US20110142877A1 - Use of a modified poxvirus for the rapid induction of immunity against a poxvirus or other infectious agents - Google Patents

Use of a modified poxvirus for the rapid induction of immunity against a poxvirus or other infectious agents Download PDF

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US20110142877A1
US20110142877A1 US11/892,479 US89247907A US2011142877A1 US 20110142877 A1 US20110142877 A1 US 20110142877A1 US 89247907 A US89247907 A US 89247907A US 2011142877 A1 US2011142877 A1 US 2011142877A1
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Paul Chaplin
Luis Mateo
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Bavarian Nordic AS
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/275—Poxviridae, e.g. avipoxvirus
    • A61K39/285—Vaccinia virus or variola virus
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates to the rapid induction of a protective immune response against poxviruses and poxvirus infections such as smallpox by vaccination of an animal, including a human, with a poxvirus that is replication incompetent in said animal, including the human.
  • a poxvirus is a Modified Vaccinia virus Ankara (MVA).
  • the invention further relates to the use of a recombinant poxvirus that is replication incompetent in the animal, including the human, that is vaccinated with the virus, such as a recombinant MVA expressing heterologous antigens and/or antigenic epitopes for a rapid induction of a protective immune responses against said heterologous antigen and/or antigenic epitope, e.g., against an antigen and/or antigenic epitope that is part of an infectious agent.
  • a recombinant poxvirus that is replication incompetent in the animal, including the human, that is vaccinated with the virus, such as a recombinant MVA expressing heterologous antigens and/or antigenic epitopes for a rapid induction of a protective immune responses against said heterologous antigen and/or antigenic epitope, e.g., against an antigen and/or antigenic epitope that is part of an infectious agent.
  • vaccines For many diseases, such as infectious diseases, vaccines have been developed or are in the process of being developed. These vaccines induce a protective immune response within a certain time frame. Since most vaccines are used for the vaccination against diseases that are rather rare in the population, there is usually no need that the generation of the immune response be particularly rapid. However, there are situations in which an immune response, such as a protective immune response, should be generated as fast as possible. This may be the case in an outbreak of smallpox or in any other human poxvirus disease.
  • the causative agent of smallpox is the variola virus, a member of the genus Orthopoxvirus.
  • Vaccinia virus also a member of the genus Orthopoxvirus in the family of Poxviridae, was used as a live vaccine to immunize against smallpox.
  • Successful worldwide vaccination with Vaccinia virus culminated in the eradication of variola virus (The global eradication of smallpox. Final report of the global commission for the certification of smallpox eradication; History of Public Health, No. 4, Geneva: World Health Organization, 1980).
  • most of the stocks of infectious variola viruses have been destroyed.
  • poxviruses, inducing smallpox or smallpox-like diseases might again become a major health problem.
  • there is a risk that a poxvirus disease of animals is spread to humans.
  • the invention encompasses the use of a poxvirus for the preparation of a vaccine for the rapid induction of a protective immune response in an animal, including a human, wherein the poxvirus is replication incompetent in said animal, including in the human.
  • the invention encompasses a method for the rapid induction of a protective immune response in an animal, including a human, comprising the step of administering to the animal, including the human, a poxvirus that is replication incompetent in said animal, including in the human.
  • the invention encompasses a use or method as above, wherein the protective immune response is generated within 7 days or less.
  • the poxvirus is a Modified Vaccinia virus Ankara (MVA), particularly MVA 575, MVA 572 and, preferably, MVA-BN®.
  • MVA Modified Vaccinia virus Ankara
  • the invention also encompasses uses or method as above, wherein the virus is a cloned, purified virus.
  • the invention encompasses viruses obtained in a serum free cultivation process.
  • the poxvirus is administered in a dose of 10 5 to 5 ⁇ 10 8 TCID 50 /ml.
  • the poxvirus can be administered intravenously, intramuscularly or subcutaneously.
  • the immune response is a protective immune response against a poxvirus infection, preferably, a smallpox infection.
  • the poxvirus is a recombinant poxvirus, preferably a recombinant MVA-BN.
  • the poxvirus can comprise at least one heterologous nucleic acid sequence.
  • the heterologous nucleic acid sequence is a sequence coding for at least one antigen, antigenic epitope, and/or a therapeutic compound.
  • the antigenic epitopes and/or the antigens can be antigenic epitopes and/or antigens of an infectious agent.
  • the infectious agents can be a viruses, fungi, pathogenic unicellular eukaryotic or prokaryotic organisms, and parasitic organisms.
  • the viruses can be selected from the family of Influenza virus, Flavivirus, Paramyxovirus, Hepatitis virus, Human immunodeficiency virus, or from viruses causing hemorrhagic fever.
  • the infectious agent can be bacillus anthracis.
  • the invention includes a method for inducing a immune response against an infectious agent in an animal comprising administering to the animal an immunogenic composition comprising an MVA, preferably MVA-BN, at 7 to 2, 6 to 2, 5 to 2, 4 to 2, 3 to 2, or any other combination of these days (i.e., 6 to 4, 6 to 3, 5 to 4, 5 to 3, etc.) prior to infection with an infectious agent.
  • the infectious agent is a replication competent poxvirus.
  • the animal is a human.
  • the invention further encompasses uses of the above methods and kits comprising an immunogenic composition comprising an MVA, preferably MVA-BN, and instructions to deliver the immunogenic composition at a time point between 7 and 2 days prior to exposure to an infectious agent, including 7, 6, 5, 4, 3, or 2 days prior to exposure.
  • an immunogenic composition comprising an MVA, preferably MVA-BN
  • instructions to deliver the immunogenic composition at a time point between 7 and 2 days prior to exposure to an infectious agent, including 7, 6, 5, 4, 3, or 2 days prior to exposure.
  • FIG. 1 Changes in body weight of differently vaccinated mice following an intranasal challenge with 1 ⁇ the MLD 50 of VV-WR.
  • BALB/c mice were vaccinated subcutaneously with MVA-BN® or saline (PBS), or by scarification with Elstree, Dryvax®. Mice were treated with Saline (PBS) or Elstree, Dryvax 4 days, or with MVA-BN® 3 days or 2 days prior to challenge with 4 ⁇ 10 6 TCID 50 /ml, 1 ⁇ 10 7 TCID 50 /ml, or 4 ⁇ 10 7 TCID 50 /ml VV-WR per mouse. Body weight was measured prior to challenge (day 0) and then daily post challenge at the same time each day. The graph represents the average body weight changes per group over time using normalized (day 0 as baseline value) individual values.
  • FIG. 2 Changes in body weight of differently vaccinated mice following an intranasal challenge with 12.5 ⁇ the MLD 50 of VV-WR.
  • BALB/c mice were vaccinated subcutaneously with MVA-BN® or saline (PBS), or by scarification with Elstree, Dryvax®. Mice were treated with Saline (PBS) or Elstree, Dryvax 4 days, or with MVA-BN® 3 days prior to challenge with 4 ⁇ 10 6 TCID 50 /ml, 1 ⁇ 10 7 TCID 50 /ml, or 4 ⁇ 10 7 TCID 50 /ml VV-WR per mouse. Body weight was measured prior to challenge (day 0) and then daily post challenge at the same time each day. The graph represents the average body weight changes per group over time using normalized (day 0 as baseline value) individual values.
  • FIG. 3 Changes in body weight of differently vaccinated mice following an intranasal challenge with 50 ⁇ the MLD 50 of VV-WR.
  • BALB/c mice were vaccinated subcutaneously with MVA-BN® or saline (PBS) or by scarification with Elstree, Dryvax®. Mice were treated with Saline (PBS) or Elstree, Dryvax 4 days, or with MVA-BN® 3 days prior to challenge with 4 ⁇ 10 6 TCID 50 /ml, 1 ⁇ 10 7 TCID 50 /ml, or 4 ⁇ 10 7 TCID 50 /ml VV-WR per mouse. Body weight was measured prior to challenge (day 0) and then daily post challenge at the same time each day. The graph represents the average body weight changes per group over time using normalized (day 0 as baseline value) individual values.
  • FIG. 4 Titers of the VV within the lungs following challenge.
  • BALB/c mice were vaccinated with a single administration of MVA-BN®, Elstree-BN, Dryvax, or treated with Saline (PBS).
  • PBS Saline
  • mice were challenged with either 1 ⁇ , 12.5 ⁇ , or 50 ⁇ MLD 50 of VV-WR per mouse.
  • the titers of VV-WR in the lungs were determined by a standard plaque assay 4 to 8 days post challenge and expressed at the man log 10 together with SEM.
  • FIG. 5 Comparison of antibody responses induced by MVA-BN®, Elstree-BN or Dryvax® immunizations.
  • Balb/c mice were vaccinated with a single administration of MVA-BN®, Elstree-BN or Dryvax.
  • Sera samples prepared on days 0 (pre-vaccination), 3, 4, 8, 12, 15 and 22 were analyzed by ELISA for vaccinia-specific IgG titers. The titers have been plotted as GMT together with the SEM.
  • FIG. 6 A-D Body weight loss and lung VV-WR titers in mice challenged with either 1 ⁇ (A & B) or 50 ⁇ (C & D) MLD 50 VV-WR on days 7 or 14 post-vaccination. Mice were vaccinated with either IMVAMUNE® (s.c.), Elstree-BN (scarification) or Dryvax® (scarification) and then challenged with either 1 ⁇ or 50 ⁇ MLD 50 VV-WR on day 7 or 14 post vaccination. Body weights were monitored and the animals sacrificed day 5 post challenge and the titers of VV-WR in the lungs were determined by a standard plaque assay.
  • the present invention relates to a method for the rapid induction of a protective immune response in an animal, including a human, comprising the step of administering to the animal, including the human, a poxvirus that is replication incompetent in said animal, including the human.
  • the invention further relates to the use of said replication incompetent poxvirus for the preparation of a vaccine for the rapid induction of a protective immune response, as well as to a poxvirus as vaccine for the rapid induction of a protective immune response, wherein the poxvirus is replication incompetent in said animal, including the human.
  • replication incompetent poxvirus and the synonymous term virus that is “not capable of being replicated to infectious progeny virus” both refer to poxviruses that do not replicate at all in the cells of the vaccinated animal, and to viruses that show a minor residual replication activity that is controlled by the immune system of the animal, including the human, to which the poxvirus is administered.
  • the replication incompetent poxviruses are viruses that are capable of infecting cells of the animal, including the human, in which the virus is used as vaccine.
  • Viruses that are “capable of infecting cells” are viruses that are capable of interacting with the host cells to such an extent that the virus, or at least the viral genome, becomes incorporated into the host cell.
  • the viruses used according to the present invention are capable of infecting cells of the vaccinated animal, including a human, they are either not capable of being replicated to infectious progeny virus in the cells of the vaccinated animal, or they show only a minor residual replication activity that is controlled by the immune system of the animal, including the human, to which the poxvirus is administered.
  • a virus that is capable of infecting cells of a first animal species but not capable of being replicated to infectious progeny virus in said cells may behave differently in a second animal species.
  • MVA-BN® and its derivatives are viruses that are capable of infecting cells of the human but that are not capable of being replicated to infectious progeny virus in human cells.
  • the same viruses are very efficiently replicated in chickens; i.e. in chickens, MVA-BN® is a virus that is capable of infecting cells and capable of being replicated to infectious progeny virus. It is known to the person skilled in the art which virus has to be chosen for a specific animal species.
  • a test that allows determining whether a virus is capable or not capable of being replicated in severely immunocompromised mice is disclosed in WO 02/42480 and uses the AGR129 mice strain (see below), or any other mouse strain that is incapable of producing mature B and T cells and as such is severely immune compromised and highly susceptible to a replicating virus. The results obtained in this mouse model are indicative for humans.
  • MVAs such as MVA-572 and MVA-575
  • MVA-572 is capable of killing severely immunocompromised mice.
  • the viruses according to the present invention are capable of being replicated in at least one type of cells of at least one animal species.
  • MVA-BN® that can be amplified in CEF (chicken embryo fibroblasts) cells but that is a virus that is not capable of being replicated to infectious progeny virus in humans.
  • Modified Vaccinia virus Ankara (MVA) is used in humans and several animal species, such as mice and non-human primates. MVA is known to be exceptionally safe. MVA has been generated by long-term serial passages of the Ankara strain of Vaccinia virus (CVA) on chicken embryo fibroblasts (for review see Mayr, A., Hochstein-Mintzel, V. and Stickl, H. [1975] Infection 3, 6-14; Swiss Patent No. 568, 392).
  • MVA virus strains that have been deposited in compliance with the requirements of the Budapest Treaty and that are useful in the practice of the present invention are strains MVA 572 deposited at the European Collection of Animal Cell Cultures (ECACC), Salisbury (UK) with the deposition number ECACC 94012707 on Jan. 27, 1994, MVA 575 deposited under ECACC 00120707 on Dec. 7, 2000, and MVA-BN® deposited with the number 00083008 at the ECACC on Aug. 30, 2000. Although MVA-BN is preferred to its higher safety (less replication competent), all MVAs are suitable for this invention.
  • ECACC European Collection of Animal Cell Cultures
  • UK Salisbury
  • MVA-BN® deposited with the number 00083008 at the ECACC on Aug. 30, 2000.
  • the MVA strain is MVA-BN® and its derivatives.
  • a definition of MVA-BN® and its derivatives is given in PCT/EP01/13628.
  • MVA-BN® and its derivatives as disclosed in PCT/EP01/13628 are characterized in having at least one, at least two, at least three or all of the following properties:
  • WO 02/42480 PCT/EP01/13628.
  • This publication also discloses how viruses having the desired properties can be obtained.
  • the person skilled in the art can test whether an MVA strain has one or more of said features and is, thus, a virus according to said embodiment of the present invention.
  • the following summary is not to be understood as to limit the relevance of WO 02/42480 for the present application to the following information. Instead, WO 02/42480 is herewith incorporated in its entirety by reference.
  • a virus that is “not capable of reproductive replication” in a cell line is a virus that shows an amplification ratio of less than 1 in said cell line.
  • the “amplification ratio” of a virus is the ratio of virus produced from an infected cell (Output) to the amount originally used to infect the cells in the first place (Input).
  • a ratio of “1” between Output and Input defines an amplification status wherein the amount of virus produced from the infected cells is the same as the amount initially used to infect the cells.
  • the viruses that are “not capable of reproductive replication” in human cell lines may have an amplification ratio of 1.0 (average value) or less, or even 0.8 (average value) or less, in any of the above human cell lines HeLa, HaCat and 143B.
  • average refers to the average values obtained from at least 2, but possibly 3, 4, 5, 6, 7, 8, 9, 10 or more experiments. It will be understood by a person skilled in the art that single experiments may deviate from average values due to the inherent variability of biological systems.
  • AGR 129 mice The mice used in WO 02/42480 are incapable of producing mature B- and T-cells (AGR 129 mice). MVA-BN® and its derivatives do not kill AGR129 mice within an average time period of at least 45 days (average value), such as within at least 60 days (average value), or within 90 days (average value) after the infection of the mice with 10 7 pfu virus administered intraperitonealy.
  • the viruses that show “failure to replicate in vivo” are further characterized in that no virus can be recovered from organs or tissues of the AGR129 mice 45 days (average value), alternatively 60 days (average value), and alternatively 90 days (average value), after the infection of the mice with 10 7 pfu virus administered intra peritonealy.
  • the AGR129 mice any other mouse strain can be used that is incapable of producing mature B and T cells, and as such is severely immune compromised and highly susceptible to a replicating virus.
  • the data obtained in said mouse model are predictive for humans.
  • the viruses of the present invention such as MVA-BN® and its derivatives, do not replicate at all in humans.
  • viruses that are within the scope of the present invention are those that show a minor residual replication activity that is controlled by the immune system of the human to which the poxvirus is administered.
  • mice die after the infection with replication competent vaccinia strains, such as the Western Reserve strain L929 TK+ and IHD-J.
  • the infection with replication competent vaccinia viruses is referred to as “challenge” in the context of description of the lethal challenge model.
  • the mice are usually killed and the viral titer in the ovaries is determined by standard plaque assays using VERO cells. The viral titer is determined for unvaccinated mice and for mice vaccinated with MVA-BN® and its derivatives.
  • MVA-BN® and its derivatives are characterized in that, in this test, after the vaccination with 10 2 TCID 50 /ml virus, the ovary virus titers are reduced by at least 70% (average value), alternatively by at least 80% (average value), alternatively by at least 90% (average value), compared to unvaccinated mice.
  • a vaccinia virus such as an MVA strain, is regarded as inducing at least substantially the same level of immunity in vaccinia virus prime/vaccinia virus boost regimes when compared to DNA-prime/vaccinia virus boost regimes if the CTL response as measured in one of the “assay 1” and “assay 2” as disclosed in WO 02/42480 is at least substantially the same in vaccinia virus prime/vaccinia virus boost regimes when compared to DNA-prime/vaccinia virus boost regimes.
  • the CTL response is at least substantially the same in vaccinia virus prime/vaccinia virus boost regimes when compared to DNA-prime/vaccinia virus boost regimes as measured in both of the “assay 1” and “assay 2” as disclosed in WO 02/42480.
  • the CTL response after vaccinia virus prime/vaccinia virus boost administration is higher in at least one of the assays, when compared to DNA-prime/vaccinia virus boost regimes.
  • the CTL response is higher in both assays.
  • the derivatives of MVA-BN® are characterized (i) in being capable of reproductive replication in chicken embryo fibroblasts (CEF) and in the Baby hamster kidney cell line BHK, but not capable of reproductive replication in human cell lines, wherein according to an embodiment of the present invention the human cell lines are the human bone osteosarcoma cell line 143B, the human keratinocyte cell line HaCat and the human cervix adenocarcinoma cell line HeLa; and (ii) by a failure to replicate in vivo in severely immune compromised mice.
  • CEF chicken embryo fibroblasts
  • BHK Baby hamster kidney cell line
  • the human cell lines are the human bone osteosarcoma cell line 143B, the human keratinocyte cell line HaCat and the human cervix adenocarcinoma cell line HeLa; and (ii) by a failure to replicate in vivo in severely immune compromised mice.
  • the virus is a cloned purified virus, such as a monoclonal virus.
  • the virus is a virus that has been produced/passaged under serum free conditions to reduce the risk of infections with agents contained in serum.
  • MVA according to the present invention is administered in a concentration range of 10 4 to 10 9 TCID50/ml, e.g. in a concentration range of e.g. 10 5 to 5 ⁇ 10 8 TCID 50 /ml or in a concentration range of e.g. 10 6 to 10 8 TCID 50 /ml.
  • concentration range depends on the type of the virus and the animal species to be vaccinated.
  • MVA-BN® a typical vaccination dose for humans comprises 5 ⁇ 10 7 TCID 50 to 5 ⁇ 10 8 TCID 50 , e.g. about 1 ⁇ 10 8 TCID 50 , administered subcutaneously.
  • the poxvirus as defined above e.g. an MVA strain, such as MVA-BN® and its derivatives is administered in a single administration to induce a rapid protective immune response.
  • Clinical data have shown that a single vaccination with MVA-BN® resulted in a detectable immune response in almost 100% of the vaccinated individuals.
  • the poxvirus as defined above e.g. an MVA strain, such as MVA-BN® and its derivatives may also be used in homologous prime boost regimes.
  • MVA-BN® e.g. MVA-BN®
  • the poxvirus as defined above e.g.
  • an MVA strain such as MVA-BN® and its derivatives may also be used in heterologous prime-boost regimes in which one or more of the vaccinations is done with a poxvirus as defined above and in with one or more of the vaccinations is done with another type of vaccine, e.g. another virus vaccine, a protein or a nucleic acid vaccine.
  • another type of vaccine e.g. another virus vaccine, a protein or a nucleic acid vaccine.
  • the mode of administration may be intravenously, intradermal, intranasal, or subcutaneously. Any other mode of administration may be used.
  • the poxvirus used according to the present invention may be a non-recombinant poxvirus such as an MVA strain, e.g. MVA-BN® and its derivatives.
  • the vaccination may be done to rapidly induce a protective immune response against a poxvirus infection such as smallpox.
  • the poxvirus as defined above such as an MVA strain, e.g. MVA-BN® and its derivatives is suitable to rapidly induce a protective immune response against smallpox.
  • MVA-BN® a strain according to the present invention
  • non-MVA strains such as Dryvax® and Elstree.
  • MVA-BN® clearly has improved properties compared to Elstee and Dyvax, in that a single vaccination of mice with MVA-BN® leads to a significant protective immune response, when the vaccination is administered within four, three and even two days before exposure to the pathogenic vaccinia virus strain. For example, this is demonstrated by assessing, in the mice's lungs, the titer of a pathogenic Vaccinia virus strain Western reserve (VV-WR) administered to a mouse two, three or four days after the vaccination with MVA-BN®.
  • VV-WR pathogenic Vaccinia virus strain Western reserve
  • mice When the mice were challenged with 12.5 ⁇ MLD 50 of VV-WR three days after the vaccination, no VV-WR viral titer could be detected in mice vaccinated with a standard dose of MVA-BN®, whereas the mice vaccinated with Dryvax® or Elstree were not protected and had a lung titer that was very similar to the titer of unvaccinated control mice.
  • mice When the mice were challenged with 50 ⁇ MLD 50 four days after the vaccination, no VV-WR viral titer could be detected in mice vaccinated with a standard dose of MVA-BN®, whereas the mice vaccinated with Dryvax® or Elstree were not protected and had a lung titer that was very similar to the titer of unvaccinated control mice.
  • MLD 50 refers to the concentration of a pathogenic Vaccinia virus strain at which 50% of the inoculated mice die.
  • mice data are predictive for humans. Moreover, it is to be taken into account that concentrations of a pathogenic virus that are 50 times the lethal dose usually do not occur in nature, in particular not for human poxviruses that induce smallpox.
  • the term “rapid induction of a protective immune response in an animal, including a human” refers preferably to the generation of a protective immune response within 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, or even 2 days or less, after the vaccination with a virus according to the present invention. This is unexpected since it was a dogma in the state of the art that it takes at least 10 to 14 days until a protective immune response is generated against traditional smallpox vaccines, based on replicating vaccinia virus strains. The rapidity of the induction of a protective immune response can be evaluated in the animal model described in the examples section. Said model is also predictive for humans.
  • a poxvirus vaccine is effective in inducing a rapid immune response in mice if after vaccination of mice with an effective dose of a poxvirus vaccine such as MVA, e.g. MVA-BN® and derivatives thereof, and challenge with 1 ⁇ , 12.5 ⁇ , and 50 ⁇ MLD 50 of VV-WR four days after vaccination, the lung titers of the virus are below an average of 5 ⁇ 10 3 pfu (corresponding to log 3.69), as determined in the test system described in the examples section.
  • MVA poxvirus vaccine
  • a poxvirus vaccine is effective in inducing a rapid immune response if the lung titer values are below an average of 5 ⁇ 10 3 pfu (corresponding to log 3.69) after a challenge with 1 ⁇ , and 12.5 ⁇ MLD 50 of VV-WR three days after vaccination with an effective dose of the poxvirus vaccine.
  • a virus leads to a rapid induction of a protective immune response in mice if said virus behaves similarly to MVA-BN® in the lung titer assay and the body weight assay described in the examples section.
  • the limits, threshold values, conditions and parameters as described in the examples section also apply in a general sense for other poxvirus vaccines that are regarded as rapid inducers of a protective immune response. From this, it is obvious that the data and information given in the examples section can be generally used to supplement any missing data and information in this paragraph, such as information relating to the description of the test system.
  • the rapidity of the induction of the protective immune response can be evaluated with the serum conversion test explained below; in this context, the time point at which seroconversion is observed is regarded as the time point at which the protective immune response was induced.
  • the animal including a human, is an animal that is naäve with respect to poxvirus infections, i.e. an animal that has never been in contact with poxviruses and that has not been vaccinated with poxvirus vaccines.
  • the animal including a human
  • the animal is an animal that was in contact with poxviruses and/or that was vaccinated with a poxvirus vaccine.
  • Such animal including a human, might have raised an immune response against poxviruses and/or poxvirus vaccines, such as MVA.
  • the term “protective immune response” means that the vaccinated animal is able to control an infection with the pathogenic agent against which the vaccination was done. Usually, the animal having developed a “protective immune response” develops only mild to moderate clinical symptoms or no symptoms at all. Usually, an animal having a “protective immune response” against a certain agent will not die as a result of the infection with said agent.
  • a concentration of MVA-BN® or a derivative thereof used for the generation of a protective immune response in humans against smallpox is in the range of 5 ⁇ 10 7 TCID 50 to 5 ⁇ 10 8 TCID 50 , such as 1 ⁇ 10 8 TCID 50 , wherein the virus may be administered subcutaneously or intramuscularly.
  • a poxvirus as defined above such as an MVA strain, e.g. MVA-BN® and its derivatives
  • MVA-BN® an MVA strain
  • its derivatives the mechanism of the development of a rapid immune protection after vaccination with a poxvirus as defined above, such as an MVA strain, e.g. MVA-BN® and its derivatives, depends on whether the vaccinated animal, including a human, is a naäve animal (that was never in contact with a poxvirus before) or an animal that had been in contact with a poxvirus before (e.g. by vaccination).
  • the administration of the poxvirus according to the present invention such as MVA-BN® or its derivatives efficiently primes the immune system, even if neutralizing antibodies may not be detectable in the first few days after vaccination (see Example 2).
  • the infection with a pathogenic virus boosts the immune system, in such way that the effectively primed immune system can control said infection unexpectedly effective and fast (see Example 2).
  • naäve animals that have been vaccinated with a virus according to the present invention are readily protected against the infection with the pathogenic virus against which the vaccination is done after a single vaccination only.
  • viruses as defined according to the present invention such as MVA-BN® and its derivatives also are unexpectedly efficient and fast in boosting the earlier vaccination in animals that have been in contact with a poxvirus before, so that a protective immune response is also rapidly generated in this situation.
  • the rapidity of the induction of a protective immune response is also reflected by an unexpectedly fast seroconversion after vaccination of animals, including humans, with a virus according to the present invention such as MVA, e.g. MVA-BN® and its derivatives.
  • MVA e.g. MVA-BN®
  • seroconversion occurs within less than 10 days, e.g. within 7 days, which is one week faster than the seroconversion after vaccination with other smallpox vaccines, such as Elstree.
  • MVA-BN® and its derivatives smallpox vaccines
  • the only modification that is required to assess the seroconversion induced by said other viruses is to quantify the total IgG antibodies specific for said other viruses, instead of quantifying the total MVA-BN® specific IgG antibodies.
  • the cut off values and the criteria to evaluate whether a sample is positive are determined in basically the same way, with optional minor modifications that are within the skills of the skilled artisan.
  • total MVA-BN® specific IgG antibodies are quantified in test sera using a direct Enzyme-Linked Immunosorbent Assay (ELISA). A detailed description of a study applying this method is provided in Example 2.
  • the ELISA is a sensitive method used for the detection of antibodies in sera.
  • the MVA-BN® specific ELISA is a standard binding ELISA used to detect total IgG antibodies in human test sera.
  • ELISA results are expressed as an end point antibody titer obtained by direct determination of logarithmic trend lines. A cut off, or end point absorbance of 0.35 has been defined.
  • the end point titer of the sample is determined by generating a logarithmic plot, e.g. by using the commercially available computer program Excel (expressing optical density (OD) on the y axis and the log of the sera dilution on the x axis). Again, the data in non-human primates are predictive for humans.
  • a test sample is deemed positive when the OD of the sample is greater than 0.35 at a 1:50 dilution of a test sample.
  • the geometric mean titer (GMT) is calculated by taking the antilogarithm of the mean of the log 10 titer transformations.
  • the GMT is usually the reported titer for ELISA titers.
  • Seroconversion rate is defined as percentage of initially seronegative subjects with appearance of antibody titers ⁇ 1:50 in the MVA-specific IgG ELISA.
  • the term “rapid induction of a protective immune response in an animal, including a human” refers to a seroconversion as defined above, with the test as defined above, within 10 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, or even 2 days or less, after the vaccination with a virus according to the present invention.
  • the poxvirus as defined above such as an MVA strain, e.g. MVA-BN® and its derivatives may also be a recombinant poxvirus strain such as recombinant MVA-BN® or its derivatives.
  • the recombinant viruses according to the present invention such as recombinant MVA-BN® and its derivatives, may contain at least one heterologous nucleic acid sequence.
  • heterologous is used hereinafter for any combination of nucleic acid sequences that is not normally found intimately associated with the virus in nature.
  • the heterologous sequences may be antigenic epitopes or antigens, which are selected from any non-vaccinia source.
  • said recombinant virus expresses one or more antigenic epitopes or antigens, which are antigenic epitopes or antigens from an infectious agent.
  • the infectious agent may be any infectious agent, such as a virus, a fungus, a pathogenic unicellular eukaryotic or prokaryotic organism, and a parasitic organism. Examples of infectious agents are Plasmodium falciparum, Mycobacteria, Influenza virus, Flaviviruses, Paramyxoviruses, Hepatitis viruses, Human immunodeficiency viruses, viruses causing hemorrhagic fever such as Hantaviruses or Filoviruses, i.e., Ebola and Marburg virus.
  • the infectious agent can be bacillus anthracis , which causes anthrax.
  • the recombinant poxvirus as defined above may not only be used to induce a rapid immune response against a poxvirus infection, but may also (or alternatively) be used to induce a rapid immune response against the heterologous antigenic epitope/antigen expressed from the heterologous nucleic acid comprised in the recombinant virus.
  • a recombinant MVA expresses an HIV epitope or a yellow fever virus epitope
  • the recombinant MVA may be used to induce a rapid immune response against HIV or Yellow fever virus, respectively.
  • the recombinant virus may alternatively express an antigenic epitope/antigen that further increases the immunogenicity of MVA.
  • the recombinant virus used according to the present invention may also comprise a heterologous gene/nucleic acid expressing a therapeutic compound.
  • a “therapeutic compound” encoded by the heterologous nucleic acid in the virus can be, for example, a therapeutic nucleic acid such as an antisense nucleic acid, or a peptide, or a protein with desired biological activity.
  • the expression of heterologous nucleic acid sequence may be under the transcriptional control of a poxvirus promoter.
  • a poxvirus promoter is the cowpox ATI promoter (see WO 03/097844).
  • the insertion of a heterologous nucleic acid sequence is done into a non-essential region of the virus genome.
  • the heterologous nucleic acid sequence is inserted at a naturally occurring deletion site of the MVA genome (disclosed in PCT/EP96/02926).
  • the heterologous sequence may be inserted into an intergenic region of the poxviral genome (see WO 03/097845). Methods on how to insert heterologous sequences into the poxviral genome are known to a person skilled in the art.
  • kits for the induction of a protective immune response comprises an immunogenic composition comprising an MVA and instructions for the delivery of the immunogenic composition.
  • the MVA is preferably MVA-BN.
  • the immunogenic composition contains 10 5 to 5 ⁇ 10 8 TCID 50 /ml of MVA.
  • the instructions for delivery of the immunogenic composition can direct the delivery at various time points prior to exposure to an infectious agent. These time points can include time points between 7 and 2 days prior to exposure to an infectious agent.
  • an “exposure” means contact with the infectious agent itself, or with an animal (human) harboring the infectious agent.
  • the time points can also include time points between 6 and 2 days, 5 and 2 days, 4 and 2 days, 3 and 2 days, and 2 days prior to exposure to an infectious agent.
  • the instructions can direct that the immunogenic composition can be delivered at 7, 6, 5, 4, 3, or 2 days prior to exposure to an infectious agent.
  • the infectious agent is smallpox or bacillus anthracis.
  • the instructions can direct that the MVA be administered MVA intravenously, intramuscularly, and/or subcutaneously.
  • mice are vaccinated with vaccines the efficiency of which is to be determined.
  • Control mice receive a saline control instead of the vaccine.
  • the mice are infected with a pathogenic Vaccinia virus strain, such as the vaccinia virus strain Western Reserve (VV-WR).
  • the murine lethal dose 50 (MLD 50 ) of the vaccinia virus strain Western Reserve (VV-WR) was determined to be 3.6 ⁇ 10 4 TCID 50 in unvaccinated mice.
  • the time required after vaccination to establish protection from a lethal challenge with VV-WR was investigated: challenging of MVA-BN®-vaccinated mice with a sub-lethal dose of VV-WR 3 days after the vaccination, revealed protection (with regard to body weight loss and viral lung titers).
  • the objective of this example was to narrow down the time required after MVA-BN® (or Elstree or Dryvax®) vaccination to obtain protection following a lethal challenge with VV-WR.
  • Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN®/IMVAMUNE®), in a concentration of 5.0E+08 TCID 50 /ml. Formulation: in 10 mM Tris 140 mM NaCl pH7.4.
  • Vaccinia virus strain Elstree with a nominal concentration of 1.0E+08 TCID 50 /ml. Formulation: in 10 mM Tris 140 mM NaCl pH7.4.
  • Dryvax® with a nominal concentration of 2.9E+07 TCID 50 /ml. Formulation: in 10 mM Tris 140 mM NaCl pH7.4.
  • test vaccines 1 to 3 were administered with its optimal dose and route of administration.
  • VV-WR Vaccinia Virus Western Reserve
  • mice H-2d Female Balb/c mice H-2d were obtained from Taconic M&B, P.O. Box 1079, DK-8680 Ry, Denmark. Number of animals in the study: 60. Age at initiation of challenge: 9 weeks. Body weight range at initiation of challenge: 18-23 grams.
  • the BALB/c mouse strain has been used extensively to test the immunogenicity and efficacy of smallpox vaccines. The strain is highly susceptible to VV-WR challenge.
  • Allocation to treatment groups On arrival, animals were randomly allocated to a treatment group consisting of 5 animals per test group (and cage).
  • MVA-BN® was used at an optimal dose that has been demonstrated in previous experiments to induce strong humoral and cell mediated immune responses in mice.
  • Elstree and Dryvax® were used at a dose suggested for humans.
  • mice were either challenged with 1 ⁇ , 12.5 ⁇ , or 50 ⁇ the MLD 50 of VV-WR, 4 days after vaccination with either MVA-BN®, or Elstree, or Dryvax®.
  • mice have been challenged with 1 ⁇ , 12.5 ⁇ , or 50 ⁇ the MLD 50 of VV-WR, 3 days after vaccination with MVA-BN®; or mice have been challenged with 1 ⁇ the MLD 50 of VV-WR, 2 days after vaccination with MVA-BN®.
  • mice have been challenged with 1 ⁇ , 12.5 ⁇ , or 50 ⁇ the MLD 50 of VV-WR, without prior vaccination.
  • Control animals receiving the 1 ⁇ and 12.5 ⁇ , or 50 ⁇ the MLD 50 of VV-WR were sacrificed 5 or 4 days after challenge, respectively, in case body weight loss exceeded 20% from initial body weight, or in case the animals suffered from dyspnea. This was done to reduce suffering.
  • Vaccinations were performed in a microbiological safety cabinet (SW 1000 40/class II, Holten Lamin Air). Mice were vaccinated with 200 ⁇ l of MVA-BN® (1 ⁇ 10 8 TCID 50 /ml) or Saline control (200 ⁇ l PBS) via the subcutaneous route in the skin wrinkle of the hind leg using a 1 ml 29 G tuberculin insulin syringe (Terumo).
  • mice receiving Elstree and Dryvax® were anaesthetized before the scarification of the tail: a fresh mixture containing 75 mg Ketamine, 5 mg Xylazine and water was prepared, and 80 ⁇ l of the anaesthetic was administered via the subcutaneous route using a 1 ml 27 G insulin syringe. All mice belonging to the same cage were anaesthetized before administering the vaccine. Subsequently, 2.5 ⁇ l or 8 ⁇ l of Elstree or Dryvax®, respectively, was applied via tail scarification.
  • test article i.e. VV-WR
  • SW 1000 40/class II, Holten Lamin Air a microbiological safety cabinet
  • a fresh mixture of 75 mg Ketamine, 5 mg Xylazine in water was prepared as anaesthetic. 80 ⁇ l of the anaesthetic was administered via the subcutaneous route using a 1 ml 29 G insulin syringe. All mice belonging to the same cage were anaesthetized before administering the VV-WR test article.
  • Intranasal challenge was performed in a microbiological safety cabinet (SW 1000 40/class II, Holten Lamin Air). The challenge virus working dilution was removed from the ice and mixed by gently vortexing for a few seconds. 50 ⁇ l of the diluted VV-WR test article was measured using a 100 ⁇ l pipette. Each anaesthetized mouse was held by the skin/fur on the back of the neck and the body was supported in the palm of the same hand. The test item was slowly added into a single nostril of each mouse. Each mouse was held as described above until the gasping ceased.
  • the saline group that received 50 ⁇ the MLD 50 of VV-WR exceeded the body weight cut off set by the Dyrefors ⁇ gstilsyn and was sacrificed on day 4 post challenge.
  • the saline groups that received 1 ⁇ or 12.5 ⁇ the MLD 50 of VV-WR exceeded the body weight cut off set by the Dyrefors ⁇ gstilsyn and were sacrificed on day 5 post challenge.
  • Vaccinated animals challenged with 1 ⁇ the MLD 50 of VV-WR were sacrificed on day 5 post challenge, whereas MVA-BN®-vaccinated animals challenged with 12.5 ⁇ or 50 ⁇ the MLD 50 of VV-WR were sacrificed latest on day 8 post challenge.
  • VV-WR vaccinia virus strain Western Reserve
  • mice vaccinated with MVA-BN® 3 days prior to challenge did not show any body weight loss following a challenge with 1 ⁇ the MLD 50 of VV-WR.
  • mice were challenged with 12.5 ⁇ the MLD 50 of VV-WR and body weight of the mice were again monitored prior to challenge and then daily post challenge.
  • body weight loss in the group of non-vaccinated (Saline control) mice was first detectable 2 days after the challenge. The body weight continued to drop until sacrifice on day 5 to an average of 23.3% below the average initial body weight. Thus, the body weight loss was detectable one day earlier than in the non-vaccinated group challenged with 1 ⁇ the MLD 50 of VV-WR, and was more pronounced on the day of sacrifice (see FIG. 1 ).
  • a body weight loss similar to that shown by the non-vaccinated mice was detected in the groups vaccinated with Elstree or Dryvax® 4 days prior to challenge with VV-WR.
  • a first small body weight loss (about 1.7% from average initial body weight) was detected 2 days post challenge.
  • the average body weight continued to drop in this group until day 4 post challenge, with an average body weight of 16.1% below the initial one. Thereafter, the average body weight started to recover in this group, and on day 8 post challenge an average body weight that was 2.3% below the average initial body weight was detected.
  • mice vaccinated with MVA-BN® 4 days prior to challenge an average body weight loss of 10.8% compared to the average initial body weight was detected on day 2 post challenge.
  • a maximal average body weight loss of 13.8% was detected on day 3 post challenge.
  • Recovery of body weight was detected on the subsequent days with a similar average body weight detected 8 days post challenge than that detected prior to challenge.
  • mice were challenged with 50 ⁇ the MLD 50 of VV-WR and the body weight of the mice was again monitored prior to challenge and then daily post challenge.
  • a first body weight loss in the group of non-vaccinated (Saline control) mice was already detectable 1 day post challenge.
  • the average body weight continued to drop until sacrifice on day 4 to 20.1% below the average initial body weight.
  • the body weight loss was detectable 2 days or 1 day earlier than that in the non-vaccinated group challenged with 1 ⁇ or 12.5 ⁇ the MLD 50 of VV-WR, respectively.
  • the body weight loss in the groups vaccinated with Elstree or Dryvax® started to be detectable 2 days post challenge, and by day 4 post challenge the mice in these groups revealed an average body weight loss of 20.1% or 19.7% from the initial body weight, respectively.
  • the first body weight loss (about 1.6% from average initial body weight) was detected the first day post challenge.
  • the average body weight continued to drop in this group until sacrifice on day 4 post challenge, with an average body weight of 24.0% below the initial one.
  • mice vaccinated with MVA-BN® 4 days prior to challenge a first body weight loss was detectable on the first day post challenge, and the average body weight continued to drop to 22.5% below the average initial body weight on day 4 post challenge. Recovery of body weight was detected on subsequent days, and on day 8 post challenge an average body weight was detected that was 5.1% below the average initial one.
  • mice After death or sacrifice of mice, lungs were removed and the total amount of virus in this tissue was determined using a standard plaque assay on Vero cells. Animals were considered completely protected when lung titers were below log 10 3.69 (5 ⁇ 10 3 pfu), the lowest titer detectable using our method of virus titration on Vero cells.
  • mice challenged with 1 ⁇ the MLD 50 of VV-WR were compared.
  • non-vaccinated mice revealed an average virus load of log 10 7.81.
  • Mice vaccinated with Elstree or Dryvax® 4 days prior to challenge revealed an average lung virus load of log 10 7.75 and log 10 6.68.
  • the Elstree vaccinated mice were unable, and the Dryvax® vaccinated mice were only to some degree able, to prevent lung viral infection.
  • mice challenged with 12.5 ⁇ the MLD 50 of VV-WR were compared.
  • non-vaccinated mice revealed an average virus load of log 10 8.38.
  • Mice vaccinated with Elstree or Dryvax® 4 days prior to challenge revealed an average lung virus load of log 10 8.17 and log 10 8.00.
  • the Elstree and the Dryvax® vaccinated mice were unable to prevent lung viral infection.
  • the group of mice vaccinated with MVA-BN® 4 or 3 days prior to challenge no lung viral titers could be detected and these mice are thus completely protected from viral infection following intranasal challenge with 12.5 ⁇ the MLD 50 of VV-WR.
  • mice challenged with 50 ⁇ the MLD 50 of VV-WR were compared.
  • non-vaccinated mice revealed an average virus load of log 10 8.59.
  • Mice vaccinated with Elstree or Dryvax® 4 days prior to challenge revealed an average lung virus load of log 10 8.49 and log 10 8.25.
  • the Elstree and the Dryvax® vaccinated mice were unable to prevent lung viral infection.
  • MVA-BN® no lung viral titers was detected when vaccination was administered 4 days prior to challenge. Consequently, these mice are protected from viral infection following intranasal challenge with 50 ⁇ the MLD 50 of VV-WR.
  • an average lung viral load of log 10 7.63 was determined. Thus, this group is only to some degree protected from viral infection.
  • Example 1 recovery from body weight loss as well as viral lung titers have been determined to indicate “protection” from a lethal intranasal challenge with VV-WR.
  • the smallpox vaccine candidate IMVAMUNETM (MVA-BN®) was able to protect against an intranasal challenge with up to 50 ⁇ the MLD 50 of VV-WR. This protection was associated with recovery of body weight after initial body weight loss and was also associated with lack of virus in the lungs.
  • the higher the challenge dose of VV-WR the longer the post challenge period required for body weight recovery in the mice vaccinated 4 days prior to the challenge with MVA-BN®. Indeed, when challenged with 12.5 ⁇ the MLD 50 of VV-WR body weight recovery was detected on day 4 post challenge, whereas body weight recovery was detected on day 5 post challenge when mice have been challenged with 50 ⁇ the MLD 50 of VV-WR.
  • MVA-BN® MVA-BN®
  • Elstree and Dryvax® were unable to protect against an intranasal challenge with up to 50 ⁇ the MLD 50 of VV-WR when administered 4 days prior to the challenge.
  • MVA-BN® was administered to mice (and is administered in clinical trials to humans) subcutaneously
  • Elstree and Dryvax® was administered to mice (and is administered in clinical trials to humans) via scarification.
  • Example 1 clearly demonstrates the superiority of MVA-BN® over Elstree and Dryvax® with regard to onset of immune protection.
  • Example 2 summarises a series of studies that have investigated the onset of protection afforded by various smallpox vaccines, including MVA-BN®, using the VV challenge model in mice. as assessed by measurements of vaccinia-specific IgG titers, in addition to body weight and lung titers.
  • Test System was as described above in Example 1.
  • mice were challenged with either 1 ⁇ , 12.5 ⁇ or 50 ⁇ the MLD 50 of VV-WR either 7 or 14 days after a single subcutaneous (s.c.) administration of either Saline (s.c.) or MVA-BN®.
  • s.c. subcutaneous
  • MVA-BN® MVA-BN®
  • other groups were vaccinated with either Dryvax® or Elstree-BN by tail scarification.
  • Control animals receiving VV-WR challenge were sacrificed 4 or 5 days after challenge when the mean body weight loss exceeded 20% from initial body weight, or when the animals suffered from dyspnea.
  • Blood (100-150 ⁇ l) from the individual mice was collected prior to the first vaccine or saline administration and at varying intervals throughout the respective study prior to and post-challenge with VV-WR. Respective study sera sample time points are indicated in the results section.
  • the blood was collected, and separated using MicrotainerTM serum separation tubes according to the manufacturer's instructions (Becton Dickinson). The tubes containing sera from each mouse were labelled and stored below ⁇ 15° C. until required for ELISA analysis to determine vaccinia specific IgG titers.
  • Lungs were harvested at the end of the observation period post-challenge and placed into 5 ml of DMEM tissue culture medium (Invitrogen) supplemented with 100 U penicillin/100 ⁇ g/ml streptomycin (Sigma) and 2% foetal bovine serum, FBS (PAA).
  • the tubes containing lungs from each mouse were labelled using appropriate computer printed adhesive labels and stored below ⁇ 15° C. until required for use in a Vero cell plaque assay to determine VV-WR viral lung titer.
  • Vaccinia-specific IgG ELISA titers were determined from serum samples as described in SOP/PRE/005.
  • the antibody titers (log 10) were calculated by linear regression (OD on the y-axis and log of the sera dilution on the x-axis) and defined as the serum dilution that resulted in an optical density (OD 492 nm) of 0.3.
  • the regression analysis was performed using the Magread Macro software as described in SOP/IMM/028. Assay acceptance criteria of OD ⁇ 0.20 and OD>1.0 have been defined for the negative and positive samples respectively.
  • the mean antibody titers were illustrated as Geometric Mean Titer (GMT), together with the SEM.
  • VV-WR viral titers from the prepared lungs were determined by virus titration on Vero cells as described in SOP/PRE/001. Plaque numbers were counted using photographic images of the plates and a computerised system (Zeiss Imaging System). The resulting plaque counting raw data were automatically inserted into an Excel spread sheet that was then used to calculate viral titer as Log 10 PFU (plaque forming units). For summarizing the generated data, the calculated viral titers were manually inserted into a further (Excel) template. For assay acceptance, the positive control sample had to generate plaque numbers ⁇ 150/well in the 6400 ⁇ dilution. The detection limit of the assay was Log 10 3.69.
  • Microsoft Excel 2000 was used to generate templates for data documentation. Appropriate raw data was entered manually into the printed templates and then attached to laboratory notebooks. Manually entered data was then transferred into Excel for analysis (e.g. calculation of average values, SEMs and GMTs).
  • Body weight (in grams) was monitored prior to challenge (Day 0) and daily post challenge. Changes in body weight for the post-challenge period were calculated in % using Microsoft Excel for the individual mice. The average change for each group +/ ⁇ the standard error was calculated for each time point post challenge. Lung VV-WR and sera vaccinia IgG titers (as log 10 titers) were expressed as average +/ ⁇ standard error per test group. Body weight and lung titer data sets were illustrated graphically using Microsoft Excel.
  • mice vaccinated with MVA-BN® generate an equivalent immune response to traditional smallpox vaccines
  • time course studies have revealed that the immune response is induced faster following MVA-BN®, compared to the traditional vaccines.
  • the antibody responses induced by the various smallpox vaccines were compared for up to 22 days post vaccination, and to overcome the problem of vaccine take failures, 5 animals vaccinated with MVA-BN® were compared (at certain time points) to groups sizes of 25 and 21 for Elstree-BN and Dryvax® respectively.
  • Example 1 demonstrated the superiority of MVA-BN® over traditional vaccines Elstree and Dryvax® in affording protection from viral challenges given at days 2, 3, or 4 post-vaccination.
  • additional studies were performed whereby vaccinated animals were challenged with either a low (1 ⁇ MLD 50 ) or standard (50 ⁇ MLD 50 ) challenge dose at 7 or 14 days post vaccination.
  • the placebo treated groups had a mean body weight loss of ⁇ 24% 5 days post challenge (1 ⁇ MLD 50 ), with a mean VV titer in the lung of log 10 7.62 pfu ( FIG.
  • the group of placebo treated animals challenged (50 ⁇ MLD 50 ) 14 days post vaccination had a mean body weight loss of 21% by day 4 post challenge at which time point they were sacrificed due to the ethical constraints (weight loss not to exceed 20%).
  • the placebo animals recorded a mean VV-WR titer of log 10 8.49 pfu in their lungs ( FIG. 6D ).
  • all the animals vaccinated once with MVA-BN® were fully protected 7 or 14 days post vaccination, as these animals had completely cleared the challenge VV from their lungs 5 days post challenge ( FIG. 6B and FIG. 6D ).
  • Antibodies are not detected in MVA-BN®-vaccinated mice by ELISA until day 7 to day 10 post vaccination, and even later for mice vaccinated with traditional smallpox vaccines. Therefore, in an attempt to better understand the protective mechanism observed, particularly in the MVA-BN® treated animals, blood was analyzed after the challenge period for total IgG titers specific against vaccinia by ELISA.
  • the remaining 4 protected animals all had detectable antibodies following challenge, with a GMT of 282.
  • the 4 animals vaccinated with Dryvax® that were protected when challenged (50 ⁇ MLD 50 ) 14 days following vaccination also all had a detectable antibody response post challenge. Again the one non-protected animal had a lung titer of log 10 7.87 and had no detectable antibodies following challenge.
  • all the MVA-BN® vaccinated animal that were challenged (1 ⁇ MLD 50 ) 2 days post treatment had detectable antibodies (GMT of 106) following challenge and were un-protected with a mean log 10 titer of 4.68.
  • Lung titers are expressed as log10 +/ ⁇ the standard deviation from the mean. Statistical significance from the saline control is indicated by * and ** for p ⁇ 0.05 and 0.01 respectively.
  • b Total IgG titers of 1 were assigned when the absorbance at a 1:50 starting dilution was below 0.3.
  • c Control mice were sacrificed on day 4 post challenge. Vaccinated mice were sacrificed on day 4 or 5 post challenge. Lung viral load determined by plaque assay.
  • d Mice were sacrificed on day 8 post challenge. e Lung titers were statistically different from MVA-BN vaccinated groups with no virus detected in the lungs (p ⁇ 0.01)
  • MVA-BN® fails to replicate, this allows a much higher dose to be administered in one injection. Again without being bound by a specific theory, this allows for a rapid induction of B and T cells, because following a s.c. injection MVA-BN® will travel directly to the draining lymph nodes, the sites of specific immune induction, allowing the direct stimulation of the immune system.
  • traditional smallpox vaccines rely on administering a small quantity (dose) of the virus to the skin, which subsequently needs to replicate (leading to the formation of a pustule) in order to stimulate the immune system to induce the same immune response as MVA-BN®; a process that takes longer than a bolus injection of MVA.
  • MVA-BN® vaccinated animals could protect by day 4 post challenge, but not by day 3 at the same challenge dose (50 ⁇ MLD 50 ), whereas at the lower challenge doses (1 ⁇ & 12 ⁇ MLD 50 ), MVA-BN® could afford protection a day earlier (day 3).
  • the unprotected animals failed to mount an immune response and had not sera-converted after the challenge.
  • Examples 1 and 2 have shown that MVA-BN® (IMVAMUNE®) is superior at inducing a protective immune response in animal models compared to Dryvax®.

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US10183986B2 (en) 2005-12-15 2019-01-22 Industrial Technology Research Institute Trimeric collagen scaffold antibodies
AU2007307080B2 (en) 2006-10-06 2014-01-09 Bavarian Nordic A/S Methods for treating cancer with MVA
EP2111869A1 (en) 2008-04-23 2009-10-28 Stichting Sanquin Bloedvoorziening Compositions and methods to enhance the immune system
US10653766B2 (en) 2014-03-12 2020-05-19 Bavarian Nordic A/S Use of oil and water emulsions for increasing B cell responses with modified Vaccinia Ankara virus
FR3042121A1 (fr) 2015-10-08 2017-04-14 Jean-Marc Limacher Composition anti-tumorale

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