Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-20 (of 20 Records) |
Query Trace: Garten RJ[original query] |
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Birth cohort effects in influenza surveillance data: Evidence that first influenza infection affects later influenza-associated illness
Budd AP , Beacham L , Smith CB , Garten RJ , Reed C , Kniss K , Mustaquim D , Ahmad FB , Cummings CN , Garg S , Levine MZ , Fry AM , Brammer L . J Infect Dis 2019 220 (5) 820-829 BACKGROUND: The evolution of influenza A viruses results in birth cohorts that have different initial influenza virus exposures. Historically, A/H3 predominant seasons have been associated with more severe influenza-associated disease; however, since the 2009 pandemic there are suggestions that some birth cohorts experience more severe illness in A/H1 predominant seasons. METHODS: U.S. influenza virologic, hospitalization and mortality surveillance data during 2000-2017 were analyzed for cohorts born between 1918 and 1989 that likely had different initial influenza virus exposures based on viruses circulating during early childhood. Relative risk/rate during H3 compared to H1 predominant seasons during pre-pandemic versus pandemic and later periods were calculated for each cohort. RESULTS: During the pre-pandemic period, all cohorts had more influenza-associated disease during H3 predominant seasons than H1 predominant seasons. During the pandemic and later period, four cohorts had higher hospitalization and mortality rates during H1 predominant seasons than H3 predominant seasons. DISCUSSION: Birth cohort differences in risk of influenza-associated disease by influenza A virus subtype can be seen in U.S. influenza surveillance data and differ between pre-pandemic and pandemic and later periods. As the population ages, the amount of influenza-associated disease may be greater in future H1 predominant seasons than H3 predominant seasons. |
Interim estimates of 2018-19 seasonal influenza vaccine effectiveness - United States, February 2019
Doyle JD , Chung JR , Kim SS , Gaglani M , Raiyani C , Zimmerman RK , Nowalk MP , Jackson ML , Jackson LA , Monto AS , Martin ET , Belongia EA , McLean HQ , Foust A , Sessions W , Berman L , Garten RJ , Barnes JR , Wentworth DE , Fry AM , Patel MM , Flannery B . MMWR Morb Mortal Wkly Rep 2019 68 (6) 135-139 In the United States, annual vaccination against seasonal influenza is recommended for all persons aged >/=6 months (https://www.cdc.gov/flu/protect/whoshouldvax.htm). Effectiveness of seasonal influenza vaccine varies by season. During each influenza season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine to prevent laboratory-confirmed influenza associated with medically attended acute respiratory illness (ARI). This interim report uses data from 3,254 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness Network (U.S. Flu VE Network) during November 23, 2018-February 2, 2019. During this period, overall adjusted vaccine effectiveness against all influenza virus infection associated with medically attended ARI was 47% (95% confidence interval [CI] = 34%-57%). For children aged 6 months-17 years, overall vaccine effectiveness was 61% (44%-73%). Seventy-four percent of influenza A infections for which subtype information was available were caused by A(H1N1)pdm09 viruses. Vaccine effectiveness was estimated to be 46% (30%-58%) against illness caused by influenza A(H1N1)pdm09 viruses. CDC recommends that health care providers continue to administer influenza vaccine because influenza activity is ongoing and the vaccine can still prevent illness, hospitalization, and death associated with currently circulating influenza viruses, or other influenza viruses that might circulate later in the season. During the 2017-18 influenza season, in which influenza A(H3N2) predominated, vaccination was estimated to prevent 7.1 million illnesses, 3.7 million medical visits, 109,000 hospitalizations, and 8,000 deaths (1). Vaccination can also reduce the severity of influenza-associated illness (2). Persons aged >/=6 months who have not yet been vaccinated this season should be vaccinated. |
Influence of birth cohort on effectiveness of 2015-2016 influenza vaccine against medically attended illness due to 2009 pandemic influenza A(H1N1) virus in the United States
Flannery B , Smith C , Garten RJ , Levine MZ , Chung JR , Jackson ML , Jackson LA , Monto AS , Martin ET , Belongia EA , McLean HQ , Gaglani M , Murthy K , Zimmerman R , Nowalk MP , Griffin MR , Keipp Talbot H , Treanor JJ , Wentworth DE , Fry AM . J Infect Dis 2018 218 (2) 189-196 Background: The effectiveness of influenza vaccine during 2015-2016 was reduced in some age groups as compared to that in previous 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09 virus)-predominant seasons. We hypothesized that the age at first exposure to specific influenza A(H1N1) viruses could influence vaccine effectiveness (VE). Methods: We estimated the effectiveness of influenza vaccine against polymerase chain reaction-confirmed influenza A(H1N1)pdm09-associated medically attended illness from the 2010-2011 season through the 2015-2016 season, according to patient birth cohort using data from the Influenza Vaccine Effectiveness Network. Birth cohorts were defined a priori on the basis of likely immunologic priming with groups of influenza A(H1N1) viruses that circulated during 1918-2015. VE was calculated as 100 x [1 - adjusted odds ratio] from logistic regression models comparing the odds of vaccination among influenza virus-positive versus influenza test-negative patients. Results: A total of 2115 A(H1N1)pdm09 virus-positive and 14 696 influenza virus-negative patients aged >/=6 months were included. VE was 61% (95% confidence interval [CI], 56%-66%) against A(H1N1)pdm09-associated illness during the 2010-2011 through 2013-2014 seasons, compared with 47% (95% CI, 36%-56%) during 2015-2016. During 2015-2016, A(H1N1)pdm09-specific VE was 22% (95% CI, -7%-43%) among adults born during 1958-1979 versus 61% (95% CI, 54%-66%) for all other birth cohorts combined. Conclusion: Findings suggest an association between reduced VE against influenza A(H1N1)pdm09-related illness during 2015-2016 and early exposure to specific influenza A(H1N1) viruses. |
Antiviral drug-resistant influenza B viruses carrying H134N substitution in neuraminidase, Laos, February 2016
Baranovich T , Vongphrachanh P , Ketmayoon P , Sisouk T , Chomlasack K , Khanthamaly V , Nguyen HT , Mishin VP , Marjuki H , Barnes JR , Garten RJ , Stevens J , Wentworth DE , Gubareva LV . Emerg Infect Dis 2017 23 (4) 686-690 In February 2016, three influenza B/Victoria/2/87 lineage viruses exhibiting 4- to 158-fold reduced inhibition by neuraminidase inhibitors were detected in Laos. These viruses had an H134N substitution in the neuraminidase and replicated efficiently in vitro and in ferrets. Current antiviral drugs may be ineffective in controlling infections caused by viruses harboring this mutation. |
Enhanced genetic characterization of influenza A(H3N2) viruses and vaccine effectiveness by genetic group, 2014-2015.
Flannery B , Zimmerman RK , Gubareva LV , Garten RJ , Chung JR , Nowalk MP , Jackson ML , Jackson LA , Monto AS , Ohmit SE , Belongia EA , McLean HQ , Gaglani M , Piedra PA , Mishin VP , Chesnokov AP , Spencer S , Thaker SN , Barnes JR , Foust A , Sessions W , Xu X , Katz J , Fry AM . J Infect Dis 2016 214 (7) 1010-9 BACKGROUND: During the 2014-15 US influenza season, expanded genetic characterization of circulating influenza A(H3N2) viruses was used to assess the impact of genetic variability of influenza A(H3N2) viruses on influenza vaccine effectiveness (VE). METHODS: A novel pyrosequencing assay was used to determine genetic group based on hemagglutinin (HA) gene sequences of influenza A(H3N2) viruses from patients enrolled US Flu Vaccine Effectiveness network sites. Vaccine effectiveness was estimated using a test-negative design comparing vaccination among patients infected with influenza A(H3N2) viruses and uninfected patients. RESULTS: Among 9710 enrollees, 1868 (19%) tested positive for influenza A(H3N2); genetic characterization of 1397 viruses showed 1134 (81%) belonged to one HA genetic group (3C.2a) of antigenically drifted H3N2 viruses. Effectiveness of 2014-15 influenza vaccination varied by A(H3N2) genetic group from 1% (95% confidence interval [CI], -14% to 14%) against illness caused by antigenically drifted A(H3N2) group 3C.2a viruses versus 44% (95% CI, 16% to 63%) against illness caused by vaccine-like A(H3N2) group 3C.3b viruses. CONCLUSION: Effectiveness of 2014-15 influenza vaccination varied by genetic group of influenza A(H3N2) virus. Changes in hemagglutinin genes related to antigenic drift were associated with reduced vaccine effectiveness. |
Diverse antigenic site targeting of influenza hemagglutinin in the murine antibody recall response to A(H1N1)pdm09 virus.
Wilson JR , Guo Z , Tzeng WP , Garten RJ , Xiyan X , Blanchard EG , Blanchfield K , Stevens J , Katz JM , York IA . Virology 2015 485 252-262 Here we define the epitopes on HA that are targeted by a group of 9 recombinant monoclonal antibodies (rmAbs) isolated from memory B cells of mice, immunized by infection with A(H1N1)pdm09 virus followed by a seasonal TIV boost. These rmAbs were all reactive against the HA1 region of HA, but display 7 distinct binding footprints, targeting each of the 4 known antigenic sites. Although the rmAbs were not broadly cross-reactive, a group showed subtype-specific cross-reactivity with the HA of A/South Carolina/1/18. Screening these rmAbs with a panel of human A(H1N1)pdm09 virus isolates indicated that naturally-occurring changes in HA could reduce rmAb binding, HI activity, and/or virus neutralization activity by rmAb, without showing changes in recognition by polyclonal antiserum. In some instances, virus neutralization was lost while both ELISA binding and HI activity were retained, demonstrating a discordance between the two serological assays traditionally used to detect antigenic drift. |
Determination of predominance of influenza virus strains in the Americas
Azziz-Baumgartner E , Garten RJ , Palekar R , Cerpa M , Mirza S , Ropero AM , Palomeque FS , Moen A , Bresee J , Shaw M , Widdowson MA . Emerg Infect Dis 2015 21 (7) 1209-12 During 2001-2014, predominant influenza A(H1N1) and A(H3N2) strains in South America predominated in all or most subsequent influenza seasons in Central and North America. Predominant A(H1N1) and A(H3N2) strains in North America predominated in most subsequent seasons in Central and South America. Sharing data between these subregions may improve influenza season preparedness. |
Structural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers
Wan H , Yang H , Shore DA , Garten RJ , Couzens L , Gao J , Jiang L , Carney PJ , Villanueva J , Stevens J , Eichelberger MC . Nat Commun 2015 6 6114 A(H1N1)pdm09 influenza A viruses predominated in the 2013-2014 USA influenza season, and although most of these viruses remain sensitive to Food and Drug Administration-approved neuraminidase (NA) inhibitors, alternative therapies are needed. Here we show that monoclonal antibody CD6, selected for binding to the NA of the prototypic A(H1N1)pdm09 virus, A/California/07/2009, protects mice against lethal virus challenge. The crystal structure of NA in complex with CD6 Fab reveals a unique epitope, where the heavy-chain complementarity determining regions (HCDRs) 1 and 2 bind one NA monomer, the light-chain CDR2 binds the neighbouring monomer, whereas HCDR3 interacts with both monomers. This 30-amino-acid epitope spans the lateral face of an NA dimer and is conserved among circulating A(H1N1)pdm09 viruses. These results suggest that the large, lateral CD6 epitope may be an effective target of antibodies selected for development as therapeutic agents against circulating H1N1 influenza viruses. |
Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013-14.
Okomo-Adhiambo M , Fry AM , Su S , Nguyen HT , Elal AA , Negron E , Hand J , Garten RJ , Barnes J , Xiyan X , Villanueva JM , Gubareva LV . Emerg Infect Dis 2015 21 (1) 136-41 We report characteristics of oseltamivir-resistant influenza A(H1N1)pdm09 viruses and patients infected with these viruses in the United States. During 2013-14, fifty-nine (1.2%) of 4,968 analyzed US influenza A(H1N1)pdm09 viruses had the H275Y oseltamivir resistance-conferring neuraminidase substitution. Our results emphasize the need for local surveillance for neuraminidase inhibitor susceptibility among circulating influenza viruses. |
Improving pandemic influenza risk assessment.
Russell CA , Kasson PM , Donis RO , Riley S , Dunbar J , Rambaut A , Asher J , Burke S , Davis CT , Garten RJ , Gnanakaran S , Hay SI , Herfst S , Lewis NS , Lloyd-Smith JO , Macken CA , Maurer-Stroh S , Neuhaus E , Parrish CR , Pepin KM , Shepard SS , Smith DL , Suarez DL , Trock SC , Widdowson MA , George DB , Lipsitch M , Bloom JD . Elife 2014 3 e03883 Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response. |
Antiviral susceptibility of variant influenza A(H3N2)v viruses isolated in the United States from 2011 to 2013
Sleeman K , Mishin VP , Guo Z , Garten RJ , Balish A , Fry AM , Villanueva J , Stevens J , Gubareva LV . Antimicrob Agents Chemother 2014 58 (4) 2045-51 Since 2011, outbreaks caused by influenza A(H3N2) variant [A(H3N2)v] viruses have become a public health concern in the United States. The A(H3N2)v viruses share the A(H1N1)pdm09 M gene containing the marker of M2 blocker resistance, S31N, but do not contain any known molecular markers associated with resistance to neuraminidase (NA) inhibitors (NAIs). Using a fluorescent NA inhibition (NI) assay, the susceptibilities of recovered A(H3N2)v viruses (n = 168) to FDA-approved (oseltamivir and zanamivir) and other (peramivir, laninamivir, and A-315675) NAIs were assessed. All A(H3N2)v viruses tested, with the exception of a single virus strain, A/Ohio/88/2012, isolated from an untreated patient, were susceptible to the NAIs tested. The A/Ohio/88/2012 virus contained two rare substitutions, S245N and S247P, in the NA and demonstrated reduced inhibition by oseltamivir (31-fold) and zanamivir (66-fold) in the NI assay. Using recombinant NA (recNA) proteins, S247P was shown to be responsible for the observed altered NAI susceptibility, in addition to an approximately 60% reduction in NA enzymatic activity. The S247P substitution has not been previously reported as a molecular marker of reduced susceptibility to the NAIs. Using cell culture assays, the investigational antiviral drugs nitazoxanide, favipiravir, and fludase were shown to inhibit the replication of A(H3N2)v viruses, including the virus with the S247P substitution in the NA. This report demonstrates the importance of continuous monitoring of susceptibility of zoonotic influenza viruses to available and investigational antiviral drugs. |
Swine influenza virus A (H3N2) infection in human, Kansas, USA, 2009
Cox CM , Neises D , Garten RJ , Bryant B , Hesse RA , Anderson GA , Trevino-Garrison I , Shu B , Lindstrom S , Klimov AI , Finelli L . Emerg Infect Dis 2011 17 (6) 1143-4 Triple-reassortant swine influenza viruses (SIVs), which contain genes from human, swine, and avian influenza A viruses, have been enzootic among swine herds in the United States since the late 1990s. Although uncommon, occasional transmission of triple-reassortant SIVs from swine to humans has occurred. Before April 2009, only limited, nonsustained human-to-human transmission of SIVs had been reported. Although an animal source for pandemic (H1N1) 2009 virus has yet to be identified, the pandemic strain resulted from the reassortment of 2 different lineages of SIV. |
Influenza pandemic epidemiologic and virologic diversity: reminding ourselves of the possibilities
Kasowski EJ , Garten RJ , Bridges CB . Clin Infect Dis 2011 52 S44-S49 The 2009 influenza A (H1N1) pandemic serves as a stark reminder of the inherently unpredictable nature of influenza virus. Although most planning centered on the potential emergence of a wholly new influenza A subtype of avian origin causing the next pandemic, a very different scenario occurred: a mammalian-adapted reassortant drift variant of a familiar subtype caused the first pandemic of the 21st Century. This pandemic also reminds us of the variability possible with respect to the epidemiology of pandemic influenza, the effects of population immunity to novel influenza strains on age-specific morbidity and mortality, and the potential importance of domestic animals in the ecology of influenza and the formation of new virus strains with pandemic potential. Future pandemic preparedness planning should include addressing gaps in influenza surveillance among nonhuman mammalian species at the animal human interface as part of pandemic risk assessment. |
Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008-2010
Sheu TG , Fry AM , Garten RJ , Deyde VM , Shwe T , Bullion L , Peebles PJ , Li Y , Klimov AI , Gubareva LV . J Infect Dis 2011 203 (1) 13-7 Two distinct genetic clades of seasonal influenza A(H1N1) viruses have cocirculated in the recent seasons: clade 2B oseltamivir-resistant and adamantane-susceptible viruses, and clade 2C viruses that are resistant to adamantanes and susceptible to oseltamivir. We tested seasonal influenza A(H1N1) viruses collected in 2008-2010 from the United States and globally for resistance to antivirals approved by the Food and Drug Administration. We report 28 viruses with both adamantane and oseltamivir (dual) resistance from 5 countries belonging to 4 distinct genotypes. Because of limited options for antiviral treatment, emergence of dual-resistant influenza viruses poses a public health concern, and their circulation needs to be closely monitored. |
Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro
Gubareva LV , Trujillo AA , Okomo-Adhiambo M , Mishin VP , Deyde VM , Sleeman K , Nguyen HT , Sheu TG , Garten RJ , Shaw MW , Fry AM , Klimov AI . Antivir Ther 2010 15 (8) 1151-9 BACKGROUND: Antiviral drugs are an important option for managing infections caused by influenza viruses. This study assessed the drug susceptibility of 2009 pandemic influenza A (H1N1) viruses collected globally between April 2009 and January 2010. METHODS: Virus isolates were tested for adamantane susceptibility, using pyrosequencing to detect the S31N marker of adamantane resistance in the M2 protein and biological assays to assess viral replication in cell culture. To assess neuraminidase (NA) inhibitor (NAI) susceptibility, virus isolates were tested in chemiluminescent NA inhibition assays and by pyrosequencing to detect the H275Y (H274Y in N2 numbering) marker of oseltamivir resistance in the NA. RESULTS: With the exception of three, all viruses that were tested for adamantane susceptibility (n=3,362) were resistant to this class of drugs. All viruses tested for NAI susceptibility (n=3,359) were sensitive to two US Food and Drug Administration-approved NAIs, oseltamivir (mean +/-sd 50% inhibitory concentration [IC(50)] 0.25 +/-0.12 nM) and zanamivir (mean IC(50) 0.29 +/-0.09 nM), except 23 (0.7%), which were resistant to oseltamivir, but sensitive to zanamivir. Oseltamivir-resistant viruses had the H275Y mutation in their NA and were detected in patients exposed to the drug through prophylaxis or treatment. NA activity of all viruses was inhibited by the NAIs peramivir, laninamivir (R-125489) and A-315675, except for H275Y variants, which exhibited approximately 100-fold reduction in peramivir susceptibility. CONCLUSIONS: This report provides data regarding antiviral susceptibility of 2009 pandemic influenza A (H1N1) surveillance viruses, the majority of which were resistant to adamantanes and sensitive to NAIs. These findings provide information essential for antiviral resistance monitoring and development of novel diagnostic tests for detecting influenza antiviral resistance. |
Genomic signature-based identification of influenza A viruses using RT-PCR/electro-spray ionization mass spectrometry (ESI-MS) technology
Deyde VM , Sampath R , Garten RJ , Blair PJ , Myers CA , Massire C , Matthews H , Svoboda P , Reed MS , Pohl J , Klimov AI , Gubareva LV . PLoS One 2010 5 (10) e13293 BACKGROUND: The emergence and rapid spread of the 2009 H1N1 pandemic influenza A virus (H1N1pdm) in humans highlights the importance of enhancing the capability of existing influenza surveillance systems with tools for rapid identification of emerging and re-emerging viruses. One of the new approaches is the RT-PCR electrospray ionization mass spectrometry (RT-PCR/ESI-MS) technology, which is based on analysis of base composition (BC) of RT-PCR amplicons from influenza "core" genes. Combination of the BC signatures represents a "genomic print" of an influenza A virus. METHODOLOGY/PRINCIPAL FINDINGS: Here, 757 samples collected between 2006 and 2009 were tested, including 302 seasonal H1N1, 171 H3N2, 7 swine triple reassortants, and 277 H1N1pdm viruses. Of the 277 H1N1pdm samples, 209 were clinical specimens (throat, nasal and nasopharyngeal swabs, nasal washes, blood and sputum). BC signatures for the clinical specimen from one of the first cases of the 2009 pandemic, A/California/04/2009, confirmed it as an unusual, previously unrecognized influenza A virus, with "core" genes related to viruses of avian, human and swine origins. Subsequent analysis of additional 276 H1N1pdm samples revealed that they shared the genomic print of A/California/04/2009, which differed from those of North American swine triple reassortant viruses, seasonal H1N1 and H3N2 and other viruses tested. Moreover, this assay allowed distinction between "core" genes of co-circulating groups of seasonal H1N1, such as clades 2B, 2C, and their reassortants with dual antiviral resistance to adamantanes and oseltamivir. CONCLUSIONS/SIGNIFICANCE: The RT-PCR/ESI-MS assay is a broad range influenza identification tool that can be used directly on clinical specimens for rapid and accurate detection of influenza virus genes. The assay differentiates the H1N1pdm from seasonal and other nonhuman hosts viruses. Although not a diagnostic tool, this assay demonstrates its usefulness and robustness in influenza virus surveillance and detection of novel and unusual viruses with previously unseen genomic prints. |
Influenza epidemiology and characterization of influenza viruses in patients seeking treatment for acute fever in Cambodia
Blair PJ , Wierzba TF , Touch S , Vonthanak S , Xu X , Garten RJ , Okomo-Adhiambo MA , Klimov AI , Kasper MR , Putnam SD . Epidemiol Infect 2010 138 (2) 199-209 The epidemiology, symptomology, and viral aetiology of endemic influenza remain largely uncharacterized in Cambodia. In December 2006, we established passive hospital-based surveillance to identify the causes of acute undifferentiated fever in patients seeking healthcare. Fever was defined as tympanic membrane temperature >38 degrees C. From December 2006 to December 2008, 4233 patients were screened for influenza virus by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR). Of these patients, 1151 (27.2%) were positive for influenza. Cough (68.8% vs. 50.5%, P < 0.0001) and sore throat (55.0% vs. 41.9%, P < 0.0001) were more often associated with laboratory-confirmed influenza-infected patients compared to influenza-negative enrollees. A clear influenza season was evident between July and December with a peak during the rainy season. Influenza A and B viruses were identified in 768 (66.3%) and 388 (33.7%) of the influenza-positive population (n = 1153), respectively. In December 2008, passive surveillance identified infection of the avian influenza virus H5N1 in a 19-year-old farmer from Kandal province who subsequently recovered. From a subset of diagnostic samples submitted in 2007, 15 A(H1N1), seven A(H3N2) and seven B viruses were isolated. The predominant subtype tested was influenza A(H1N1), with the majority antigenically related to the A/Solomon Island/03/2006 vaccine strain. The influenza A(H3N2) isolates and influenza B viruses analysed were closely related to A/Brisbane/10/2007 or B/Ohio/01/2005 (B/Victoria/2/87-lineage) vaccine strains, respectively. Phylogenetic analysis of the HA1 region of the HA gene of influenza A(H1N1) viruses demonstrated that the Cambodian isolates belonged to clade 2C along with representative H1N1 viruses circulating in SE Asia at the time. These viruses remained sensitive to oseltamivir. In total, our data suggest that viral influenza infections contribute to nearly one-fifth of acute febrile illnesses and demonstrate the importance of influenza surveillance in Cambodia. |
Host cell selection of influenza neuraminidase variants: implications for drug resistance monitoring in A(H1N1) viruses
Okomo-Adhiambo M , Nguyen HT , Sleeman K , Sheu TG , Deyde VM , Garten RJ , Xu X , Shaw MW , Klimov AI , Gubareva LV . Antiviral Res 2009 85 (2) 381-8 The neuraminidase inhibitors (NAIs), oseltamivir and zanamivir, are essential for treatment and prevention of influenza A and B infections. Oseltamivir resistance among influenza A (H1N1) viruses rapidly emerged and spread globally during the 2007-2008 and 2008-2009 influenza seasons. Approximately 20% and 90% of viruses tested for NAI susceptibility at CDC during these seasons, respectively, were resistant to oseltamivir (IC(50) approximately 100-3000 time>those of sensitive viruses), based on the chemiluminescent NA inhibition assay. Pyrosequencing analysis confirmed H274Y mutation (H275Y in N1 numbering) in the neuraminidase (NA) gene of oseltamivir-resistant viruses. Full NA sequence analysis of a subset of oseltamivir-resistant and sensitive virus isolates from both seasons (n=725) showed that 53 (7.3%) had mutations at residue D151 (D-->E/G/N), while 9 (1.2%) had mutations at Q136 (Q-->K) and 2 (0.3%) had mutations at both residues. Viruses with very high IC(50) for oseltamivir and peramivir, and elevated IC(50) for zanamivir, had H274Y in addition to mutations at D151 and/or Q136, residues which can potentially confer NAI-resistance based on recent N1 NA crystal structure data. Mutations at D151 without H274Y, did not elevate IC(50) for any tested NAI, however, Q136K alone significantly reduced susceptibility to zanamivir (36-fold), peramivir (80-fold) and A-315675 (114-fold) but not oseltamivir. Mutations at D151 and Q136 were present only in MDCK-grown viruses but not in matching original clinical specimens (n=33) which were available for testing, suggesting that these variants were the result of cell culture selection or they were present in very low proportions. Our findings provide evidence that propagation of influenza virus outside its natural host may lead to selection of virus variants with mutations in the NA that affect sensitivity to NAIs and thus poses implications for drug resistance monitoring and diagnostics. |
Detection of antiviral resistance and genetic lineage markers in influenza B virus neuraminidase using pyrosequencing
Sheu TG , Deyde VM , Garten RJ , Klimov AI , Gubareva LV . Antiviral Res 2009 85 (2) 354-60 We report here the design of a pyrosequencing approach for the detection of molecular markers of resistance to the neuraminidase inhibitors zanamivir and oseltamivir in influenza viruses of type B. Primers were designed to analyze the sequences at eight amino acid positions E119, R152, D198, I222, S250, H274, R371, and G402 (universal A/N2 numbering) in the neuraminidase (NA) which have been previously found to be associated with resistance or reduced susceptibility to oseltamivir and/or zanamivir in the NA inhibition assay. In addition, the designed primers could be utilized to the distinguish between the NAs of influenza B viruses from the two major lineages (Victoria and Yamagata) that have co-circulated globally in recent years, thus providing a valuable tool for virus strain surveillance. |
Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans
Garten RJ , Davis CT , Russell CA , Shu B , Lindstrom S , Balish A , Sessions WM , Xu X , Skepner E , Deyde V , Okomo-Adhiambo M , Gubareva L , Barnes J , Smith CB , Emery SL , Hillman MJ , Rivailler P , Smagala J , de Graaf M , Burke DF , Fouchier RA , Pappas C , Alpuche-Aranda CM , Lopez-Gatell H , Olivera H , Lopez I , Myers CA , Faix D , Blair PJ , Yu C , Keene KM , Dotson PD Jr , Boxrud D , Sambol AR , Abid SH , St George K , Bannerman T , Moore AL , Stringer DJ , Blevins P , Demmler-Harrison GJ , Ginsberg M , Kriner P , Waterman S , Smole S , Guevara HF , Belongia EA , Clark PA , Beatrice ST , Donis R , Katz J , Finelli L , Bridges CB , Shaw M , Jernigan DB , Uyeki TM , Smith DJ , Klimov AI , Cox NJ . Science 2009 325 (5937) 197-201 Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North American and Eurasian swine lineages has continued to circulate in humans. The lack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period. Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses. Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1). |
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