the luciferase gene at various positions within the vector were quantified and analyzed for luciferase activity.
  • Vero E6 cells were infected with the different recombinant VSV vectors at a multiplicity of infection (MOI) of 1.
  • MOI multiplicity of infection
  • Analysis of the different recombinant viruses demonstrated a dramatic decrease in luciferase expression if a gene was cloned into position 2 of the vector, a position upstream of the nucleocapsid gene.
  • the highest level of luciferase expression was obtained by cloning the luciferase gene into position 3, a position downstream of the matrix protein gene ( Figure 3).
  • Multivalent VSV vaccines expressing hemorrhagic fever viral genes are constructed using any combination of up to four hemorrhagic fever viral genes (or fragments thereof).
  • the glycoprotein gene (GP) of three different species of Ebola virus e.g., the Zaire strain (ZEBOV), the Sudan strain (SEBOV), and the Ivory Coast strain (ICEBOV)
  • a single strain of Marburg virus e.g., the Musoke strain
  • Two glycoprotein genes can be cloned into positions 3 and 4 ( Figure 1) of the pATX VSV ⁇ G4 vector, as outlined in Table 2. Subsequently, either one or two additional glycoprotein genes can be cloned into positions 1 and 2 (Table 2). Cloning and rescue is performed as previously described for other recombinant VSV vectors (see, e.g., Garbutt et al., J Virol. 78: 5458-5465, 2004).
  • Cloning and rescue of the multivalent rVSV vectors are performed as previously described for other recombinant VSV vectors (see, e.g., Garbutt et al., J Virol. 78: 5458-5465, 2004). Following successful rescue, the different multivalent rVSV vectors are transfected into Vero E6 cells and other cell lines (e.g., primary macrophages or endothelial cells) and analyzed for their ability to induce viral growth. Depending on the number of exogenous genes in the vector and the position of the genes within the vector, it is expected that the resulting viruses will be attenuated in vitro.
  • a set of mutations is sequentially introduced into the M protein gene. Initially, the methionine residue at position 51 is deleted. The alteration of this residue has been shown to remove the inhibition of host gene expression that is normally seen during VSV infection, leading to decreased neurovirulence (Stojdl et al., Cancer Cell 4: 263-275, 2003; Cooper et al., J Virol. 82: 207-19, 2008). The incorporation of this mutation is labeled as delM51. The effect of altering four additional amino acids in the M protein (amino acid residues 121-124) is also monitored.

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Abstract

La présente invention concerne des compositions et des procédés destinés au traitement ou à l’inhibition d’un ou de plusieurs virus au moyen d’un vecteur viral recombinant qui code pour et exprime au moins un gène viral à partir de deux virus ou davantage. Les gènes viraux codés dans le vecteur viral recombinant peuvent être des séquences géniques provenant de différents virus ou peuvent être des séquences provenant de différentes souches du même virus.
PCT/US2009/001821 2008-03-25 2009-03-24 Vecteur de vaccin multivalent dans le traitement et l’inhibition d’infection virale WO2009120306A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107002079A (zh) * 2014-09-17 2017-08-01 衣阿华大学研究基金会 作为免疫调节剂和疫苗组分的病毒rna区段
CN107475294A (zh) * 2017-08-16 2017-12-15 四川农业大学 携带海肾荧光素酶的鸭坦布苏报告病毒的制备方法及其产品和应用
WO2018178593A1 (fr) * 2017-03-31 2018-10-04 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Composition d'immunoglobulines utiles pour traiter des infections virales
WO2020010474A1 (fr) * 2018-07-13 2020-01-16 UNIVERSITé LAVAL Glycoprotéine du virus ebola utilisée comme outil pour stimuler une réponse immunitaire
WO2024050498A3 (fr) * 2022-09-02 2024-04-11 International Aids Vaccine Initiative, Inc. Vaccin contre le virus de marburg et le virus de la stomatite vésiculaire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020155127A1 (en) * 2000-06-02 2002-10-24 Danher Wang Genetic vaccine against human immunodeficiency virus

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020155127A1 (en) * 2000-06-02 2002-10-24 Danher Wang Genetic vaccine against human immunodeficiency virus

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
DADDARIO-DICAPRIO K M ET AL: "Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment", LANCET THE, LANCET LIMITED. LONDON, GB, vol. 367, no. 9520, 29 April 2006 (2006-04-29), pages 1399 - 1404, XP025094029, ISSN: 0140-6736, [retrieved on 20060429] *
GARBUTT MICHAEL ET AL: "Properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses.", JOURNAL OF VIROLOGY MAY 2004, vol. 78, no. 10, May 2004 (2004-05-01), pages 5458 - 5465, XP002527147, ISSN: 0022-538X *
GEISBERT T W ET AL: "Vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with Ebola and Marburg viruses", VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 26, no. 52, 9 December 2008 (2008-12-09), pages 6894 - 6900, XP025711319, ISSN: 0264-410X, [retrieved on 20081018] *
GEISBERT THOMAS W ET AL: "Recombinant vesicular stomatitis virus vector mediates postexposure protection against Sudan Ebola hemorrhagic fever in nonhuman primates.", JOURNAL OF VIROLOGY JUN 2008, vol. 82, no. 11, June 2008 (2008-06-01), pages 5664 - 5668, XP002527153, ISSN: 1098-5514 *
GEISBERT THOMAS W ET AL: "Vesicular stomatitis virus-based ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates.", PLOS PATHOGENS NOV 2008, vol. 4, no. 11, November 2008 (2008-11-01), pages e1000225, XP002527160, ISSN: 1553-7374 *
HOLMAN D H ET AL: "Multi-antigen vaccines based on complex adenovirus vectors induce protective immune responses against H5N1 avian influenza viruses", VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 26, no. 21, May 2008 (2008-05-01), pages 2627 - 2639, XP022639507, ISSN: 0264-410X, [retrieved on 20080314] *
HOLMAN DAVID H ET AL: "Two complex, adenovirus-based vaccines that together induce immune responses to all four dengue virus serotypes.", CLINICAL AND VACCINE IMMUNOLOGY : CVI FEB 2007, vol. 14, no. 2, February 2007 (2007-02-01), pages 182 - 189, XP002527150, ISSN: 1556-6811 *
JONES STEVEN M ET AL: "Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses.", NATURE MEDICINE JUL 2005, vol. 11, no. 7, July 2005 (2005-07-01), pages 786 - 790, XP002527152, ISSN: 1078-8956 *
SCHEPP-BERGLIND JENNIFER ET AL: "Complex adenovirus-mediated expression of West Nile virus C, PreM, E, and NS1 proteins induces both humoral and cellular immune responses.", CLINICAL AND VACCINE IMMUNOLOGY : CVI SEP 2007, vol. 14, no. 9, September 2007 (2007-09-01), pages 1117 - 1126, XP002527149, ISSN: 1556-6811 *
SULLIVAN NANCY J ET AL: "Immune protection of nonhuman primates against Ebola virus with single low-dose adenovirus vectors encoding modified GPs.", PLOS MEDICINE JUN 2006, vol. 3, no. 6, June 2006 (2006-06-01), pages e177, XP002527151, ISSN: 1549-1676 *
SWENSON DANA L ET AL: "Vaccine to confer to nonhuman primates complete protection against multistrain Ebola and Marburg virus infections.", CLINICAL AND VACCINE IMMUNOLOGY : CVI MAR 2008, vol. 15, no. 3, March 2008 (2008-03-01), pages 460 - 467, XP002527148, ISSN: 1556-679X *
WANG D ET AL: "De novo syntheses of Marburg virus antigens from adenovirus vectors induce potent humoral and cellular immune responses", VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 24, no. 15, 5 April 2006 (2006-04-05), pages 2975 - 2986, XP025151807, ISSN: 0264-410X, [retrieved on 20060405] *
WANG ET AL: "Complex adenovirus-vectored vaccine protects guinea pigs from three strains of Marburg virus challenges", VIROLOGY, ACADEMIC PRESS,ORLANDO, US, vol. 353, no. 2, 30 September 2006 (2006-09-30), pages 324 - 332, XP005654108, ISSN: 0042-6822 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107002079A (zh) * 2014-09-17 2017-08-01 衣阿华大学研究基金会 作为免疫调节剂和疫苗组分的病毒rna区段
US10493141B2 (en) 2014-09-17 2019-12-03 The University Of Iowa Research Foundation Viral RNA segments as immunomodulatory agents and vaccine components
WO2018178593A1 (fr) * 2017-03-31 2018-10-04 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Composition d'immunoglobulines utiles pour traiter des infections virales
FR3064484A1 (fr) * 2017-03-31 2018-10-05 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Composition d'immunoglobulines utiles pour traiter des infections virales
CN107475294A (zh) * 2017-08-16 2017-12-15 四川农业大学 携带海肾荧光素酶的鸭坦布苏报告病毒的制备方法及其产品和应用
CN107475294B (zh) * 2017-08-16 2020-10-09 四川农业大学 携带海肾荧光素酶的鸭坦布苏报告病毒的制备方法及其产品和应用
WO2020010474A1 (fr) * 2018-07-13 2020-01-16 UNIVERSITé LAVAL Glycoprotéine du virus ebola utilisée comme outil pour stimuler une réponse immunitaire
WO2024050498A3 (fr) * 2022-09-02 2024-04-11 International Aids Vaccine Initiative, Inc. Vaccin contre le virus de marburg et le virus de la stomatite vésiculaire

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