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  1 / 215 MEDLINE  
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PMID:27228671
Autor:Markushin SG; Svitich OA; Kinkulkina AR; Koptyaeva IB; Lisovskaya KV
Título:[MECHANISMS OF ATTENUATION OF COLD-ADAPTED STRAIN A/KRASNO- DAR/101/35/59 (H2N2)].
Fuente:Zh Mikrobiol Epidemiol Immunobiol; (2):49-56, 2016 Mar-Apr.
ISSN:0372-9311
País de publicación:Russia (Federation)
Idioma:rus
Resumen:AIM: Study of mechanisms of attenuation of cold-adapted (ca) influenza virus strain A/ Krasnodar/101/35/59 (H2N2), associated with disruption of NS1 protein functions. MATERIALS AND METHODS: Study of interferonogenic activity of ca strain A/Krasnodar/101/35/59 (H2N2), its parent variant A/Krasnodar/101/59 (H2N2), virulent strain A/WSN/33 (H1N1) and a number of single gene and multiple gene reassortants between these strains, obtained using reverse genetics, was carried out. Study of dynamics of IFNß gene expression was carried out by using a methodical approach of RT-PCR in real time mode. RESULTS: Inclusion of PB-1 gene of ca strain A/ Krasnodar/101/35/59 (H2N2) with reversion to wild type into genome composition of virulent strain A/WSN/33 (H1N1) does not result in a sharp change of interferonogenic activity of the reassortant. At the same time, similar inclusion of PB-1 gene of ca strain resulted in an incredible growth of interferonogenic activity of the reassortant. On the other hand, inclusion of NP-gene of wild type strain A/Krasnodar/101/59 (H2N2) into genome composition of the wild type strain A/WSN/33 did not differ by effect on interferonogenicity of the reassortant from inclusion of NP-gene of ca strain. CONCLUSION: Both constellations of genes of parent variants and mutations localized in these genes could affect formation of attenuation phenotype of reassortants. The data obtained allow to assume possible mechanisms of attenuation of ca strains, associated with disruption.of NS gene function.
Tipo de publicación:ENGLISH ABSTRACT; JOURNAL ARTICLE
Nombre de substancia:0 (NS protein, influenza virus); 0 (Viral Nonstructural Proteins); 9008-11-1 (Interferons)


  2 / 215 MEDLINE  
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PMID:26908781
Autor:Viboud C; Simonsen L; Fuentes R; Flores J; Miller MA; Chowell G
Dirección:Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland.
Título:Global Mortality Impact of the 1957-1959 Influenza Pandemic.
Fuente:J Infect Dis; 213(5):738-45, 2016 Mar 01.
ISSN:1537-6613
País de publicación:United States
Idioma:eng
Resumen:BACKGROUND: Quantitative estimates of the global burden of the 1957 influenza pandemic are lacking. Here we fill this gap by modeling historical mortality statistics. METHODS: We used annual rates of age- and cause-specific deaths to estimate pandemic-related mortality in excess of background levels in 39 countries in Europe, the Asia-Pacific region, and the Americas. We modeled the relationship between excess mortality and development indicators to extrapolate the global burden of the pandemic. RESULTS: The pandemic-associated excess respiratory mortality rate was 1.9/10,000 population (95% confidence interval [CI], 1.2-2.6 cases/10,000 population) on average during 1957-1959. Excess mortality rates varied 70-fold across countries; Europe and Latin America experienced the lowest and highest rates, respectively. Excess mortality was delayed by 1-2 years in 18 countries (46%). Increases in the mortality rate relative to baseline were greatest in school-aged children and young adults, with no evidence that elderly population was spared from excess mortality. Development indicators were moderate predictors of excess mortality, explaining 35%-77% of the variance. Overall, we attribute 1.1 million excess deaths (95% CI, .7 million-1.5 million excess deaths) globally to the 1957-1959 pandemic. CONCLUSIONS: The global mortality rate of the 1957-1959 influenza pandemic was moderate relative to that of the 1918 pandemic but was approximately 10-fold greater than that of the 2009 pandemic. The impact of the pandemic on mortality was delayed in several countries, pointing to a window of opportunity for vaccination in a future pandemic.
Tipo de publicación:HISTORICAL ARTICLE; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.


  3 / 215 MEDLINE  
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PMID:26703222
Autor:Chin AW; Yen HL; Krauss S; Webby RJ; Poon LL
Dirección:1​Centre of Influenza Research & School of Public Health, University of Hong Kong, Hong Kong, PR China.
Título:Recombinant influenza virus with a pandemic H2N2 polymerase complex has a higher adaptive potential than one with seasonal H2N2 polymerase complex.
Fuente:J Gen Virol; 97(3):611-9, 2016 Mar.
ISSN:1465-2099
País de publicación:England
Idioma:eng
Resumen:The reassortment of influenza viral gene segments plays a key role in the genesis of pandemic strains. All of the last three pandemic viruses contained reassorted polymerase complexes with subunits derived from animal viruses, suggesting that the acquisition of a reassorted polymerase complex might have a role in generating these pandemic viruses. Here, we studied polymerase activities of the pandemic H2N2, seasonal H2N2 and pandemic H3N2 viruses. We observed that the viral ribonucleoprotein (vRNP) of pandemic H2N2 virus has a highly robust activity. The polymerase activity of seasonal H2N2 viruses, however, was much reduced. We further identified three mutations (PB2-I114V, PB1-S261N and PA-D383N) responsible for the reduced activity. To determine the potential impact of viral polymerase activity on the viral life cycle, recombinant H3N2 viruses carrying pandemic and seasonal H2N2 vRNP were studied in cell cultures supplemented with oseltamivir carboxylate and tested for their abilities to develop adaptive or resistant mutations. It was found that the recombinant virus with pandemic H2N2 vRNP was more capable of restoring the viral fitness than the one with seasonal vRNP. These results suggest that a robust vRNP is advantageous to influenza virus to cope with a new selection pressure.
Tipo de publicación:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Nombre de substancia:0 (PB2 protein, Influenzavirus A); 0 (Viral Proteins); EC 2.7.7.48 (RNA Replicase)


  4 / 215 MEDLINE  
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PMID:26519883
Autor:Shcherbik S; Pearce N; Kiseleva I; Larionova N; Rudenko L; Xu X; Wentworth DE; Bousse T
Dirección:Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, MS-G16, 1600 Clifton Road, Atlanta, GA 30333, United States; Battelle, Atlanta, GA 30329, United States.
Título:Implementation of new approaches for generating conventional reassortants for live attenuated influenza vaccine based on Russian master donor viruses.
Fuente:J Virol Methods; 227:33-9, 2016 Jan.
ISSN:1879-0984
País de publicación:Netherlands
Idioma:eng
Resumen:Cold-adapted influenza strains A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69, originally developed in Russia, have been reliable master donors of attenuation for preparing live attenuated influenza vaccines (LAIV). The classical strategy for generating LAIV reassortants is robust, but has some disadvantages. The generation of reassortants requires at least 3 passages under selective conditions after co-infection; each of these selective passages takes six days. Screening the reassortants for a genomic composition traditionally starts after a second limiting dilution cloning procedure, and the number of suitable reassortants is limited. We developed a new approach to shorten process of preparing LAIV seed viruses. Introducing the genotyping of reassortants by pyrosequencing and monitoring sequence integrity of surface antigens starting at the first selective passage allowed specific selection of suitable reassortants for the next cloning procedure and also eliminate one of the group selective passage in vaccine candidate generation. Homogeneity analysis confirmed that reducing the number of selective passages didn't affect the quality of LAIV seed viruses. Finally, the two-way hemagglutination inhibition test, implemented for all the final seed viruses, confirmed that any amino acid substitutions acquired by reassortants during egg propagation didn't affect antigenicity of the vaccine. Our new strategy reduces the time required to generate a vaccine and was used to generate seasonal LAIVs candidates for the 2012/2013, 2014/2015, and 2015/2016 seasons more rapidly.
Tipo de publicación:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nombre de substancia:0 (Influenza Vaccines)


  5 / 215 MEDLINE  
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PMID:26829850
Autor:Markushin SG; Tsfasman TM; Terekhov AV; Lisovskaya KV; Akopova II
Título:[COLD-ADAPTED A/KRASNODAR/101/35/59 (H2N2) STRAIN--A PROMISING STRAIN-DONOR OF ATTENUATION FOR PROCURATION OF LIVE INFLUENZA VACCINES].
Fuente:Zh Mikrobiol Epidemiol Immunobiol; (5):27-32, 2015 Sep-Oct.
ISSN:0372-9311
País de publicación:Russia (Federation)
Idioma:rus
Resumen:AIM: Study of ts, ca, att phenotype, immunogenicity and protective effectiveness of reassortants obtained by a way of recombination of a new influenza cold-adapted (ca) strain donor of attenuation A/Krasnodar/101/35/59 (H2N2) and virulent strain of influenza virus. MATERIALS AND METHODS: Viruses were used: ca strain A/Krasnodar/101/35.59 (H2N2), virulent strains: A/Kumamoto/102/02 (H3N2) and A/Bern/07/95. For determination of ts and ca phenotype, titration of viruses in chicken embryos was carried out simultaneously at optimal, decreased and increased temperature. Protective effect of immunization was evaluated during intranasal infection of mice with a virulent strain of influenza virus. RESULTS: All the obtained reassortants possessed 6 internal genes from strain-donor of attenuation and 2 genes, coding HA and NA-proteins from virulent strains. Ca reassortants were characterized by ts and ca phenotype, had antigenic specificity and good immunogenicity, had high protective effectiveness. CONCLUSION: The data obtained indicate on the perspectiveness of ca strain A/Krasnodar/101/35/59 (H2N2)as a donor of attenuation for live influenza vaccines.
Tipo de publicación:ENGLISH ABSTRACT; JOURNAL ARTICLE
Nombre de substancia:0 (Influenza Vaccines); 0 (Vaccines, Attenuated)


  6 / 215 MEDLINE  
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Registro de Ensayos Clínicos
Registro de Ensayos Clínicos
Registro de Ensayos Clínicos
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PMID:26432909
Autor:Kiseleva I; Dubrovina I; Fedorova E; Larionova N; Isakova-Sivak I; Bazhenova E; Pisareva M; Kuznetsova V; Flores J; Rudenko L
Dirección:Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia. Electronic address: irina.v.kiseleva@mail.ru.
Título:Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses.
Fuente:Vaccine; 33(49):7008-14, 2015 Dec 08.
ISSN:1873-2518
País de publicación:Netherlands
Idioma:eng
Resumen:BACKGROUND: Ensuring genetic stability is a prerequisite for live attenuated influenza vaccine (LAIV). This study describes the results of virus shedding and clinical isolates' testing of Phase I clinical trials of Russian LAIVs against potentially pandemic influenza viruses in healthy adults. METHODS: Three live attenuated vaccines against potentially pandemic influenza viruses, H2N2 LAIV, H5N2 LAIV and H7N3 LAIV, generated by classical reassortment in eggs, were studied. For each vaccine tested, subjects were randomly distributed into two groups to receive two doses of either LAIV or placebo at a 3:1 vaccine/placebo ratio. Nasal swabs were examined for vaccine virus shedding by culturing in eggs and by PCR. Vaccine isolates were tested for temperature sensitivity and cold-adaptation (ts/ca phenotypes) and for nucleotide sequence. RESULTS: The majority of nasal wash positive specimens were detected on the first day following vaccination. PCR method demonstrated higher sensitivity than routine virus isolation in eggs. None of the placebo recipients had detectable vaccine virus replication. All viruses isolated from the immunized subjects retained the ts/ca phenotypic characteristics of the master donor virus (MDV) and were shown to preserve all attenuating mutations described for the MDV. These data suggest high level of vaccine virus genetic stability after replication in humans. During manufacture process, no additional mutations occurred in the genome of H2N2 LAIV. In contrast, one amino acid change in the HA of H7N3 LAIV and two additional mutations in the HA of H5N2 LAIV manufactured vaccine lot were detected, however, they did not affect their ts/ca phenotypes. CONCLUSIONS: Our clinical trials revealed phenotypic and genetic stability of the LAIV viruses recovered from the immunized volunteers. In addition, no vaccine virus was detected in the placebo groups indicating the lack of person-to-person transmission. LAIV TRIAL REGISTRATION at ClinicalTrials.gov: H7N3-NCT01511419; H5N2-NCT01719783; H2N2-NCT01982331.
Tipo de publicación:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Nombre de substancia:0 (Hemagglutinin Glycoproteins, Influenza Virus); 0 (Influenza Vaccines); 0 (Vaccines, Attenuated)


  7 / 215 MEDLINE  
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PMID:26346523
Autor:Muñoz-Medina JE; Sánchez-Vallejo CJ; Méndez-Tenorio A; Monroy-Muñoz IE; Angeles-Martínez J; Santos Coy-Arechavaleta A; Santacruz-Tinoco CE; González-Ibarra J; Anguiano-Hernández YM; González-Bonilla CR; Ramón-Gallegos E; Díaz-Quiñonez JA
Dirección:Laboratorio Central de Epidemiología, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Avenida Jacarandas S/N, Esquina Circuito Interior, Colonia La Raza Delegación Azcapotzalco, 02990 México, DF, Mexico.
Título:In Silico Identification of Highly Conserved Epitopes of Influenza A H1N1, H2N2, H3N2, and H5N1 with Diagnostic and Vaccination Potential.
Fuente:Biomed Res Int; 2015:813047, 2015.
ISSN:2314-6141
País de publicación:United States
Idioma:eng
Resumen:The unpredictable, evolutionary nature of the influenza A virus (IAV) is the primary problem when generating a vaccine and when designing diagnostic strategies; thus, it is necessary to determine the constant regions in viral proteins. In this study, we completed an in silico analysis of the reported epitopes of the 4 IAV proteins that are antigenically most significant (HA, NA, NP, and M2) in the 3 strains with the greatest world circulation in the last century (H1N1, H2N2, and H3N2) and in one of the main aviary subtypes responsible for zoonosis (H5N1). For this purpose, the HMMER program was used to align 3,016 epitopes reported in the Immune Epitope Database and Analysis Resource (IEDB) and distributed in 34,294 stored sequences in the Pfam database. Eighteen epitopes were identified: 8 in HA, 5 in NA, 3 in NP, and 2 in M2. These epitopes have remained constant since they were first identified (~91 years) and are present in strains that have circulated on 5 continents. These sites could be targets for vaccination design strategies based on epitopes and/or as markers in the implementation of diagnostic techniques.
Tipo de publicación:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nombre de substancia:0 (Epitopes); 0 (Influenza Vaccines)


  8 / 215 MEDLINE  
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PMID:26259268
Autor:Kashirina OS; Chernikova MI; Vasiliev YM
Título:[COMPARATIVE STUDY OF IMMUNOGENICITY AND PROTECTIVE EFFECT OF LIVE COLD-ADAPTED AND INACTIVATED VACCINES AGAINST TYPE A INFLUENZA].
Fuente:Zh Mikrobiol Epidemiol Immunobiol; (3):38-46, 2015 May-Jun.
ISSN:0372-9311
País de publicación:Russia (Federation)
Idioma:rus
Resumen:AIM: Direct comparative studies of immunogenicity and protective effect of live cold-adapted (ca) and inactivated vaccines against type A influenza. MATERIALS AND METHODS: Groups of mice were immunized intramuscularly (i/m) or intranasally (i/n) twice with inactivated or live ca vaccines based on wild-type parent strain A/Krasnodar/101/59 (H2N2) and the corresponding ca donor strain A/Krasnodar/101/59/30CE/5MDCK/l/7/4 (H2N2), respectively. Immunogenicity was determined by HAI antibodies in sera and lungs (extracts) against both vaccine strains. Protective effect--by the level of wild-type strain in lungs of immunized mice after the infection. RESULTS: Live ca and inactivated vaccines based on similar strains increase immunogenicity and protective effect when administered via different routes in varying patterns. A significant increase of immunogenicity was only observed for i/m (sera antibodies) and i/n (lung antibodies) administration of the live ca vaccine, and could be determined by antigenic features of the vaccine strains. At the same time, all the vaccine variants and administration routes induced at least partial protection from infection compared with unimmunized control. However, complete protection from infection was only noted for the i/m administered live ca vaccine. CONCLUSION: A combination of immunization variant and vaccine type determines immunogenicity and protective effect, and their interconnection requires further studies using all the possible combinations of preparations and administration routes as well as determination of induction of various components of the immune system.
Tipo de publicación:ENGLISH ABSTRACT; JOURNAL ARTICLE
Nombre de substancia:0 (Antibodies, Viral); 0 (Influenza Vaccines); 0 (Vaccines, Attenuated); 0 (Vaccines, Inactivated)


  9 / 215 MEDLINE  
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PMID:26168339
Autor:Pérez-Girón JV; Gómez-Medina S; Lüdtke A; Munoz-Fontela C
Dirección:Laboratory of Emerging Viruses, Heinrich Pette Institute, Leibniz Institute for Experimental Virology.
Título:Intranasal Administration of Recombinant Influenza Vaccines in Chimeric Mouse Models to Study Mucosal Immunity.
Fuente:J Vis Exp; (100):e52803, 2015 Jun 25.
ISSN:1940-087X
País de publicación:United States
Idioma:eng
Resumen:Vaccines are one of the greatest achievements of mankind, and have saved millions of lives over the last century. Paradoxically, little is known about the physiological mechanisms that mediate immune responses to vaccines perhaps due to the overall success of vaccination, which has reduced interest into the molecular and physiological mechanisms of vaccine immunity. However, several important human pathogens including influenza virus still pose a challenge for vaccination, and may benefit from immune-based strategies. Although influenza reverse genetics has been successfully applied to the generation of live-attenuated influenza vaccines (LAIVs), the addition of molecular tools in vaccine preparations such as tracer components to follow up the kinetics of vaccination in vivo, has not been addressed. In addition, the recent generation of mouse models that allow specific depletion of leukocytes during kinetic studies has opened a window of opportunity to understand the basic immune mechanisms underlying vaccine-elicited protection. Here, we describe how the combination of reverse genetics and chimeric mouse models may help to provide new insights into how vaccines work at physiological and molecular levels, using as example a recombinant, cold-adapted, live-attenuated influenza vaccine (LAIV). We utilized laboratory-generated LAIVs harboring cell tracers as well as competitive bone marrow chimeras (BMCs) to determine the early kinetics of vaccine immunity and the main physiological mechanisms responsible for the initiation of vaccine-specific adaptive immunity. In addition, we show how this technique may facilitate gene function studies in single animals during immune responses to vaccines. We propose that this technique can be applied to improve current prophylactic strategies against pathogens for which urgent medical countermeasures are needed, for example influenza, HIV, Plasmodium, and hemorrhagic fever viruses such as Ebola virus.
Tipo de publicación:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; VIDEO-AUDIO MEDIA
Nombre de substancia:0 (Influenza Vaccines); 0 (Vaccines, Synthetic)


  10 / 215 MEDLINE  
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PMID:26085153
Autor:Chlanda P; Schraidt O; Kummer S; Riches J; Oberwinkler H; Prinz S; Kräusslich HG; Briggs JA
Dirección:Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Título:Structural Analysis of the Roles of Influenza A Virus Membrane-Associated Proteins in Assembly and Morphology.
Fuente:J Virol; 89(17):8957-66, 2015 Sep.
ISSN:1098-5514
País de publicación:United States
Idioma:eng
Resumen:UNLABELLED: The assembly of influenza A virus at the plasma membrane of infected cells leads to release of enveloped virions that are typically round in tissue culture-adapted strains but filamentous in strains isolated from patients. The viral proteins hemagglutinin (HA), neuraminidase (NA), matrix protein 1 (M1), and M2 ion channel all contribute to virus assembly. When expressed individually or in combination in cells, they can all, under certain conditions, mediate release of membrane-enveloped particles, but their relative roles in virus assembly, release, and morphology remain unclear. To investigate these roles, we produced membrane-enveloped particles by plasmid-derived expression of combinations of HA, NA, and M proteins (M1 and M2) or by infection with influenza A virus. We monitored particle release, particle morphology, and plasma membrane morphology by using biochemical methods, electron microscopy, electron tomography, and cryo-electron tomography. Our data suggest that HA, NA, or HANA (HA plus NA) expression leads to particle release through nonspecific induction of membrane curvature. In contrast, coexpression with the M proteins clusters the glycoproteins into filamentous membrane protrusions, which can be released as particles by formation of a constricted neck at the base. HA and NA are preferentially distributed to differently curved membranes within these particles. Both the budding intermediates and the released particles are morphologically similar to those produced during infection with influenza A virus. Together, our data provide new insights into influenza virus assembly and show that the M segment together with either of the glycoproteins is the minimal requirement to assemble and release membrane-enveloped particles that are truly virus-like. IMPORTANCE: Influenza A virus is a major respiratory pathogen. It assembles membrane-enveloped virus particles whose shapes vary from spherical to filamentous. Here we examine the roles of individual viral proteins in mediating virus assembly and determining virus shape. To do this, we used a range of electron microscopy techniques to obtain and compare two- and three-dimensional images of virus particles and virus-like particles during and after assembly. The virus-like particles were produced using different combinations of viral proteins. Among our results, we found that coexpression of one or both of the viral surface proteins (hemagglutinin and neuraminidase) with the viral membrane-associated proteins encoded by the M segment results in assembly and release of filamentous virus-like particles in a manner very similar to that of the budding and release of influenza virions. These data provide novel insights into the roles played by individual viral proteins in influenza A virus assembly.
Tipo de publicación:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nombre de substancia:0 (Hemagglutinin Glycoproteins, Influenza Virus); 0 (M1 protein, Influenza A virus); 0 (M2 protein, Influenza A virus); 0 (Viral Matrix Proteins); EC 3.2.1.18 (Neuraminidase)



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