scholarly journals Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards

2015 ◽  
Vol 81 (7) ◽  
pp. 2378-2383 ◽  
Author(s):  
Anna Gillman ◽  
Shaman Muradrasoli ◽  
Hanna Söderström ◽  
Fredrik Holmberg ◽  
Neus Latorre-Margalef ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza Pandemic ◽  
Sewage Treatment ◽  
Wild Birds ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Resistance Mutations ◽  
Drug Pressure ◽  
Influenza A H1n1 ◽  
H274y Mutation

ABSTRACTInfluenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In thisin vivomallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.

scholarly journals Evaluation of Recombinant 2009 Pandemic Influenza A (H1N1) Viruses Harboring Zanamivir Resistance Mutations in Mice and Ferrets

2013 ◽  
Vol 57 (4) ◽  
pp. 1784-1789 ◽  
Author(s):  
Andrés Pizzorno ◽  
Yacine Abed ◽  
Chantal Rhéaume ◽  
Xavier Bouhy ◽  
Guy Boivin
Keyword(s):  
Influenza A ◽  
Fold Increase ◽  
Viral Fitness ◽  
Wild Type ◽  
Resistance Mutations ◽  
Nasal Wash ◽  
Influenza A H1n1 ◽  
Ratio Versus ◽  
Viral Titers

ABSTRACTRecombinant influenza A(H1N1)pdm09 wild-type (WT) and zanamivir-resistant E119G and Q136K neuraminidase mutants were generated to determine their enzymatic and replicative propertiesin vitro, as well as their infectivity and transmissibility in mice and ferrets. Viral titers of recombinant E119G and Q136K mutants were significantly lower than those of the WT in the first 36 h postinoculation (p.i.)in vitro. The E119G and Q136K mutations were both associated with a significant reduction of total neuraminidase (NA) activity at the cell surface of 293T cells, with relative total NA activities of 14% (P< 0.01) and 20% (P< 0.01), respectively, compared to the WT. The E119G mutation significantly reduced the affinity (8-fold increase inKm) but not theVmax. The Q136K mutation increased the affinity (5-fold decrease inKm) with a reduction inVmax(8%Vmaxratio versus the WT). In mice, infection with the E119G and Q136K mutants resulted in lung viral titers that were significantly lower than those of the WT on days 3 p.i. (3.4 × 106± 0.8 × 106and 2.1 × 107± 0.4 × 107PFU/ml, respectively, versus 8.8 × 107± 1.1 × 107;P< 0.05) and 6 p.i. (3.0 × 105± 0.5 × 105and 8.6 × 105± 1.4 ×105PFU/ml, respectively, versus 5.8 × 107± 0.3 × 107;P< 0.01). In experimentally infected ferrets, the E119G mutation rapidly reverted to the WT in donor and contact animals. The Q136K mutation was maintained in ferrets, although nasal wash viral titers from the Q136K contact group were significantly lower than those of the WT on days 3 to 5 p.i. Our results demonstrate that zanamivir-resistant E119G and Q136K mutations compromise viral fitness and transmissibility in A(H1N1)pdm09 viruses.

scholarly journals Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation

2009 ◽  
Vol 83 (20) ◽  
pp. 10366-10373 ◽  
Author(s):  
Aeron C. Hurt ◽  
Jessica K. Holien ◽  
Michael Parker ◽  
Anne Kelso ◽  
Ian G. Barr
Keyword(s):  
Southeast Asia ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Mdck Cells ◽  
The United States ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Clinical Specimens ◽  
Influenza A H1n1

ABSTRACT The neuraminidase inhibitors zanamivir and oseltamivir are marketed for the treatment and prophylaxis of influenza and have been stockpiled by many countries for use in a pandemic. Although recent surveillance has identified a striking increase in the frequency of oseltamivir-resistant seasonal influenza A (H1N1) viruses in Europe, the United States, Oceania, and South Africa, to date there have been no reports of significant zanamivir resistance among influenza A (H1N1) viruses or any other human influenza viruses. We investigated the frequency of oseltamivir and zanamivir resistance in circulating seasonal influenza A (H1N1) viruses in Australasia and Southeast Asia. Analysis of 391 influenza A (H1N1) viruses isolated between 2006 and early 2008 from Australasia and Southeast Asia revealed nine viruses (2.3%) that demonstrated markedly reduced zanamivir susceptibility and contained a previously undescribed Gln136Lys (Q136K) neuraminidase mutation. The mutation had no effect on oseltamivir susceptibility but caused approximately a 300-fold and a 70-fold reduction in zanamivir and peramivir susceptibility, respectively. The role of the Q136K mutation in conferring zanamivir resistance was confirmed using reverse genetics. Interestingly, the mutation was not detected in the primary clinical specimens from which these mutant isolates were grown, suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens or arose during MDCK cell culture passage. Compared to susceptible influenza A (H1N1) viruses, the Q136K mutant strains displayed greater viral fitness than the wild-type virus in MDCK cells but equivalent infectivity and transmissibility in a ferret model.

scholarly journals A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance

2013 ◽  
Vol 58 (3) ◽  
pp. 1639-1645 ◽  
Author(s):  
Lan Huang ◽  
Yang Cao ◽  
Jianfang Zhou ◽  
Kun Qin ◽  
Wenfei Zhu ◽  
...  
Keyword(s):  
Binding Site ◽  
Influenza A ◽  
Double Mutant ◽  
Mdck Cells ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Close Monitoring ◽  
Conformational Restriction ◽  
Influenza A H1n1

ABSTRACTThe I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site. Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the binding pocket, which otherwise only subtends the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.

scholarly journals Multiple Influenza A (H3N2) Mutations Conferring Resistance to Neuraminidase Inhibitors in a Bone Marrow Transplant Recipient

2014 ◽  
Vol 58 (12) ◽  
pp. 7188-7197 ◽  
Author(s):  
Alireza Eshaghi ◽  
Sarah Shalhoub ◽  
Paul Rosenfeld ◽  
Aimin Li ◽  
Rachel R. Higgins ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Therapy ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Marrow Transplant ◽  
Viral Fitness ◽  
H3n2 Virus ◽  
Resistance Mutations ◽  
Depth Analysis ◽  
Resistant Strains

ABSTRACTImmunocompromised patients are predisposed to infections caused by influenza virus. Influenza virus may produce considerable morbidity, including protracted illness and prolonged viral shedding in these patients, thus prompting higher doses and prolonged courses of antiviral therapy. This approach may promote the emergence of resistant strains. Characterization of neuraminidase (NA) inhibitor (NAI)-resistant strains of influenza A virus is essential for documenting causes of resistance. In this study, using quantitative real-time PCR along with conventional Sanger sequencing, we identified an NAI-resistant strain of influenza A (H3N2) virus in an immunocompromised patient. In-depth analysis by deep gene sequencing revealed that various known markers of antiviral resistance, including transient R292K and Q136K substitutions and a sustained E119K (N2 numbering) substitution in the NA protein emerged during prolonged antiviral therapy. In addition, a combination of a 4-amino-acid deletion at residues 245 to 248 (Δ245-248) accompanied by the E119V substitution occurred, causing resistance to or reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir). Resistant variants within a pool of viral quasispecies arose during combined antiviral treatment. More research is needed to understand the interplay of drug resistance mutations, viral fitness, and transmission.

scholarly journals Children under 10 years of age were more affected by the 2018/19 influenza A(H1N1)pdm09 epidemic in Canada: ‎possible cohort effect following the 2009 influenza pandemic

2019 ◽  
Vol 24 (15) ◽  
Author(s):  
Danuta M Skowronski ◽  
Siobhan Leir ◽  
Gaston De Serres ◽  
Michelle Murti ◽  
James A Dickinson ◽  
...  
Keyword(s):  
General Population ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Age Distribution ◽  
Cohort Effect ◽  
Surveillance Network ◽  
Medical Visits ◽  
Influenza A H1n1 ◽  
2009 Influenza Pandemic ◽  
Negative Controls

Introduction Findings from the community-based Canadian Sentinel Practitioner Surveillance Network (SPSN) suggest children were more affected by the 2018/19 influenza A(H1N1)pdm09 epidemic. Aim To compare the age distribution of A(H1N1)pdm09 cases in 2018/19 to prior seasonal influenza epidemics in Canada. Methods The age distribution of unvaccinated influenza A(H1N1)pdm09 cases and test-negative controls were compared across A(H1N1)pdm09-dominant epidemics in 2018/19, 2015/16 and 2013/14 and with the general population of SPSN provinces. Similar comparisons were undertaken for influenza A(H3N2)-dominant epidemics. Results In 2018/19, more influenza A(H1N1)pdm09 cases were under 10 years old than controls (29% vs 16%; p < 0.001). In particular, children aged 5–9 years comprised 14% of cases, greater than their contribution to controls (4%) or the general population (5%) and at least twice their contribution in 2015/16 (7%; p < 0.001) or 2013/14 (5%; p < 0.001). Conversely, children aged 10–19 years (11% of the population) were under-represented among A(H1N1)pdm09 cases versus controls in 2018/19 (7% vs 12%; p < 0.001), 2015/16 (7% vs 13%; p < 0.001) and 2013/14 (9% vs 12%; p = 0.12). Conclusion Children under 10 years old contributed more to outpatient A(H1N1)pdm09 medical visits in 2018/19 than prior seasonal epidemics in Canada. In 2018/19, all children under 10 years old were born after the 2009 A(H1N1)pdm09 pandemic and therefore lacked pandemic-induced immunity. In addition, more than half those born after 2009 now attend school (i.e. 5–9-year-olds), a socio-behavioural context that may enhance transmission and did not apply during prior A(H1N1)pdm09 epidemics.

scholarly journals Roles of Different Transport Modes in the Spatial Spread of the 2009 Influenza A(H1N1) Pandemic in Mainland China

2019 ◽  
Vol 16 (2) ◽  
pp. 222 ◽  
Author(s):  
Jun Cai ◽  
Bo Xu ◽  
Karen Kie Yan Chan ◽  
Xueying Zhang ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Significant Role ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Mainland China ◽  
H1n1 Pandemic ◽  
Railway Stations ◽  
Early Arrival ◽  
Influenza A H1n1 ◽  
Transport Modes ◽  
Rail Travel

There is increasing concern about another influenza pandemic in China. However, the understanding of the roles of transport modes in the 2009 influenza A(H1N1) pandemic spread across mainland China is limited. Herein, we collected 127,797 laboratory-confirmed cases of influenza A(H1N1)pdm09 in mainland China from May 2009 to April 2010. Arrival days and peak days were calculated for all 340 prefectures to characterize the dissemination patterns of the pandemic. We first evaluated the effects of airports and railway stations on arrival days and peak days, and then we applied quantile regressions to quantify the relationships between arrival days and air, rail, and road travel. Our results showed that early arrival of the virus was not associated with an early incidence peak. Airports and railway stations in prefectures significantly advanced arrival days but had no significant impact on peak days. The pandemic spread across mainland China from the southeast to the northwest in two phases that were split at approximately 1 August 2009. Both air and road travel played a significant role in accelerating the spread during phases I and II, but rail travel was only significant during phase II. In conclusion, in addition to air and road travel, rail travel also played a significant role in accelerating influenza A(H1N1)pdm09 spread between prefectures. Establishing a multiscale mobility network that considers the competitive advantage of rail travel for mid to long distances is essential for understanding the influenza pandemic transmission in China.

Hospital Capacity during an Influenza Pandemic—Buenos Aires, Argentina, 2009

2011 ◽  
Vol 32 (1) ◽  
pp. 87-90 ◽  
Author(s):  
Elissa Meites ◽  
Daniel Farias ◽  
Lucrecia Raffo ◽  
Rachel Albalak ◽  
Oreste Luis Carlino ◽  
...  
Keyword(s):  
Critical Care ◽  
Influenza A ◽  
Buenos Aires ◽  
Influenza Pandemic ◽  
Rapid Expansion ◽  
H1n1 Pandemic ◽  
Surge Capacity ◽  
Hospital Capacity ◽  
Preparedness Planning ◽  
Influenza A H1n1

At a major referral hospital in the Southern Hemisphere, the 2009 influenza A (H1N1) pandemic brought increased critical care demand and more unscheduled nursing absences. Because of careful preparedness planning, including rapid expansion and redistribution of the numbers of available beds and staff, hospital surge capacity was not exceeded.

scholarly journals Real-time estimation of the hospitalization fatality risk of influenza A(H1N1)pdm09 in Hong Kong

2015 ◽  
Vol 144 (8) ◽  
pp. 1579-1583
Author(s):  
J. Y. WONG ◽  
P. WU ◽  
E. H. Y. LAU ◽  
T. K. TSANG ◽  
V. J. FANG ◽  
...  
Keyword(s):  
Hong Kong ◽  
Real Time ◽  
Influenza A ◽  
Early Stage ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Right Censoring ◽  
Fatality Risk ◽  
Influenza A H1n1 ◽  
The Impact

SUMMARYDuring the early stage of an epidemic, timely and reliable estimation of the severity of infections are important for predicting the impact that the influenza viruses will have in the population. We obtained age-specific deaths and hospitalizations for patients with laboratory-confirmed H1N1pdm09 infections from June 2009 to December 2009 in Hong Kong. We retrospectively obtained the real-time estimates of the hospitalization fatality risk (HFR), using crude estimation or allowing for right-censoring for final status in some patients. Models accounting for right-censoring performed better than models without adjustments. The risk of deaths in hospitalized patients with confirmed H1N1pdm09 increased with age. Reliable estimates of the HFR could be obtained before the peak of the first wave of H1N1pdm09 in young and middle-aged adults but after the peak in the elderly. In the next influenza pandemic, timely estimation of the HFR will contribute to risk assessment and disease control.

scholarly journals Pandemic H1N1 influenza: predicting the course of a pandemic and assessing the efficacy of the planned vaccination programme in the United States

2009 ◽  
Vol 14 (41) ◽  
Author(s):  
S Towers ◽  
Z Feng
Keyword(s):  
United States ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Vaccination Campaign ◽  
H1n1 Influenza ◽  
The United States ◽  
Pandemic H1n1 ◽  
Pandemic H1n1 Influenza ◽  
Influenza A H1n1 ◽  
Control And Prevention

We use data on confirmed cases of pandemic influenza A(H1N1), disseminated by the United States Centers for Disease Control and Prevention(US CDC), to fit the parameters of a seasonally forced Susceptible, Infective, Recovered (SIR) model. We use the resulting model to predict the course of the H1N1 influenza pandemic in autumn 2009, and we assess the efficacy of the planned CDC H1N1 vaccination campaign. The model predicts that there will be a significant wave in autumn, with 63% of the population being infected, and that this wave will peak so early that the planned CDC vaccination campaign will likely not have a large effect on the total number of people ultimately infected by the pandemic H1N1 influenza virus.

Sign in / Sign up

Export Citation Format

Share Document