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      Immunogenicity and Protective Efficacy of a Vero Cell Culture-Derived Whole-Virus H7N9 Vaccine in Mice and Guinea Pigs

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          Abstract

          Background

          A novel avian H7N9 virus with a high case fatality rate in humans emerged in China in 2013. We evaluated the immunogenicity and protective efficacy of a candidate Vero cell culture-derived whole-virus H7N9 vaccine in small animal models.

          Methods

          Antibody responses induced in immunized DBA/2J mice and guinea pigs were evaluated by hemagglutination inhibition (HI), microneutralization (MN), and neuraminidase inhibition (NAi) assays. T-helper cell responses and IgG subclass responses in mice were analyzed by ELISPOT and ELISA, respectively. Vaccine efficacy against lethal challenge with wild-type H7N9 virus was evaluated in immunized mice. H7N9-specific antibody responses induced in mice and guinea pigs were compared to those induced by a licensed whole-virus pandemic H1N1 (H1N1pdm09) vaccine.

          Results

          The whole-virus H7N9 vaccine induced dose-dependent H7N9-specific HI, MN and NAi antibodies in mice and guinea pigs. Evaluation of T-helper cell responses and IgG subclasses indicated the induction of a balanced Th1/Th2 response. Immunized mice were protected against lethal H7N9 challenge in a dose-dependent manner. H7N9 and H1N1pdm09 vaccines were similarly immunogenic.

          Conclusions

          The induction of H7N9-specific antibody and T cell responses and protection against lethal challenge suggest that the Vero cell culture-derived whole-virus vaccine would provide an effective intervention against the H7N9 virus.

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          Most cited references43

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          Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

          New England Journal of Medicine, 368(20), 1888-1897
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            Clinical findings in 111 cases of influenza A (H7N9) virus infection.

            During the spring of 2013, a novel avian-origin influenza A (H7N9) virus emerged and spread among humans in China. Data were lacking on the clinical characteristics of the infections caused by this virus. Using medical charts, we collected data on 111 patients with laboratory-confirmed avian-origin influenza A (H7N9) infection through May 10, 2013. Of the 111 patients we studied, 76.6% were admitted to an intensive care unit (ICU), and 27.0% died. The median age was 61 years, and 42.3% were 65 years of age or older; 31.5% were female. A total of 61.3% of the patients had at least one underlying medical condition. Fever and cough were the most common presenting symptoms. On admission, 108 patients (97.3%) had findings consistent with pneumonia. Bilateral ground-glass opacities and consolidation were the typical radiologic findings. Lymphocytopenia was observed in 88.3% of patients, and thrombocytopenia in 73.0%. Treatment with antiviral drugs was initiated in 108 patients (97.3%) at a median of 7 days after the onset of illness. The median times from the onset of illness and from the initiation of antiviral therapy to a negative viral test result on real-time reverse-transcriptase-polymerase-chain-reaction assay were 11 days (interquartile range, 9 to 16) and 6 days (interquartile range, 4 to 7), respectively. Multivariate analysis revealed that the presence of a coexisting medical condition was the only independent risk factor for the acute respiratory distress syndrome (ARDS) (odds ratio, 3.42; 95% confidence interval, 1.21 to 9.70; P=0.02). During the evaluation period, the novel H7N9 virus caused severe illness, including pneumonia and ARDS, with high rates of ICU admission and death. (Funded by the National Natural Science Foundation of China and others.).
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              The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses.

              The intranasal inoculation of volunteers with living partially attenuated strains of influenza A and B viruses offers a new opportunity to determine the protective effect of serum haemagglutin-inhibiting antibody against a strictly homologous virus, under conditions where the time and dosage of the infective challenge can be controlled, the scoring of proven infections can be more precise and higher rates of infection can be achieved than in most natural epidemics.In 1032 adult volunteers, whose serum HI antibody titre was determined immediately before virus challenge, there was a consistent inverse quantitative relationship between the HI titre and the likelihood of infection. The PD 50 (50% protective dose) of HI antibody was 1/18-1/36, but an unusual finding was that volunteers with no detectable pre-challenge antibody often seem to be less susceptible to infection than those with pre-challenge antibody in low titre.In one group of volunteers challenged with an influenza B strain there was no evidence that pre-challenge antibody titres against viral neuraminidase had any significant protective effect against challenge infection.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 February 2015
                2015
                : 10
                : 2
                : e0113963
                Affiliations
                [1 ]Vaccine R&D, Baxter BioScience, Orth/Donau, Austria
                [2 ]Pharmacology R&D, Baxter BioScience, Orth/Donau, Austria
                [3 ]Process Development R&D, Baxter BioScience, Orth/Donau, Austria
                University of Georgia, UNITED STATES
                Author notes

                Competing Interests: W.W., M.G.S., H.S.D., B.A.C., C.H., R.F., P.B., D.P., A.K.P., D.B., L.G., O.K., P.N.B. and M.K.H. report being employed by Baxter. W.W., M.S., H.S.D., B.A.C., P.B., L.G., O.K., P.N.B. and M.K.H. report having an equity interest in the company. L.G., O.K. and P.N.B. report holding patents on influenza vaccines derived from Vero cell cultures. (“Formulation of sugar solutions for continuous ultracentrifugation for virus purification” WO2008135229 A1; “Two-step temperature profile for the propagation of viruses” WO2008135230 A1; “Animal protein free media for cultivation of cells” WO2004005493 A1; “Method for producing biologicals in protein-free culture” WO1996015231 A2; “Method for producing viral vaccines” WO2009029695 A1.) This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: BAC OK PNB MKH. Performed the experiments: WW MGS HSD CH RF PB AKP DB LG. Analyzed the data: WW MGS BAC CH RF DP OK PNB MKH. Wrote the paper: WW MGS HSD BAC CH RF PB DP AKP DB LG OK PNB MKH. Read the final manuscript and approved it for submission: WW MGS HSD BAC CH RF PB DP AKP DB LG OK PNB MKH.

                Article
                PONE-D-14-21480
                10.1371/journal.pone.0113963
                4342221
                25719901
                4f7a74d9-772d-4059-aa6c-554444ba8c37
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 16 May 2014
                : 3 November 2014
                Page count
                Figures: 3, Tables: 3, Pages: 16
                Funding
                The study was funded by Baxter. Baxter employees were responsible for study design, data collection and analysis, decision to publish, and preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper.

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