Publications by authors named "Aeron C Hurt"

137 Publications

Reducing influenza virus transmission: the value of antiviral treatment.

Clin Infect Dis 2021 Jul 10. Epub 2021 Jul 10.

University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication following antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients appears to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of influenza antivirals. A controlled trial examining baloxavir treatment efficacy to reduce transmission, including the risk of transmitting virus with reduced baloxavir susceptibility, is currently in progress. If reduced transmission risk is confirmed, modelling studies indicate that early treatment would have major epidemiologic benefits in seasonal and pandemic influenza.
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http://dx.doi.org/10.1093/cid/ciab625DOI Listing
July 2021

RNA virome abundance and diversity is associated with host age in a bird species.

Virology 2021 Sep 21;561:98-106. Epub 2021 Jun 21.

Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, Sydney, 2006, New South Wales, Australia. Electronic address:

Despite the ongoing interest in virus discovery, little is known about the factors that shape communities of viruses within individual hosts. Here, we address how virus communities might be impacted by the age of the hosts they infect, using total RNA sequencing to reveal the RNA viromes of different age groups of Ruddy Turnstones (Arenaria interpres). From oropharyngeal and cloacal swabs we identified 14 viruses likely infecting birds, 11 of which were novel, including members of the Reoviridae, Astroviridae, and Picornaviridae. Strikingly, 12 viruses identified were from juvenile birds sampled in the first year of their life, compared to only two viruses in adult birds. Both viral abundance and alpha diversity were marginally higher in juvenile than adult birds. As well as informing studies of virus ecology, that host age might be associated with viral composition is an important consideration for the future surveillance of novel and emerging viruses.
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http://dx.doi.org/10.1016/j.virol.2021.06.007DOI Listing
September 2021

Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients.

Nat Commun 2021 05 11;12(1):2691. Epub 2021 May 11.

Department of Biochemistry and Genetics, La Trobe Institute For Molecular Science, La Trobe University, Bundoora, VIC, Australia.

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 or CD4 T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
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http://dx.doi.org/10.1038/s41467-021-23018-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113517PMC
May 2021

Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model.

PLoS Pathog 2021 05 6;17(5):e1009527. Epub 2021 May 6.

WHO Collaborating Centre for Reference and Research on Influenza, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.

Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.
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http://dx.doi.org/10.1371/journal.ppat.1009527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130947PMC
May 2021

Neutralizing Antibody Therapeutics for COVID-19.

Viruses 2021 04 7;13(4). Epub 2021 Apr 7.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant "escape" mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.
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http://dx.doi.org/10.3390/v13040628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067572PMC
April 2021

Reassortment and Persistence of Influenza A Viruses from Diverse Geographic Origins within Australian Wild Birds: Evidence from a Small, Isolated Population of Ruddy Turnstones.

J Virol 2021 04 12;95(9). Epub 2021 Apr 12.

Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria Australia

Australian lineages of avian influenza A viruses (AIVs) are thought to be phylogenetically distinct from those circulating in Eurasia and the Americas, suggesting the circulation of endemic viruses seeded by occasional introductions from other regions. However, processes underlying the introduction, evolution and maintenance of AIVs in Australia remain poorly understood. Waders (order Charadriiformes, family Scolopacidae) may play a unique role in the ecology and evolution of AIVs, particularly in Australia, where ducks, geese, and swans (order Anseriformes, family Anatidae) rarely undertake intercontinental migrations. Across a 5-year surveillance period (2011 to 2015), ruddy turnstones () that "overwinter" during the Austral summer in southeastern Australia showed generally low levels of AIV prevalence (0 to 2%). However, in March 2014, we detected AIVs in 32% (95% confidence interval [CI], 25 to 39%) of individuals in a small, low-density, island population 90 km from the Australian mainland. This epizootic comprised three distinct AIV genotypes, each of which represent a unique reassortment of Australian-, recently introduced Eurasian-, and recently introduced American-lineage gene segments. Strikingly, the Australian-lineage gene segments showed high similarity to those of H10N7 viruses isolated in 2010 and 2012 from poultry outbreaks 900 to 1,500 km to the north. Together with the diverse geographic origins of the American and Eurasian gene segments, these findings suggest extensive circulation and reassortment of AIVs within Australian wild birds over vast geographic distances. Our findings indicate that long-term surveillance in waders may yield unique insights into AIV gene flow, especially in geographic regions like Oceania, where Anatidae species do not display regular inter- or intracontinental migration. High prevalence of avian influenza viruses (AIVs) was detected in a small, low-density, isolated population of ruddy turnstones in Australia. Analysis of these viruses revealed relatively recent introductions of viral gene segments from both Eurasia and North America, as well as long-term persistence of introduced gene segments in Australian wild birds. These data demonstrate that the flow of viruses into Australia may be more common than initially thought and that, once introduced, these AIVs have the potential to be maintained within the continent. These findings add to a growing body of evidence suggesting that Australian wild birds are unlikely to be ecologically isolated from the highly pathogenic H5Nx viruses circulating among wild birds throughout the Northern Hemisphere.
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http://dx.doi.org/10.1128/JVI.02193-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104097PMC
April 2021

Understanding the Impact of Resistance to Influenza Antivirals.

Clin Microbiol Rev 2021 03 10;34(2). Epub 2021 Feb 10.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.

Influenza poses a significant burden on society and health care systems. Although antivirals are an integral tool in effective influenza management, the potential for the emergence of antiviral-resistant viruses can lead to uncertainty and hesitation among front-line prescribers and policy makers. Here, we provide an overview of influenza antiviral resistance in context, exploring the key concepts underlying its development and clinical impact. Due to the acute nature of influenza in immunocompetent patients, resistant viruses that develop during antiviral treatment of a single patient ("treatment-emergent resistance") are usually cleared in a relatively short time, with no impact on future antiviral efficacy. In addition, although available data are limited by small numbers of patients, they show that antiviral treatment still provides clinical benefit to the patient within whom resistance emerges. In contrast, the sustained community transmission of resistant variants in the absence of treatment ("acquired resistance") is of greater concern and can potentially render front-line antivirals ineffective. Importantly, however, resistant viruses are usually associated with reduced fitness such that their widespread transmission is relatively rare. Influenza antivirals are an essential part of effective influenza management due to their ability to reduce the risk of complications and death in infected patients. Although antiviral resistance should be taken seriously and requires continuous careful monitoring, it is not comparable to antibiotic resistance in bacteria, which can become permanent and widespread, with far-reaching medical consequences. The benefits of antiviral treatment far outweigh concerns of potential resistance, which in the vast majority of cases does not have a significant clinical impact.
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http://dx.doi.org/10.1128/CMR.00224-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950363PMC
March 2021

Burden of influenza B virus infection and considerations for clinical management.

Antiviral Res 2021 01 5;185:104970. Epub 2020 Nov 5.

Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada. Electronic address:

Influenza B viruses cause significant morbidity and mortality, particularly in children, but the awareness of their impact is often less than influenza A viruses partly due to their lack of pandemic potential. Here, we summarise the biology, epidemiology and disease burden of influenza B, and review existing data on available antivirals for its management. There has long been uncertainty surrounding the clinical efficacy of neuraminidase inhibitors (NAIs) for influenza B treatment. In this article, we bring together the existing data on NAIs and discuss these alongside recent large randomised controlled trial data for the new polymerase inhibitor baloxavir in high-risk influenza B patients. Finally, we offer considerations for the clinical management of influenza B, with a focus on children and high-risk patients where disease burden is highest.
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http://dx.doi.org/10.1016/j.antiviral.2020.104970DOI Listing
January 2021

Influenza and COVID-19: What does co-existence mean?

Influenza Other Respir Viruses 2021 05 31;15(3):407-412. Epub 2020 Oct 31.

The Hong Kong Polytechnic University, Hung Hom, Hong Kong.

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 continues to have a major impact on healthcare and social systems throughout the world. As the clinical and epidemiological features of COVID-19 have many parallels with influenza, it is important to ensure optimal management of both respiratory diseases as we anticipate their continued co-circulation. In particular, there is a need to ensure that effective surveillance and diagnostic capacities are in place to monitor these and other respiratory viruses, as this will underpin decisions on the appropriate clinical management of the respective diseases. As such, we propose a series of key recommendations for stakeholders, public health authorities, primary care physicians and surveillance bodies that will help mitigate the combined risks of concurrent influenza epidemics and the COVID-19 pandemic. We advocate the judicious use of influenza vaccines and antivirals, particularly among groups at high risk of complications, with healthcare workers also considered a priority for vaccination. It is likely that the increased use of emerging technologies such as telemedicine and contact tracing will permanently change our approach to managing infectious disease. The use of these technologies, alongside existing pharmaceutical strategies, will ensure that we achieve a holistic approach to the global public health measures needed to deal with the combined threat of influenza and COVID-19. Ensuring that this approach is optimal will be key as we move from a reactive pandemic response towards preparing for the long-term management of the remarkable clinical burden associated with these respiratory pathogens.
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http://dx.doi.org/10.1111/irv.12824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051702PMC
May 2021

Viral burden, inflammatory milieu and CD8 T-cell responses to influenza virus in a second-generation thiazolide (RM-5061) and oseltamivir combination therapy study.

Influenza Other Respir Viruses 2020 11 25;14(6):678-687. Epub 2020 Jun 25.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.

Background: Influenza viruses cause significant morbidity and mortality, especially in young children, elderly, pregnant women and individuals with co-morbidities. Patients with severe influenza disease are typically treated with one neuraminidase inhibitor, oseltamivir or zanamivir. These antivirals need to be taken early to be most effective and often lead to the emergence of drug resistance and/or decreased drug susceptibility. Combining oseltamivir with another antiviral with an alternative mode of action has the potential to improve clinical effectiveness and reduce drug resistance.

Methods: In this study, we utilized a host-targeting molecule RM-5061, a second-generation thiazolide, in combination with oseltamivir to determine whether these compounds could reduce viral burden and understand their effects on the immune response to influenza virus infection in mice, compared with either monotherapy or placebo.

Results: The combination of RM-5061 and OST administered for 5 days after influenza infection reduced viral burden at day 5 post-infection, when compared to placebo and RM-5061 monotherapy, but was not significantly different from oseltamivir monotherapy. The inflammatory cytokine milieu was also reduced in animals which received a combination therapy when compared to RM-5061 and placebo-treated animals. Antiviral treatment in all groups led to a reduction in CD8 T-cell responses in the BAL when compared to placebo.

Conclusions: To our knowledge, this is the first time a combination of a host-targeting compound, RM-5061, and neuraminidase inhibitor, OST, has been tested in vivo. This antiviral combination was safe in mice and led to reduced inflammatory responses following viral infection when compared to untreated animals.
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http://dx.doi.org/10.1111/irv.12776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578329PMC
November 2020

Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility.

PLoS Pathog 2020 06 18;16(6):e1008592. Epub 2020 Jun 18.

WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

The neuraminidase (NA) inhibitor (NAI) oseltamivir (OST) is the most widely used influenza antiviral drug. Several NA amino acid substitutions are reported to reduce viral susceptibility to OST in in vitro assays. However, whether there is a correlation between the level of reduction in susceptibility in vitro and the efficacy of OST against these viruses in vivo is not well understood. In this study, a ferret model was utilised to evaluate OST efficacy against circulating influenza A and B viruses with a range of in vitro generated 50% inhibitory concentrations (IC50) values for OST. OST efficacy against an A(H1N1)pdm09 and an A(H1N1)pdm09 virus with the H275Y substitution in neuraminidase was also tested in the macaque model. The results from this study showed that OST had a significant impact on virological parameters compared to placebo treatment of ferrets infected with wild-type influenza A viruses with normal IC50 values (~1 nM). However, this efficacy was lower against wild-type influenza B and other viruses with higher IC50 values. Differing pathogenicity of the viruses made evaluation of clinical parameters difficult, although some effect of OST in reducing clinical signs was observed with influenza A(H1N1) and A(H1N1)pdm09 (H275Y) viruses. Viral titres in macaques were too low to draw conclusive results. Analysis of the ferret data revealed a correlation between IC50 and OST efficacy in reducing viral shedding but highlighted that the current WHO guidelines/criteria for defining normal, reduced or highly reduced inhibition in influenza B viruses based on in vitro data are not well aligned with the low in vivo OST efficacy observed for both wild-type influenza B viruses and those with reduced OST susceptibility.
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http://dx.doi.org/10.1371/journal.ppat.1008592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326275PMC
June 2020

Host-targeted nitazoxanide has a high barrier to resistance but does not reduce the emergence or proliferation of oseltamivir-resistant influenza viruses in vitro or in vivo when used in combination with oseltamivir.

Antiviral Res 2020 08 13;180:104851. Epub 2020 Jun 13.

WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia; The University of Melbourne, Department of Microbiology and Immunology, Parkville, Victoria, 3010, Australia.

A major limitation of the currently available influenza antivirals is the potential development of drug resistance. The adamantanes, neuraminidase inhibitors, and more recently polymerase inhibitors, have all been associated with the emergence of viral resistance in preclinical, clinical studies or in clinical use. As a result, host-targeted drugs that act on cellular proteins or functions have become an attractive option for influenza treatment as they are less likely to select for resistance. Nitazoxanide (NTZ) is a host-targeted antiviral that is currently in Phase III clinical trials for the treatment of influenza. In this study, we investigated the propensity for circulating influenza viruses to develop resistance to nitazoxanide in vitro by serially passaging viruses under selective pressure. Phenotypic and genotypic analysis of viruses passaged ten times in the presence of up to 20 μM tizoxanide (TIZ; the active metabolite of nitazoxanide) showed that none had a significant change in TIZ susceptibility, and amino acid substitutions arising that were unique to TIZ passaged viruses, did not alter TIZ susceptibility. Combination therapy, particularly utilising drugs with different mechanisms of action, is another option for combatting antiviral resistance, and while combination therapy has been shown to improve antiviral effects, the effect of reducing the emergence and selection of drug-resistant virus has been less widely investigated. Here we examined the use of TIZ in combination with oseltamivir, both in vitro and using the ferret model for influenza infection and found that the combination of the two drugs did not provide significant benefit in reducing the emergence or selection of oseltamivir-resistant virus. These in vitro findings suggest that clinical use of NTZ may be significantly less likely to select for resistance in circulating influenza viruses compared to virus-targeted antivirals, and although the combination of NTZ with oseltamivir did not reduce the emergence of oseltamivir-resistant virus in vitro or in vivo, combination therapy with NTZ and other newer classes of influenza antiviral drugs should be considered due to NTZ's higher host-based barrier to resistance.
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http://dx.doi.org/10.1016/j.antiviral.2020.104851DOI Listing
August 2020

The impact of climate and antigenic evolution on seasonal influenza virus epidemics in Australia.

Nat Commun 2020 06 2;11(1):2741. Epub 2020 Jun 2.

Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Although seasonal influenza viruses circulate globally, prevention and treatment occur at the level of regions, cities, and communities. At these scales, the timing, duration and magnitude of epidemics vary substantially, but the underlying causes of this variation are poorly understood. Here, based on analyses of a 15-year city-level dataset of 18,250 laboratory-confirmed and antigenically-characterised influenza virus infections from Australia, we investigate the effects of previously hypothesised environmental and virological drivers of influenza epidemics. We find that anomalous fluctuations in temperature and humidity do not predict local epidemic onset timings. We also find that virus antigenic change has no consistent effect on epidemic size. In contrast, epidemic onset time and heterosubtypic competition have substantial effects on epidemic size and composition. Our findings suggest that the relationship between influenza population immunity and epidemiology is more complex than previously supposed and that the strong influence of short-term processes may hinder long-term epidemiological forecasts.
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http://dx.doi.org/10.1038/s41467-020-16545-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265451PMC
June 2020

Sequencing B cell receptors from ferrets (Mustela putorius furo).

PLoS One 2020 29;15(5):e0233794. Epub 2020 May 29.

Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

The domestic ferret (Mustela putorius furo) provides a critical animal model to study human respiratory diseases. However immunological insights are restricted due to a lack of ferret-specific reagents and limited genetic information about ferret B and T cell receptors. Here, variable, diversity and joining genes within the ferret kappa, lambda and heavy chain immunoglobulin loci were annotated using available genomic information. A multiplex PCR approach was derived that facilitated the recovery of paired heavy and light chain immunoglobulin sequences from single sorted ferret B cells, allowing validation of predicted germline gene sequences and the identification of putative novel germlines. Eukaryotic expression vectors were developed that enabled the generation of recombinant ferret monoclonal antibodies. This work advances the ferret as an informative immunological model for viral diseases by allowing the in-depth interrogation of antibody-based immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233794PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259655PMC
September 2020

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission.

PLoS Pathog 2020 04 15;16(4):e1008395. Epub 2020 Apr 15.

Department of Infectious Disease, Imperial College London, London, United Kingdom.

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.
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http://dx.doi.org/10.1371/journal.ppat.1008395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159184PMC
April 2020

Sustained RNA virome diversity in Antarctic penguins and their ticks.

ISME J 2020 07 14;14(7):1768-1782. Epub 2020 Apr 14.

WHO Collaborating Centre for Reference and Research on Influenza, at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

Despite its isolation and extreme climate, Antarctica is home to diverse fauna and associated microorganisms. It has been proposed that the most iconic Antarctic animal, the penguin, experiences low pathogen pressure, accounting for their disease susceptibility in foreign environments. There is, however, a limited understanding of virome diversity in Antarctic species, the extent of in situ virus evolution, or how it relates to that in other geographic regions. To assess whether penguins have limited microbial diversity we determined the RNA viromes of three species of penguins and their ticks sampled on the Antarctic peninsula. Using total RNA sequencing we identified 107 viral species, comprising likely penguin associated viruses (n = 13), penguin diet and microbiome associated viruses (n = 82), and tick viruses (n = 8), two of which may have the potential to infect penguins. Notably, the level of virome diversity revealed in penguins is comparable to that seen in Australian waterbirds, including many of the same viral families. These data run counter to the idea that penguins are subject to lower pathogen pressure. The repeated detection of specific viruses in Antarctic penguins also suggests that rather than being simply spill-over hosts, these animals may act as key virus reservoirs.
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http://dx.doi.org/10.1038/s41396-020-0643-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305176PMC
July 2020

Prophylaxis of ferrets with nitazoxanide and oseltamivir combinations is more effective at reducing the impact of influenza a virus infection compared to oseltamivir monotherapy.

Antiviral Res 2020 04 20;176:104751. Epub 2020 Feb 20.

WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; School of Health and Life Sciences, Federation University, Churchill, Victoria, Australia.

Combination therapy is an alternative approach to reduce viral shedding and improve clinical outcomes following influenza virus infections. In this study we used oseltamivir (OST), a neuraminidase inhibitor and nitazoxanide (NTZ), a host directed drug, and found in vitro that the combination of these two antivirals have a synergistic relationship. Using the ferret model of (A/Perth/265/2009, (H1N1)pdm09), virus infections, we found that the combination of NTZ and OST was more effective than either NTZ or OST independently in preventing infection and reducing duration of viral shedding. However, these benefits were only seen if treatment was administered prophylactically, as opposed to therapeutically. We also found that if prophylactically treated ferrets that had detectable virus in the upper respiratory tract, no virus was detected in the lower respiratory tract. This benefit was not observed with NTZ or OST alone. The combination of NTZ and OST enhances the antiviral effect of OST, which is the standard of care in most settings.
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http://dx.doi.org/10.1016/j.antiviral.2020.104751DOI Listing
April 2020

A rapid pyrosequencing assay for the molecular detection of influenza viruses with reduced baloxavir susceptibility due to PA/I38X amino acid substitutions.

Influenza Other Respir Viruses 2020 07 11;14(4):460-464. Epub 2020 Feb 11.

WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

Baloxavir marboxil is a novel endonuclease inhibitor licensed for treatment of otherwise healthy or high-risk individuals infected with influenza. Viruses with reduced baloxavir susceptibility due to amino acid substitutions at residue 38 of the PA have been detected in some individuals following treatment. Here, we describe a genotypic pyrosequencing method that can be used to rapidly screen circulating influenza A and B viruses for substitutions in the PA/I38 codon and to quantify mixed viral populations. This method is suitable for surveillance of baloxavir susceptibility and to analyse samples from hospitalised patients undergoing baloxavir treatment to aid in clinical decision making.
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http://dx.doi.org/10.1111/irv.12725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298287PMC
July 2020

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018.

Antiviral Res 2020 03 28;175:104718. Epub 2020 Jan 28.

National Institute for Public Health and the Environment, PO Box 1, 3720, BA Bilthoven, the Netherlands.

The global analysis of neuraminidase inhibitor (NAI) susceptibility of influenza viruses has been conducted since the 2012-13 period. In 2018 a novel cap-dependent endonuclease inhibitor, baloxavir, that targets polymerase acidic subunit (PA) was approved for the treatment of influenza virus infection in Japan and the United States. For this annual report, the susceptibilities of influenza viruses to NAIs and baloxavir were analyzed. A total of 15409 viruses, collected by World Health Organization (WHO) recognized National Influenza Centers and other laboratories between May 2017 and May 2018, were assessed for phenotypic NAI susceptibility by five WHO Collaborating Centers (CCs). The 50% inhibitory concentration (IC) was determined for oseltamivir, zanamivir, peramivir and laninamivir. Reduced inhibition (RI) or highly reduced inhibition (HRI) by one or more NAIs was exhibited by 0.8% of viruses tested (n = 122). The frequency of viruses with RI or HRI has remained low since this global analysis began (2012-13: 0.6%; 2013-14: 1.9%; 2014-15: 0.5%; 2015-16: 0.8%; 2016-17: 0.2%). PA gene sequence data, available from public databases (n = 13523), were screened for amino acid substitutions associated with reduced susceptibility to baloxavir (PA E23G/K/R, PA A36V, PA A37T, PA I38F/M/T/L, PA E119D, PA E199G): 11 (0.08%) viruses possessed such substitutions. Five of them were included in phenotypic baloxavir susceptibility analysis by two WHO CCs and IC values were determined. The PA variant viruses showed 6-17-fold reduced susceptibility to baloxavir. Overall, in the 2017-18 period the frequency of circulating influenza viruses with reduced susceptibility to NAIs or baloxavir was low, but continued monitoring is important.
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http://dx.doi.org/10.1016/j.antiviral.2020.104718DOI Listing
March 2020

Assessing the susceptibility of highly pathogenic avian influenza H5N1 viruses to oseltamivir using embryonated chicken eggs.

Indian J Med Res 2019 11;150(5):486-491

ICMR-National Institute of Virology-Mumbai Unit, Mumbai, Maharashtra, India.

Background & Objectives: The susceptibility of influenza viruses to neuraminidase inhibitors (NAIs) is studied using enzyme-based assays, sequence analysis and in vitro and in vivo studies. Oseltamivir carboxylate (OC) is the active prodrug of the NAI oseltamivir. There is lack of information on the use of embryonated chicken eggs for studying susceptibility of highly pathogenic avian influenza (HPAI) H5N1 viruses to antiviral drugs. The aim of the present study was to assess the use of 10 day old embryonated chicken eggs for studying antiviral susceptibility of HPAI H5N1 viruses.

Methods: Two HPAI H5N1 viruses isolated from India were used in the study. Fluorescence-based NAI assay was performed to determine antiviral susceptibility of these viruses. In ovo antiviral assays were carried out using 10 day old embryonated chicken eggs. The virus dilutions were incubated with 14 μg/ml of OC and inoculated in the allantoic cavity. In the eggs, 50 per cent egg infectious dose (EID) titres as well as mortality were quantitated.

Results: The two viruses used were susceptible to OC in the NAI assay. It was found that there was a significant drop in EIDtitres; however, no significant protection from mortality after OC treatment was observed.

Interpretation & Conclusions: By measuring viral titres, the egg model was suitable to study the susceptibility of HPAI viruses to antiviral drugs along with NAI assay. The present study highlights the use of eggs as a model to study susceptibility of HPAI viruses to OC.
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http://dx.doi.org/10.4103/ijmr.IJMR_845_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977371PMC
November 2019

Genetic variations on 31 and 450 residues of influenza A nucleoprotein affect viral replication and translation.

J Biomed Sci 2020 Jan 6;27(1):17. Epub 2020 Jan 6.

Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan, 701, Taiwan.

Background: Influenza A viruses cause epidemics/severe pandemics that pose a great global health threat. Among eight viral RNA segments, the multiple functions of nucleoprotein (NP) play important roles in viral replication and transcription.

Methods: To understand how NP contributes to the virus evolution, we analyzed the NP gene of H3N2 viruses in Taiwan and 14,220 NP sequences collected from Influenza Research Database. The identified genetic variations were further analyzed by mini-genome assay, virus growth assay, viral RNA and protein expression as well as ferret model to analyze their impacts on viral replication properties.

Results: The NP genetic analysis by Taiwan and global sequences showed similar evolution pattern that the NP backbones changed through time accompanied with specific residue substitutions from 1999 to 2018. Other than the conserved residues, fifteen sporadic substitutions were observed in which the 31R, 377G and 450S showed higher frequency. We found 31R and 450S decreased polymerase activity while the dominant residues (31 K and 450G) had higher activity. The 31 K and 450G showed better viral translation and replication in vitro and in vivo.

Conclusions: These findings indicated variations identified in evolution have roles in modulating viral replication in vitro and in vivo. This study demonstrates that the interaction between variations of NP during virus evolution deserves future attention.
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http://dx.doi.org/10.1186/s12929-019-0612-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943894PMC
January 2020

The evolution and genetic diversity of avian influenza A(H9N2) viruses in Cambodia, 2015 - 2016.

PLoS One 2019 9;14(12):e0225428. Epub 2019 Dec 9.

Virology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia.

Low pathogenic A(H9N2) subtype avian influenza viruses (AIVs) were originally detected in Cambodian poultry in 2013, and now circulate endemically. We sequenced and characterised 64 A(H9N2) AIVs detected in Cambodian poultry (chickens and ducks) from January 2015 to May 2016. All A(H9) viruses collected in 2015 and 2016 belonged to a new BJ/94-like h9-4.2.5 sub-lineage that emerged in the region during or after 2013, and was distinct to previously detected Cambodian viruses. Overall, there was a reduction of genetic diversity of H9N2 since 2013, however two genotypes were detected in circulation, P and V, with extensive reassortment between the viruses. Phylogenetic analysis showed a close relationship between A(H9N2) AIVs detected in Cambodian and Vietnamese poultry, highlighting cross-border trade/movement of live, domestic poultry between the countries. Wild birds may also play a role in A(H9N2) transmission in the region. Some genes of the Cambodian isolates frequently clustered with zoonotic A(H7N9), A(H9N2) and A(H10N8) viruses, suggesting a common ecology. Molecular analysis showed 100% of viruses contained the hemagglutinin (HA) Q226L substitution, which favours mammalian receptor type binding. All viruses were susceptible to the neuraminidase inhibitor antivirals; however, 41% contained the matrix (M2) S31N substitution associated with resistance to adamantanes. Overall, Cambodian A(H9N2) viruses possessed factors known to increase zoonotic potential, and therefore their evolution should be continually monitored.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225428PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901181PMC
March 2020

Serologic Evidence of Exposure to Highly Pathogenic Avian Influenza H5 Viruses in Migratory Shorebirds, Australia.

Emerg Infect Dis 2019 10;25(10):1903-1910

Highly pathogenic avian influenza (HPAI) H5Nx viruses of the goose/Guangdong/96 lineage continue to cause outbreaks in poultry and wild birds globally. Shorebirds, known reservoirs of avian influenza viruses, migrate from Siberia to Australia along the East-Asian-Australasian Flyway. We examined whether migrating shorebirds spending nonbreeding seasons in Australia were exposed to HPAI H5 viruses. We compared those findings with those for a resident duck species. We screened >1,500 blood samples for nucleoprotein antibodies and tested positive samples for specific antibodies against 7 HPAI H5 virus antigens and 2 low pathogenicity avian influenza H5 virus antigens. We demonstrated the presence of hemagglutinin inhibitory antibodies against HPAI H5 virus clade 2.3.4.4 in the red-necked stint (Calidris ruficolis). We did not find hemagglutinin inhibitory antibodies in resident Pacific black ducks (Anas superciliosa). Our study highlights the potential role of long-distance migratory shorebirds in intercontinental spread of HPAI H5 viruses.
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http://dx.doi.org/10.3201/eid2510.190699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759277PMC
October 2019

Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin.

Elife 2019 08 27;8. Epub 2019 Aug 27.

Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.

A longstanding question is how influenza virus evolves to escape human immunity, which is polyclonal and can target many distinct epitopes. Here, we map how all amino-acid mutations to influenza's major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is present among ferrets that have been infected just once with a defined viral strain. Our results show how different single mutations help influenza virus escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.
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http://dx.doi.org/10.7554/eLife.49324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711711PMC
August 2019

Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.

J Infect Dis 2020 01;221(3):346-355

Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.

Background: Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.

Methods: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.

Results: Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.

Conclusions: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.

Clinical Trial Registration: NCT02954354.
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http://dx.doi.org/10.1093/infdis/jiz244DOI Listing
January 2020

A novel I117T substitution in neuraminidase of highly pathogenic avian influenza H5N1 virus conferring reduced susceptibility to oseltamivir and zanamivir.

Vet Microbiol 2019 Aug 5;235:21-24. Epub 2019 Jun 5.

Avian Influenza Group, Microbial Containment Complex, ICMR-National Institute of Virology, 130/1, Sus Road, Pashan, Pune 411021, India.

Occurrence of avian influenza (AI) with Neuraminidase (NA) mutations which confer reduced neuraminidase inhibitor (NAI) susceptibility has remained a cause of concern. The susceptibility to NAIs of 67 highly pathogenic avian influenza H5N1 viruses isolated during 2006-2012 in India was tested in phenotypic fluorescence-based NA inhibition assay, sequence analysis and in ovo. One isolate showed a novel NA I117T amino acid substitution (N2 numbering) and eight isolates showed previously known NAI-resistance marker mutations (I117V, E119D, N294S, total 9/67). The overall incidence of resistant variants was 13.4%. The novel I117T substitution reduced oseltamivir susceptibility by 18.6-fold and zanamivir susceptibility by 11.8-fold, compared to the wild type AI H5N1virus, thus showed cross-resistance to both oseltamivir and zanamivir in NA inhibition assays. However, the other two isolates with I117V substitution were sensitive to both the NAIs. In addition, the comparison of growth of the I117T and I117V variants in presence of NAI's in the in ovo assays exhibited difference in growth levels. The present study reports the natural occurrence of a novel I117T mutation in AI H5N1 virus conferring cross-resistance to oseltamivir and zanamivir highlighting the urgent need of antiviral surveillance of AI viruses.
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http://dx.doi.org/10.1016/j.vetmic.2019.06.005DOI Listing
August 2019

Circulation and characterization of seasonal influenza viruses in Cambodia, 2012-2015.

Influenza Other Respir Viruses 2019 09 28;13(5):465-476. Epub 2019 Jun 28.

Virology Unit, Institute Pasteur in Cambodia, Institute Pasteur International Network, Phnom Penh, Cambodia.

Background: Influenza virus circulation is monitored through the Cambodian influenza-like illness (ILI) sentinel surveillance system and isolates are characterized by the National Influenza Centre (NIC). Seasonal influenza circulation has previously been characterized by year-round activity and a peak during the rainy season (June-November).

Objectives: We documented the circulation of seasonal influenza in Cambodia for 2012-2015 and investigated genetic, antigenic, and antiviral resistance characteristics of influenza isolates.

Patients/methods: Respiratory samples were collected from patients presenting with influenza-like illness (ILI) at 11 hospitals throughout Cambodia. First-line screening was conducted by the National Institute of Public Health and the Armed Forces Research Institute of Medical Sciences. Confirmation of testing and genetic, antigenic and antiviral resistance characterization was conducted by Institute Pasteur in Cambodia, the NIC. Additional virus characterization was conducted by the WHO Collaborating Centre for Reference and Research on Influenza (Melbourne, Australia).

Results: Between 2012 and 2015, 1,238 influenza-positive samples were submitted to the NIC. Influenza A(H3N2) (55.3%) was the dominant subtype, followed by influenza B (30.9%; predominantly B/Yamagata-lineage) and A(H1N1)pdm09 (13.9%). Circulation of influenza viruses began earlier in 2014 and 2015 than previously described, coincident with the emergence of A(H3N2) clades 3C.2a and 3C.3a, respectively. There was high diversity in the antigenicity of A(H3N2) viruses, and to a smaller extent influenza B viruses, during this period, with some mismatches with the northern and southern hemisphere vaccine formulations. All isolates tested were susceptible to the influenza antiviral drugs oseltamivir and zanamivir.

Conclusions: Seasonal and year-round co-circulation of multiple influenza types/subtypes were detected in Cambodia during 2012-2015.
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http://dx.doi.org/10.1111/irv.12647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692578PMC
September 2019

Antivirals targeting the polymerase complex of influenza viruses.

Antiviral Res 2019 09 25;169:104545. Epub 2019 Jun 25.

WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia. Electronic address:

Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Encouragingly, several new compounds which inhibit the polymerase of influenza viruses have recently been shown to have enhanced pre-clinical and clinical effectiveness compared to the neuraminidase inhibitors, the mainstay of influenza antiviral therapy over the last two decades. In this review we focus on four compounds which inhibit polymerase function, baloxavir marboxil, favipiravir, pimodivir and AL-794 and discuss their clinical and virological effectiveness, their propensity to select for resistance and their potential for future combination therapy with the most commonly used neuraminidase inhibitor, oseltamivir.
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http://dx.doi.org/10.1016/j.antiviral.2019.104545DOI Listing
September 2019

Virome heterogeneity and connectivity in waterfowl and shorebird communities.

ISME J 2019 10 25;13(10):2603-2616. Epub 2019 Jun 25.

Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Life and Environmental Sciences and Sydney Medical School, The University of Sydney, Sydney, Australia.

Models of host-microbe dynamics typically assume a single-host population infected by a single pathogen. In reality, many hosts form multi-species aggregations and may be infected with an assemblage of pathogens. We used a meta-transcriptomic approach to characterize the viromes of nine avian species in the Anseriformes (ducks) and Charadriiformes (shorebirds). This revealed the presence of 27 viral species, of which 24 were novel, including double-stranded RNA viruses (Picobirnaviridae and Reoviridae), single-stranded RNA viruses (Astroviridae, Caliciviridae, Picornaviridae), a retro-transcribing DNA virus (Hepadnaviridae), and a single-stranded DNA virus (Parvoviridae). These viruses comprise multi-host generalist viruses and those that are host-specific, indicative of both virome connectivity (host sharing) and heterogeneity (host specificity). Virome connectivity was apparent in two well described multi-host virus species -avian coronavirus and influenza A virus- and a novel Rotavirus species that were shared among some Anseriform species, while virome heterogeneity was reflected in the absence of viruses shared between Anseriformes and Charadriiformes, as well as differences in viral abundance and alpha diversity among species. Overall, we demonstrate complex virome structures across host species that co-exist in multi-species aggregations.
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http://dx.doi.org/10.1038/s41396-019-0458-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775988PMC
October 2019

Avian influenza in the Greater Mekong Subregion, 2003-2018.

Infect Genet Evol 2019 10 13;74:103920. Epub 2019 Jun 13.

College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia. Electronic address:

The persistent circulation of avian influenza viruses (AIVs) is an ongoing problem for many countries in South East Asia, causing large economic losses to both the agricultural and health sectors. This review analyses AIV diversity, evolution and the risk of AIV emergence in humans in countries of the Greater Mekong Subregion (GMS): Cambodia, Laos, Myanmar, Thailand and Vietnam (excluding China). The analysis was based on AIV sequencing data, serological studies, published journal articles and AIV outbreak reports available from January 2003 to December 2018. All countries of the GMS have suffered losses due repeated outbreaks of highly pathogenic (HP) H5N1 that has also caused human cases in all GMS countries. In Laos, Myanmar and Vietnam AIV outbreaks in domestic poultry have also been caused by clade 2.3.4.4 H5N6. A diverse range of low pathogenic AIVs (H1-H12) have been detected in poultry and wild bird species, though surveillance for and characterization of these subtypes is limited. Subtype H3, H4, H6 and H11 viruses have been detected over prolonged periods; whilst H1, H2, H7, H8, H10 and H12 viruses have only been detected transiently. H9 AIVs circulate endemically in Cambodia and Vietnam with seroprevalence data indicating human exposure to H9 AIVs in Cambodia, Thailand and Vietnam. As surveillance studies focus heavily on the detection of H5 AIVs in domestic poultry further research is needed to understand the true level of AIV diversity and the risk AIVs pose to humans in the GMS.
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http://dx.doi.org/10.1016/j.meegid.2019.103920DOI Listing
October 2019
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