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Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets.

ABSTRACT: The neuraminidase (NA) inhibitor oseltamivir offers an important immediate option for the control of influenza, and its clinical use has increased substantially during the recent H1N1 pandemic. In view of the high prevalence of oseltamivir-resistant seasonal H1N1 influenza viruses in 2007-2008, there is an urgent need to characterize the transmissibility and fitness of oseltamivir-resistant H1N1/2009 viruses, although resistant variants have been isolated at a low rate. Here we studied the transmissibility of a closely matched pair of pandemic H1N1/2009 clinical isolates, one oseltamivir-sensitive and one resistant, in the ferret model. The resistant H275Y mutant was derived from a patient on oseltamivir prophylaxis and was the first oseltamivir-resistant isolate of the pandemic virus. Full genome sequencing revealed that the pair of viruses differed only at NA amino acid position 275. We found that the oseltamivir-resistant H1N1/2009 virus was not transmitted efficiently in ferrets via respiratory droplets (0/2), while it retained efficient transmission via direct contact (2/2). The sensitive H1N1/2009 virus was efficiently transmitted via both routes (2/2 and 1/2, respectively). The wild-type H1N1/2009 and the resistant mutant appeared to cause a similar disease course in ferrets without apparent attenuation of clinical signs. We compared viral fitness within the host by co-infecting a ferret with oseltamivir-sensitive and -resistant H1N1/2009 viruses and found that the resistant virus showed less growth capability (fitness). The NA of the resistant virus showed reduced substrate-binding affinity and catalytic activity in vitro and delayed initial growth in MDCK and MDCK-SIAT1 cells. These findings may in part explain its less efficient transmission. The fact that the oseltamivir-resistant H1N1/2009 virus retained efficient transmission through direct contact underlines the necessity of continuous monitoring of drug resistance and characterization of possible evolving viral proteins during the pandemic.

SUBMITTER: Duan S

PROVIDER: S-EPMC2912389 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets.

Duan Susu S Boltz David A DA Seiler Patrick P Li Jiang J Bragstad Karoline K Nielsen Lars P LP Webby Richard J RJ Webster Robert G RG Govorkova Elena A EA

PLoS pathogens 20100729 7

The neuraminidase (NA) inhibitor oseltamivir offers an important immediate option for the control of influenza, and its clinical use has increased substantially during the recent H1N1 pandemic. In view of the high prevalence of oseltamivir-resistant seasonal H1N1 influenza viruses in 2007-2008, there is an urgent need to characterize the transmissibility and fitness of oseltamivir-resistant H1N1/2009 viruses, although resistant variants have been isolated at a low rate. Here we studied the trans ...[more]

PMID: 20686654

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Project description:Pandemic (H1N1) 2009 influenza is affecting countries in all five continents, with most cases so far having been reported in North and South America and Europe, and children and young adults being the most susceptible age groups. To date, the clinical course of disease is typically mild, with low hospitalization and mortality rates. Pandemic (H1N1) 2009 is susceptible to oseltamivir and, although few clinical data are yet available, current information suggests that treatment with oseltamivir appears to be beneficial. Only isolated cases of resistance to the drug have been reported to date, in keeping with the low frequency observed in clinical studies involving patients infected with seasonal influenza viruses. Current health authority guidelines recommend the use of oseltamivir in infected adults and children who have or are at elevated risk for severe disease, including pregnant women; use during the pandemic in infants < 1 year has also been authorized in Europe and a number of other countries, including the USA and Canada. Before the onset of the current pandemic, F. Hoffmann-La Roche Ltd expanded annual production capacity for oseltamivir to 400 million treatment courses per year to meet anticipated demand. However, during an influenza pandemic, and despite increased production capabilities, resources are nonetheless likely to be initially in short supply. For this reason, Roche, in line with WHO recommendations, has advocated advance stockpiling of antivirals by governments as a pandemic preparedness measure. Between 2004 and December 2009, 350 million treatment courses were supplied to governments worldwide. Support for developing countries has been a priority. Roche has established a cluster of initiatives aimed at increasing access to Tamiflu for the world's developing economies, including, making donations to the WHO, establishing the Tamiflu Reserves Program (TRP) and sub-licensing and manufacturing contracts with local companies in Asia and Africa. Furthermore, Roche has published a document outlining how it would allocate limited supplies of Tamiflu during a pandemic, which are in line with WHO recommendations stating that 'resources should be used to provide the maximum possible health benefit'. Roche is also offering support such as reprocessing of expiring capsule stocks (in development) and shelf-life extension to support governments in the management of their stockpiles. Clinical studies, either sponsored by or supported by Roche, are in progress. These trials are designed to investigate the effectiveness of oseltamivir in patients infected with the pandemic virus in greater depth, and include high-dose studies, assessment of natural and drug-induced resistance, and response to treatment in high-risk populations such as young infants, immunocompromised patients and the severely ill.

Project description:Following the emergence of 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) in the United States and Mexico in April 2009, A(H1N1)pdm09 spread rapidly all over the world. There is a dearth of information about the epidemiology of A(H1N1)pdm09 in Africa, including Morocco. We describe the epidemiologic characteristics of the A(H1N1)pdm09 epidemic in Morocco during 2009-2010, including transmissibility and risk factors associated with fatal disease.We implemented influenza surveillance for patients presenting with influenza-like illness (ILI) at 136 private and public clinics for patients with severe acute respiratory illness (SARI) at 16 regional public hospitals from June 2009 through February 2010. Respiratory samples and structured questionnaires were collected from all enrolled patients, and samples were tested by real-time reverse-transcription polymerase chain reaction for influenza viruses. We estimated the risk factors associated with fatal disease as well as the basic reproduction number (R(0)) and the serial interval of the pandemic virus.From June 2009 through February 2010, we obtained 3937 specimens, of which 1452 tested positive for influenza virus. Of these, 1398 (96%) were A(H1N1)pdm09. Forty percent of specimens from ILI cases (1056 of 2646) and 27% from SARI cases (342 of 1291) were positive for A(H1N1)pdm09. Sixty-four deaths occurred among laboratory-confirmed A(H1N1)pdm09 SARI cases. Among these cases, those who had hypertension (age-adjusted odd ratio [aOR], 28.2; 95% confidence interval [CI], 2.0-398.7), had neurological disorders (aOR, 7.5; 95% CI, 1.5-36.4), or were obese (aOR, 7.1; 95% CI, 1.6-31.1), as well as women of gestational age who were pregnant (aOR, 2.5; 95% CI, 1.1-5.6), were at increased risk of death. Across the country, elevated numbers of locally acquired infections were detected 4 months after the detection of the first laboratory-confirmed case and coincided with the expected influenza season (October-January) in Morocco. We obtained an R(0) estimate of 1.44 (95% CI, 1.32-1.56) and a mean serial interval (±SD) of 2.3 ± 1.4 days (95% CI, 1.6-3.0).Widespread but delayed community transmission of A(H1N1)pdm09 occurred in Morocco in 2009, and A(H1N1)pdm09 became the dominant influenza virus subtype during the 2009-2010 influenza season. The transmissibility characteristics were similar to those observed in other countries.

Dataset Information

Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets.

Publications

Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets.

Similar Datasets

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