Preclinical Evaluation of a Replication-Deficient Intranasal ΔNS1 H5N1 Influenza Vaccine
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{"title"=>"Preclinical evaluation of a replication-deficient intranasal ΔNS1 H5N1 influenza vaccine", "type"=>"journal", "authors"=>[{"first_name"=>"Julia", "last_name"=>"Romanova", "scopus_author_id"=>"6603602138"}, {"first_name"=>"Brigitte M.", "last_name"=>"Krenn", "scopus_author_id"=>"55904766300"}, {"first_name"=>"Markus", "last_name"=>"Wolschek", "scopus_author_id"=>"6602496673"}, {"first_name"=>"Boris", "last_name"=>"Ferko", "scopus_author_id"=>"6602073007"}, {"first_name"=>"Ekaterina", "last_name"=>"Romanovskaja-Romanko", "scopus_author_id"=>"26967934200"}, {"first_name"=>"Alexander", "last_name"=>"Morokutti", "scopus_author_id"=>"8922757300"}, {"first_name"=>"Anna Polina", "last_name"=>"Shurygina", "scopus_author_id"=>"6506174202"}, {"first_name"=>"Sabine", "last_name"=>"Nakowitsch", "scopus_author_id"=>"9337903900"}, {"first_name"=>"Tanja", "last_name"=>"Ruthsatz", "scopus_author_id"=>"26424027200"}, {"first_name"=>"Bettina", "last_name"=>"Kiefmann", "scopus_author_id"=>"32667781200"}, {"first_name"=>"Ulrich", "last_name"=>"König", "scopus_author_id"=>"26967786500"}, {"first_name"=>"Michael", "last_name"=>"Bergmann", "scopus_author_id"=>"35419805000"}, {"first_name"=>"Monika", "last_name"=>"Sachet", "scopus_author_id"=>"6603436583"}, {"first_name"=>"Shobana", "last_name"=>"Balasingam", "scopus_author_id"=>"8920459000"}, {"first_name"=>"Alexander", "last_name"=>"Mann", "scopus_author_id"=>"7201626336"}, {"first_name"=>"John", "last_name"=>"Oxford", "scopus_author_id"=>"7102877671"}, {"first_name"=>"Martin", "last_name"=>"Slais", "scopus_author_id"=>"32667981000"}, {"first_name"=>"Oleg", "last_name"=>"Kiselev", "scopus_author_id"=>"7005690458"}, {"first_name"=>"Thomas", "last_name"=>"Muster", "scopus_author_id"=>"7003689220"}, {"first_name"=>"Andrej", "last_name"=>"Egorov", "scopus_author_id"=>"7202362147"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"doi"=>"10.1371/journal.pone.0005984", "issn"=>"19326203", "scopus"=>"2-s2.0-67650113035", "pui"=>"354877202", "sgr"=>"67650113035"}, "id"=>"b765883b-79c8-3c43-8a79-f67c233ac010", "abstract"=>"Background: We developed a novel intranasal influenza vaccine approach that is based on the construction of replication-deficient vaccine viruses that lack the entire NS1 gene (?NS1 virus). We previously showed that these viruses undergo abortive replication in the respiratory tract of animals. The local release of type I interferons and other cytokines and chemokines in the upper respiratory tract may have a \"self-adjuvant effect\", in turn increasing vaccine immunogenicity. As a result, ?NS1 viruses elicit strong B- and T- cell mediated immune responses. Methodology/Principal Findings: We applied this technology to the development of a pandemic H5N1 vaccine candidate. The vaccine virus was constructed by reverse genetics in Vero cells, as a 5:3 reassortant, encoding four proteins HA, NA, M1, and M2 of the A/Vietnam/1203/04 virus while the remaining genes were derived from IVR-116. The HA cleavage site was modified in a trypsin dependent manner, serving as the second attenuation factor in addition to the deleted NS1 gene. The vaccine candidate was able to grow in the Vero cells that were cultivated in a serum free medium to titers exceeding 8 log10 TCID50/ml. The vaccine virus was replication deficient in interferon competent cells and did not lead to viral shedding in the vaccinated animals. The studies performed in three animal models confirmed the safety and immunogenicity of the vaccine. Intranasal immunization protected ferrets and mice from being infected with influenza H5 viruses of different clades. In a primate model (Macaca mulatta), one dose of vaccine delivered intranasally was sufficient for the induction of antibodies against homologous A/Vietnam/1203/04 and heterologous A/Indonesia/5/05 H5N1 strains. Conclusion/Significance: Our findings show that intranasal immunization with the replication deficient H5N1 ?NS1 vaccine candidate is sufficient to induce a protective immune response against H5N1 viruses. This approach might be attractive as an alternative to conventional influenza vaccines. Clinical evaluation of ?NS1 pandemic and seasonal influenza vaccine candidates are currently in progress. ? 2009 Romanova et al.", "link"=>"http://www.mendeley.com/research/preclinical-evaluation-replicationdeficient-intranasal-%CE%B4ns1-h5n1-influenza-vaccine", "reader_count"=>5, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>2, "Medicine and Dentistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

Scopus | Further Information

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  • {"files"=>["https://ndownloader.figshare.com/files/442802"], "description"=>"<div><h3>Background</h3><p>We developed a novel intranasal influenza vaccine approach that is based on the construction of replication-deficient vaccine viruses that lack the entire NS1 gene (ΔNS1 virus). We previously showed that these viruses undergo abortive replication in the respiratory tract of animals. The local release of type I interferons and other cytokines and chemokines in the upper respiratory tract may have a “self-adjuvant effect”, in turn increasing vaccine immunogenicity. As a result, ΔNS1 viruses elicit strong B- and T- cell mediated immune responses.</p><h3>Methodology/Principal Findings</h3><p>We applied this technology to the development of a pandemic H5N1 vaccine candidate. The vaccine virus was constructed by reverse genetics in Vero cells, as a 5∶3 reassortant, encoding four proteins HA, NA, M1, and M2 of the A/Vietnam/1203/04 virus while the remaining genes were derived from IVR-116. The HA cleavage site was modified in a trypsin dependent manner, serving as the second attenuation factor in addition to the deleted NS1 gene. The vaccine candidate was able to grow in the Vero cells that were cultivated in a serum free medium to titers exceeding 8 log<sub>10</sub> TCID<sub>50/</sub>ml. The vaccine virus was replication deficient in interferon competent cells and did not lead to viral shedding in the vaccinated animals. The studies performed in three animal models confirmed the safety and immunogenicity of the vaccine. Intranasal immunization protected ferrets and mice from being infected with influenza H5 viruses of different clades. In a primate model (<em>Macaca mulatta</em>), one dose of vaccine delivered intranasally was sufficient for the induction of antibodies against homologous A/Vietnam/1203/04 and heterologous A/Indonesia/5/05 H5N1 strains.</p><h3>Conclusion/Significance</h3><p>Our findings show that intranasal immunization with the replication deficient H5N1 ΔNS1 vaccine candidate is sufficient to induce a protective immune response against H5N1 viruses. This approach might be attractive as an alternative to conventional influenza vaccines. Clinical evaluation of ΔNS1 pandemic and seasonal influenza vaccine candidates are currently in progress.</p></div>", "links"=>[], "tags"=>["preclinical", "replication-deficient", "intranasal", "h5n1", "influenza"], "article_id"=>147260, "categories"=>["Cancer", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Preclinical_Evaluation_of_a_Replication_Deficient_Intranasal_NS1_H5N1_Influenza_Vaccine/147260", "title"=>"Preclinical Evaluation of a Replication-Deficient Intranasal ΔNS1 H5N1 Influenza Vaccine", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 02:01:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/893408"], "description"=>"<p>HBE cells were infected with VN1203ΔNS1 or VN1203 at moi 5. At 6 and 24 h p.i. supernatants were collected. The level of secreted IFN was determined by a bioassay based on the A549 cell line that was stably transfected with a luciferase reporter gene under the control of the MxA promoter. As a control, HBE cells were transfected with 0.5 µg/ml poly I:C, and supernatants were treated like these of the infected cells. Relative light units (RLU) represent the measured luciferase activity. The data from the most representative experiment are shown. * indicates p<0.03, ** p<0.02 determined by a Student's t-test.</p>", "links"=>[], "tags"=>["ifn", "bronchial", "epithelial"], "article_id"=>563840, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_IFN_in_human_bronchial_epithelial_HBE_cells_/563840", "title"=>"Induction of IFN in human bronchial epithelial (HBE) cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:04:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/893484"], "description"=>"<p>(A) Human macrophages were infected with VN1203ΔNS1 or VN1203 at a moi of 0.001. The level of viral replication was determined at different time points by a TCID<sub>50</sub> assay on Vero cells. (B) Seven day old macrophages were infected with VN1203ΔNS1 or VN1203 at a moi of 2. The supernatants of the infected cells were harvested 24 h p.i and assayed for IFN-α, TNF-α, IL-1β, and IL-6. The experiment was repeated three times. The data of one representative experiment are presented as a mean of two measurements. The mock value is subtracted.</p>", "links"=>[], "tags"=>["replication", "induction", "cytokines"], "article_id"=>563920, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Viral_replication_and_induction_of_cytokines_in_human_macrophages_/563920", "title"=>"Viral replication and induction of cytokines in human macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:05:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/893566"], "description"=>"<p>Mice were immunized once or twice with 5.3 log<sub>10</sub> TCID<sub>50</sub>/animal of the VN1204ΔNS1 virus. The control mice were treated with PBS. Serum was collected three weeks p.i. and the level of IgG was determined by ELISA. The serum titers of the individual mice (symbols) expressed as log<sub>2</sub> and the GMTs (horizontal line) for each group of mice are shown. * indicates p<0.0001 determined by a Student's t-test.</p>", "links"=>[], "tags"=>["virus-specific", "serum", "igg"], "article_id"=>563996, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Determination_of_virus_specific_mouse_serum_IgG_titers_/563996", "title"=>"Determination of virus-specific mouse serum IgG titers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:06:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/893650"], "description"=>"<p>Ferrets received two <i>i.n.</i> doses of 7.8 log<sub>10</sub> TCID<sub>50</sub>/animal of VN1203ΔNS1 virus, four weeks apart. Sera were collected 29 days after the 1<sup>st</sup> and then 21 days after the 2<sup>nd</sup> immunization and were analyzed for homologous (VN1203) and heterologous (IND05) HAI antibodies (A, B) with cRBC and hRBC or neutralizing (MNA; C, D) antibodies. The titers of the individual ferrets (symbols) and the mean titers (horizontal line) are shown. * indicates p<0.0001, and ** p<0.05 determined by a Student's t-test. An undetectable HAI antibody titer was assigned a value of <8. An undetectable neutralizing antibody titer was assigned a value of <16.</p>", "links"=>[], "tags"=>["hai", "neutralizing", "antibody", "titers", "immunization"], "article_id"=>564088, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_HAI_and_neutralizing_MNA_antibody_titers_after_single_or_double_i_n_immunization_of_ferrets_/564088", "title"=>"Serum HAI and neutralizing (MNA) antibody titers after single or double <i>i.n</i>. immunization of ferrets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:08:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/893739"], "description"=>"<p>Ferrets that received either PBS or one or two doses of 8.1 log<sub>10</sub> TCID<sub>50</sub>/animal of the VN1203ΔNS1 virus were challenged with 6.3 log<sub>10</sub> TCID<sub>50</sub>/animal of IND05 FA virus two weeks post the last immunization. Nasal samples were collected at the indicated time points and level of infectious virus was determined by the titration on Vero cells. The lower limit of detection is 2 log<sub>10</sub> TCID<sub>50</sub>/ml indicated by the horizontal dashed line.</p>", "links"=>[], "tags"=>["heterologous", "immunized"], "article_id"=>564178, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Replication_of_heterologous_challenge_virus_in_immunized_ferrets_/564178", "title"=>"Replication of heterologous challenge virus in immunized ferrets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:09:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/893814"], "description"=>"<p>Ferrets were immunized either with PBS once (6 animals) or with the vaccine virus VN1203ΔNS1 once (7 animals) or twice (8 animals) with a dose of 8.1 TCID<sub>50</sub>/animal. Nasal wash samples were collected prior to immunization (pre) and two weeks after each immunization. Individual vaccine virus specific IgA levels were normalized based on the total IgA content of each sample and expressed as vaccine virus-specific IgA RLU/100 AU (arbitrary units) of total IgA. The means (horizontal lines) and standard errors of mean (vertical lines) are presented. Animals with a 2.5-fold increase in IgA titer following immunization were considered as responders. <sup>a</sup>No. of responders/total no. of immunized animals.</p>", "links"=>[], "tags"=>["virus-specific", "iga", "nasal", "samples", "immunized"], "article_id"=>564256, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Detection_of_vaccine_virus_specific_IgA_in_the_nasal_wash_samples_of_immunized_ferrets_/564256", "title"=>"Detection of vaccine virus-specific IgA in the nasal wash samples of immunized ferrets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:10:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/893890"], "description"=>"<p>A group of four macaques was immunized <i>i.n.</i> with VN1203ΔNS1 at a dose of 7.8 log<sub>10</sub> TCID<sub>50</sub>/animal. Sera were collected four weeks p.i. and HAI with homologous VN1203 (cRBC) or heterologous IND05 (cRBC and hRBC indicated by <sup>a</sup>) antigens and MNA titers were performed. Undetectable HAI antibody titer was assigned a value of <8. An undetectable neutralizing antibody titer was assigned a value of <16. * indicates p<0.05 determined by the Mann-Whitney U-test.</p>", "links"=>[], "tags"=>["antibody", "responses", "immunization"], "article_id"=>564326, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_antibody_responses_after_the_single_i_n_immunization_of_adult_Rhesus_macaques_/564326", "title"=>"Serum antibody responses after the single <i>i.n</i>. immunization of adult <i>Rhesus macaques</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-06-19 01:12:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/893972"], "description"=>"a<p>Mice with lung virus load <1.5 log<sub>10</sub> TCID<sub>50</sub>/ml were classified as being protected.</p>b<p>The virus titers are expressed as the mean log<sub>10</sub> TCID<sub>50</sub>/ml±standard error (S.E.) from 6 animals. The limit of virus detection was 1.5 log<sub>10</sub> TCID<sub>50</sub>/ml. Tissues where no virus was detected were defined as 1.5 log<sub>10</sub> TCID<sub>50</sub>/ml for the calculation of the mean titer.</p><p>Mice (6 animals per group) were administered <i>i.n.</i> one or two doses of the VN1203ΔNS1 virus (5.3 log<sub>10</sub> TCID<sub>50</sub>/animal) three weeks apart and were challenged with homologous VN1203 (3.3 log<sub>10</sub> TCID<sub>50</sub>/animal), or heterologous HK213 (3.2 log<sub>10</sub> TCID<sub>50</sub>/animal), IND05 (2.2 log<sub>10</sub> TCID<sub>50</sub>/animal) and Dk/Sing/97 (4.2 log<sub>10</sub> TCID<sub>50</sub>/animal) viruses three weeks post each immunization. The decrease of the mean virus titers measured in the vaccinated group compared to the PBS treated group was significant in all the groups as determined by the Mann-Whitney U-test (p<0.05).</p>", "links"=>[], "tags"=>["viruses", "mice", "immunized"], "article_id"=>564403, "categories"=>["Infectious Diseases", "Immunology", "Microbiology", "Medicine"], "users"=>["Julia Romanova", "Brigitte M. Krenn", "Markus Wolschek", "Boris Ferko", "Ekaterina Romanovskaja-Romanko", "Alexander Morokutti", "Anna-Polina Shurygina", "Sabine Nakowitsch", "Tanja Ruthsatz", "Bettina Kiefmann", "Ulrich König", "Michael Bergmann", "Monika Sachet", "Shobana Balasingam", "Alexander Mann", "John Oxford", "Martin Slais", "Oleg Kiselev", "Thomas Muster", "Andrej Egorov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0005984.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Replication_of_challenge_viruses_in_mice_immunized_with_the_VN1203_916_NS1_virus_/564403", "title"=>"Replication of challenge viruses in mice immunized with the VN1203ΔNS1 virus.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-06-19 01:13:23"}

PMC Usage Stats | Further Information

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Relative Metric

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