Our previous reports demonstrated an alarming in crease in resistance to adamantanes among influenza A(H3N2) viruses isolated in 2001–2005. To continue monitoring drug resistance, we conducted a ...comprehensive analysis of influenza A(H3N2) and A(H1N1) viruses isolated globally in 2005–2006. The results obtained by pyrosequencing indicate that 96.4% (n=761) of A(H3N2) viruses circulating in the United States were adamantane resistant. Drug resistance has reached 100% among isolates from some Asian countries. Analysis of correlation between the appearance of drug resistance and the evolutionary pathway of the hemagglutinin (HA) gene suggests at least 2 separate introductions of resistance into circulating populations that gave rise to identifiable subclades. It also indicates that resistant A(H3N2) viruses may have emerged in Asia in late 2001. Among A(H1N1) viruses isolated worldwide, resistance reached 15.5% in 2005–2006; in the United States alone, it was 4.0%. Phylogenetic analysis of the HA and M genes indicates that the acquisition of resistance in A(H1N1) viruses can be linked to a specific genetic group and was not a result of reassortment between A(H3N2) and A(H1N1) viruses. The results of the study highlight the necessity of close monitoring of resistance to existing antivirals as wells as the need for new therapeutics.
Background. Although influenza is a vaccine-preventable disease that annually causes substantial disease burden, data on virus activity in tropical countries are limited. We analyzed publicly ...available influenza data to better understand the global circulation of influenza viruses. Method. We reviewed open-source, laboratory-confirmed influenza surveillance data. For each country, we abstracted data on the percentage of samples testing positive for influenza each epidemiologic week from the annual number of samples testing positive for influenza. The start of influenza season was defined as the first week when the proportion of samples that tested positive remained above the annual mean. We assessed the relationship between percentage of samples testing positive and mean monthly temperature with use of regression models. Findings. We identified data on laboratory-confirmed influenza virus infection from 85 countries. More than one influenza epidemic period per year was more common in tropical countries (41%) than in temperate countries (15%). Year-round activity (ie, influenza virus identified each week having ≥10 specimens submitted) occurred in 3 (7%) of 43 temperate, 1 (17%) of 6 subtropical, and 11 (37%) of 30 tropical countries with available data (P = .006). Percentage positivity was associated with low temperature (P = .001). Interpretation. Annual influenza epidemics occur in consistent temporal patterns depending on climate.
Influenza A viruses of domestic birds originate from the natural reservoir in aquatic birds as a result of interspecies transmission and adaptation to new host species. We previously noticed that ...influenza viruses isolated from distinct orders of aquatic and terrestrial birds may differ in their fine receptor-binding specificity by recognizing the structure of the inner parts of Neu5Ac alpha 2-3Gal-terminated sialyloligosaccharide receptors. To further characterize these differences, we studied receptor-binding properties of a large panel of influenza A viruses from wild aquatic birds, poultry, pigs and horses.
Using a competitive solid-phase binding assay, we determined viral binding to polymeric conjugates of sialyloligosaccharides differing by the type of Neu5Ac alpha-Gal linkage and by the structure of the more distant parts of the oligosaccharide chain. Influenza viruses isolated from terrestrial poultry differed from duck viruses by an enhanced binding to sulfated and/or fucosylated Neu5Ac alpha 2-3Gal-containing sialyloligosaccharides. Most of the poultry viruses tested shared a high binding affinity for the 6-sulfo sialyl Lewis X (Su-SLex). Efficient binding of poultry viruses to Su-SLex was often accompanied by their ability to bind to Neu5Ac alpha 2-6Gal-terminated (human-type) receptors. Such a dual receptor-binding specificity was demonstrated for the North American and Eurasian H7 viruses, H9N2 Eurasian poultry viruses, and H1, H3 and H9 avian-like virus isolates from pigs.
Influenza viruses of terrestrial poultry differ from ancestral duck viruses by enhanced binding to sulfated and/or fucosylated Neu5Ac alpha 2-3Gal-terminated receptors and, occasionally, by the ability to bind to Neu5Ac alpha 2-6Gal-terminated (human-type) receptors. These findings suggest that the adaptation to receptors in poultry can enhance the potential of an avian virus for avian-to-human transmission and pandemic spread.
Seasonal epidemics caused by influenza virus are driven by antigenic changes (drift) in viral surface glycoproteins that allow evasion from preexisting humoral immunity. Antigenic drift is a feature ...of not only the hemagglutinin (HA), but also of neuraminidase (NA). We have evaluated the antigenic evolution of each protein in H1N1 and H3N2 viruses used in vaccine formulations during the last 15 y by analysis of HA and NA inhibition titers and antigenic cartography. As previously shown for HA, genetic changes in NA did not always lead to an antigenic change. The noncontinuous pattern of NA drift did not correspond closely with HA drift in either subtype. Although NA drift was demonstrated using ferret sera, we show that these changes also impact recognition by NA-inhibiting antibodies in human sera. Remarkably, a single point mutation in the NA of A/Brisbane/59/2007 was primarily responsible for the lack of inhibition by polyclonal antibodies specific for earlier strains. These data underscore the importance of NA inhibition testing to define antigenic drift when there are sequence changes in NA.
Adamantanes have been used to treat influenza A virus infections for many years. Studies have shown a low incidence of resistance to these drugs among circulating influenza viruses; however, their ...use is rising worldwide and drug resistance has been reported among influenza A (H5N1) viruses isolated from poultry and human beings in Asia. We sought to assess adamantane resistance among influenza A viruses isolated during the past decade from countries participating in WHO's global influenza surveillance network.
We analysed data for influenza field isolates that were obtained worldwide and submitted to the WHO Collaborating Center for Influenza at the US Centers for Disease Control and Prevention between Oct 1, 1994, and Mar 31, 2005. We used pyrosequencing, confirmatory sequence analysis, and phenotypic testing to detect drug resistance among circulating influenza A H3N2 (n=6524), H1N1 (n=589), and H1N2 (n=83) viruses.
More than 7000 influenza A field isolates were screened for specific aminoacid substitutions in the M2 gene known to confer drug resistance. During the decade of surveillance a significant increase in drug resistance was noted, from 0·4% in 1994–1995 to 12·3% in 2003–2004. This increase in the proportion of resistant viruses was weighted heavily by those obtained from Asia with 61% of resistant viruses isolated since 2003 being from people in Asia.
Our data raise concerns about the appropriate use of adamantanes and draw attention to the importance of tracking the emergence and spread of drug-resistant influenza A viruses.
Antiviral drug resistance for influenza therapies remains a concern due to the high prevalence of H1N1 2009 seasonal influenza isolates which display H274Y associated oseltamivir-resistance. ...Furthermore, the emergence of novel H1N1 raises the potential that additional reassortments can occur, resulting in drug resistant virus. Thus, additional antiviral approaches are urgently needed. DAS181 (Fludase), a sialidase fusion protein, has been shown to have inhibitory activity against a large number of seasonal influenza strains and a highly pathogenic avian influenza (HPAI) strain (H5N1). Here, we examine the in vitro activity of DAS181 against a panel of 2009 oseltamivir-resistant seasonal H1N1 clinical isolates. The activity of DAS181 against nine 2009, two 2007, and two 2004 clinical isolates of seasonal IFV H1N1 was examined using plaque number reduction assay on MDCK cells. DAS181 strongly inhibited all tested isolates. EC50 values remained constant against isolates from 2004, 2007, and 2009, suggesting that there was no change in DAS181 sensitivity over time. As expected, all 2007 and 2009 isolates were resistant to oseltamivir, consistent with the identification of the H274Y mutation in the NA gene of all these isolates. Interestingly, several of the 2007 and 2009 isolates also exhibited reduced sensitivity to zanamivir, and accompanying HA mutations near the sialic acid binding site were observed. DAS181 inhibits IFV that is resistant to NAIs. Thus, DAS181 may offer an alternative therapeutic option for seasonal or pandemic IFVs that become resistant to currently available antiviral drugs.
CONTEXT The adamantanes, amantadine and rimantadine, have been used as first-choice
antiviral drugs against community outbreaks of influenza A viruses for many
years. Rates of viruses resistant to ...these drugs have been increasing globally.
Rapid surveillance for the emergence and spread of resistant viruses has become
critical for appropriate treatment of patients. OBJECTIVE To investigate the frequency of adamantane-resistant influenza A viruses
circulating in the United States during the initial months of the 2005-2006
influenza season. DESIGN AND SETTING Influenza isolates collected from 26 states from October 1 through December
31, 2005, and submitted to the US Centers for Disease Control and Prevention
were tested for drug resistance as part of ongoing surveillance. Isolates
were submitted from World Health Organization collaborating laboratories and
National Respiratory and Enteric Virus Surveillance System laboratories. MAIN OUTCOME MEASURES Using pyrosequencing and confirmatory assays, we identified viruses
containing mutations within the M2 gene that are known to confer resistance
to both amantadine and rimantadine. RESULTS A total of 209 influenza A(H3N2) viruses isolated from patients in 26
states were screened, of which 193 (92.3%) contained a change at amino acid
31 (serine to asparagine S31N) in the M2 gene known to be correlated with
adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same
mutation. Drug-resistant viruses were distributed across the United States. CONCLUSIONS The high proportion of influenza A viruses currently circulating in
the United States demonstrating adamantane resistance highlights the clinical
importance of rapid surveillance for antiviral resistance. Our results indicate
that these drugs should not be used for the treatment or prophylaxis of influenza
in the United States until susceptibility to adamantanes has been reestablished
among circulating influenza A isolates.Published online February 2, 2006 (doi:10.1001/jama.295.8.joc60020).
Influenza viruses are negative-sense, single-stranded, enveloped RNA viruses belonging to the family Orthomyxoviridae. Three types exist, influenza A, B, and C. All infect humans, but only A and B ...are major human pathogens. Influenza type A viruses are divided into subtypes based on genetic and antigenic differences in the two surface spike proteins, hemagglutinin (HA) and neuraminidase (NA). The appropriate cell lines to be used for isolation of influenza A or B viruses depend on the clinical information and the host of origin. MDCK cells are the preferred cell line for isolation of human influenza viruses from clinical specimens.
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