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Since 2022, three human cases of a novel H3N8 avian influenza virus infection have been reported in three provinces in China. Specific vaccines are important means of preparing for the potential influenza pandemic. Thus, H3N8 viruses [A/Henan/cnic410/2022 (HN410) and A/Changsha/1000/2022(CS1000)] were isolated from the infected patients as prototype viruses to develop candidate vaccine viruses (CVVs) using the reverse genetics (RG) technology. Five reassortant viruses with different HA and NA combinations were constructed based on the two viruses to get a high-yield and safe CVV. The results showed that all viruses had similar antigenicity but different growth characteristics. Reassortant viruses carrying NA from CS1000 exhibited better growth ability and NA enzyme activity than the ones carrying HN410 NA. Furthermore, the NA gene of CS1000 had one more potential N-glycosylation site at position 46 compared with HN410. The substitution of position 46 showed that adding or removing N-glycosylation sites to different reassortant viruses had different effects on growth ability. A reassortant virus carrying HN410 HA and CS1000 NA with high growth ability was selected as a CVV, which met the requirements for a CVV. These data suggest that different surface gene combinations and the presence or absence of potential N-glycosylation sites on position 46 in the NA gene affect the growth characteristics of H3N8 CVVs.

Background: Since the first human infection with H9N2 virus was reported in 1998, the number of cases of H9N2 infection has exceeded one hundred by 2021. However, there is no systematic description of the biological characteristics of H9N2 viruses isolated from humans. Methods: Therefore, this study analyzed the pathogenicity in mice of all available H9N2 viruses isolated from human cases in China from 2013 to 2021. Results: Although most of the H9N2 viruses analyzed showed low or no pathogenicity in mice, the leucine to glutamine substitution at residue 226 (L226Q) in the hemagglutinin (HA) protein rapidly emerged during the adaptation of H9N2 viruses, and was responsible for severe infections and even fatalities. HA amino acid 226Q conferred a remarkable competitive advantage on H9N2 viruses in mice relative to viruses containing 226L, increasing their virulence, infectivity, and replication. Conclusion: Thus, our study demonstrates that the adaptive substitution HA L226Q rapidly acquired by H9N2 viruses during the course of infection in mice contributed to their high pathogenicity.

IntroductionThe continued emergence of human infections of H9N2 avian influenza virus (AIV) poses a serious threat to public health. The prevalent Y280/G9 lineage of H9N2 AIV in Chinese poultry can directly bind to human receptors, increasing the risk of spillover infections to humans. Since 2013, the number of human cases of H9N2 avian influenza has been increasing continuously, and in 2021, China reported the highest number of human cases, at 25.MethodsIn this study, we analyzed the age, geographic, temporal, and sex distributions of humans with H9N2 avian influenza in 2021 using data from the National Influenza Center (Beijing, China). We also conducted evolutionary, gene homology, and molecular characterization analyses of the H9N2 AIVs infecting humans.ResultsOur findings show that children under the age of 12 accounted for 80% of human cases in 2021, and females were more frequently affected than males. More cases occurred in winter than in summer, and most cases were concentrated in southern China. Human-infecting H9N2 viruses showed a high level of genetic homology and belonged to the prevalent G57 genotype. Several additional α2,6-SA-binding sites and sites of mammalian adaptation were also identified in the genomes of human-infecting H9N2 viruses.DiscussionTherefore, continuous monitoring of H9N2 AIV and the implementation of further measures to control the H9N2 virus in poultry are essential to reduce the interspecies transmission of the virus.

ABSTRACTH6 avian influenza virus (AIV) is one of the most prevalent AIV subtypes in birds globally. To investigate the current situation and characteristics of H6 AIVs circulating in China, we analysed the epidemiology, genetic evolution and pathogenic features of this subtype. During 2000-2021, H6 subtype AIVs spread widely through Southern China and presented high host diversity. On analysing 171 H6 viruses isolated during 2009-2021, dynamic reassortments were observed among H6 and other co-circulating AIV subtypes, and these generated a total of 16 different genotypes. A few H6N6 strains possessed L226 and S228 mutations of hemagglutinin (H3 numbering), which may enhance the affinity of H6 viruses to human receptors. H6N6 viruses also exhibited divergent pathogenicity and growth profiles in vivo and in vitro. Some of the H6N6 viruses could infect mice without mammalian adaptation, and even caused death in this species. Therefore, our study demonstrated that the H6 AIVs posed a potential threat to human health and highlighted the urgent need for continued surveillance and evaluation of the H6 influenza viruses circulating in the field.

The continuous evolution of avian influenza viruses (AIVs) of subtype H3 in China and the emergence of human infection with AIV subtype H3N8 highlight their threat to public health. Through surveillance in poultry-associated environments during 2009–2022, we isolated and sequenced 188 H3 AIVs across China. Performing large-scale sequence analysis with publicly available data, we identified 4 sublineages of H3 AIVs established in domestic ducks in China via multiple introductions from wild birds from Eurasia. Using full-genome analysis, we identified 126 distinct genotypes, of which the H3N2 G23 genotype predominated recently. H3N8 G25 viruses, which spilled over from birds to humans, might have been generated by reassortment between H3N2 G23, wild bird H3N8, and poultry H9N2 before February 2021. Mammal-adapted and drug-resistance substitutions occasionally occurred in H3 AIVs. Ongoing surveillance for H3 AIVs and risk assessment are imperative for potential pandemic preparedness.

Wild birds are a natural reservoir for zoonotic viruses. To clarify the role of migratory birds in viruses spread in Poyang Lake, we investigated the microbiome of 250 wild bird samples from 19 species in seven orders. The bacterial and viral content abundance and diversity were preliminarily evaluated by Kraken2 and Bracken. After de novo assembly by Megahit and Vamb, viral contigs were identified by CheckV. The reads remapped to viral contigs were quantified using Bowtie2. The bacterial microbiome composition of the samples covers 1526 genera belonging to 175 bacterial orders, while the composition of viruses covers 214 species belonging to 22 viral families. Several taxonomic biomarkers associated with avian carnivory, oral sampling, and raptor migration were identified. Additionally, 17 complete viral genomes belonging to Astroviridae, Caliciviridae, Dicistroviridae, Picornaviridae, and Tombusviridae were characterized, and their phylogenetic relationships were analyzed. This pioneering metagenomic study of migratory birds in Poyang Lake, China illuminates the diverse microbial landscape within these birds. It identifies potential pathogens, and uncovers taxonomic biomarkers relevant to varied bird habitats, feeding habits, ecological classifications, and sample types, underscoring the public health risks associated with wintering migratory birds.

Abstract Background The influenza viruses pose a threat to human health and medical services, and vaccination is an important way to prevent infection. However, the effectiveness of influenza vaccines is affected by various aspects. This study aimed to explore factors related to the immune response to influenza vaccines. Methods The study was conducted from September 2019 to September 2021, and a total of 593 volunteers were recruited from the Center for Disease Control and Prevention in 3 provinces in China. The hemagglutination inhibition assay was used to measure antibody levels. The Chi-square test, multivariable logistic regression analysis, and sum-rank test were used to analyze the factors associated with influenza vaccine immune response. Results The Chi-square test showed that seroconversion rates and response rate were associated with age group, vaccination history, chronic conditions, the frequency of colds, and region (P

We conducted environmental surveillance to detect avian influenza viruses circulating at live poultry markets (LPMs) and poultry farms in Guangxi Autonomous Region, China, where near the China-Vietnam border. From November through April 2017–2018 and 2018–2019, we collected environmental samples from 14 LPMs, 4 poultry farms, and 5 households with backyard poultry in two counties of Guangxi and tested for avian influenza A, H5, H7, and H9 by real-time reverse transcription-polymerase chain reaction (rRT-PCR). In addition, we conducted four cross-sectional questionnaire surveys among stall owners on biosecurity practices in LPMs of two study sites. Among 16,713 environmental specimens collected and tested, the median weekly positive rate for avian influenza A was 53.6% (range = 33.5% − 66.0%), including 25.2% for H9, 4.9% for H5, and 21.2% for other avian influenza viruses A subtypes, whereas a total of two H7 positive samples were detected. Among the 189 LPM stalls investigated, most stall owners (73.0%) sold chickens and ducks. Therefore, continued surveillance of the avian influenza virus is necessary for detecting and responding to emerging trends in avian influenza virus epidemiology.

Objectives: The aim of this study was to explore whether indoor or outdoor relative humidity (RH) modulates the influenza epidemic transmission in temperate and subtropical climates. Methods: In this study, the daily temperature and RH in 1558 households from March 2017 to January 2019 in five cities across both temperate and subtropical regions in China were collected. City-level outdoor temperature and RH from 2013 to 2019 were collected from the weather stations. We first estimated the effective reproduction number (Rt) of influenza and then used time-series analyses to explore the relationship between indoor/outdoor RH/absolute humidity and the Rt of influenza. Furthermore, we expanded the measured 1-year indoor temperature and the RH data into 5 years and used the same method to examine the relationship between indoor/outdoor RH and the Rt of influenza. Results: Indoor RH displayed a seasonal pattern, with highs during the summer months and lows during the winter months, whereas outdoor RH fluctuated with no consistent pattern in subtropical regions. The Rt of influenza followed a U-shaped relationship with indoor RH in both temperate and subtropical regions, whereas a U-shaped relationship was not observed between outdoor RH and Rt. In addition, indoor RH may be a better indicator for Rt of influenza than indoor absolute humidity. Conclusion: The findings indicated that indoor RH may be the driver of influenza seasonality in both temperate and subtropical locations in China.

H4 avian influenza viruses (AIVs) have been widely detected in live poultry markets in China. However, the potential public health impact of H4 AIVs remains largely uncertain. Here, we fully analyzed the distribution and phylogenetic relationship of H4 AIVs in China. We obtained 31 isolates of H4 viruses in China during 2009–2022 through surveillance in poultry-associated environments, such as live poultry markets and poultry farms. Genomic sequence analysis together with publicly available data revealed that frequent reassortment and introduction of H4 AIV from wild birds to poultry may have occurred. We identified 62 genotypes among 127 whole genome sequences of H4 viruses in China, indicating that H4 AIVs had great genetic diversity in China. We also investigated molecular markers and found that drug resistance mutations frequently occurred in the M2 protein and a few mutations related to receptor binding and the host signature in H4 AIVs. Our study demonstrates the cross-species transmission potential of H4 AIVs in China and provides some reference significance for its risk assessment.

BackgroundThe world is undergoing an unprecedented wave of urbanization. However, the effect of rapid urbanization during the early or middle stages of urbanization on seasonal influenza transmission remains unknown. Since about 70% of the world population live in low-income countries, exploring the impact of urbanization on influenza transmission in urbanized countries is significant for global infection prediction and prevention. ObjectiveThe aim of this study was to explore the effect of rapid urbanization on influenza transmission in China. MethodsWe performed spatiotemporal analyses of province-level influenza surveillance data collected in Mainland China from April 1, 2010, to March 31, 2017. An agent-based model based on hourly human contact–related behaviors was built to simulate the influenza transmission dynamics and to explore the potential mechanism of the impact of urbanization on influenza transmission. ResultsWe observed persistent differences in the influenza epidemic attack rates among the provinces of Mainland China across the 7-year study period, and the attack rate in the winter waves exhibited a U-shaped relationship with the urbanization rates, with a turning point at 50%-60% urbanization across Mainland China. Rapid Chinese urbanization has led to increases in the urban population density and percentage of the workforce but decreases in household size and the percentage of student population. The net effect of increased influenza transmission in the community and workplaces but decreased transmission in households and schools yielded the observed U-shaped relationship. ConclusionsOur results highlight the complicated effects of urbanization on the seasonal influenza epidemic in China. As the current urbanization rate in China is approximately 59%, further urbanization with no relevant interventions suggests a worrisome increasing future trend in the influenza epidemic attack rate.

Very little is known about biological sex differences in influenza disease outcome. In 2013, avian influenza (H7N9) infections in humans have been reported with higher frequency in men than women. Here, Bai et al. report that low testosterone levels in men correlate with poor infection outcome. They confirm the causal link between viral infection and testosterone depletion using a mouse model.

The recent rise in the frequency of influenza A(H5N6) infections in China has raised serious concerns about whether the risk for human infection has increased. We surveyed epidemiologic, clinical, and genetic data of human infections with A(H5N6) viruses. Severe disease occurred in 93.8% of cases, and the fatality rate was 55.4%. Median patient age was 51 years. Most H5N6 hemagglutinin (HA) genes in human isolates in 2021 originated from subclade 2.3.4.4b; we estimated the time to most recent common ancestor as June 16, 2020. A total of 13 genotypes with HA genes from multiple subclades in clade 2.3.4.4 were identified in human isolates. Of note, 4 new genotypes detected in 2021 were the major causes of increased H5N6 virus infections. Mammalian-adapted mutations were found in HA and internal genes. Although we found no evidence of human-to-human transmission, continuous evolution of H5N6 viruses may increase the risk for human infections.

Influenza B virus is a significant respiratory pathogen responsible for seasonal influenza. In recent years the B/Yamagata lineage has demonstrated a rapid increase, predominantly featuring the neuraminidase (NA) N342K mutation. This study determined the impact of the NA N342K mutation on the pathogenicity of influenza B virus and elucidate the underlying mechanisms. Gene fragments with specific mutations were generated using site-directed mutagenesis PCR, resulting in recombinant viruses (rAH127 and rAH127/NA N342K ). C57BL/6 mice were infected to evaluate the impact of amino acid mutations on virus pathogenicity. Body weight, survival rate, virus replication, and lung pathology were compared among the groups. NA enzyme activity was assessed to determine the mechanisms underlying the effects of amino acid mutations on the pathogenicity of influenza B virus. The NA N342K mutant virus exhibited significantly increased NA enzyme activity (3.19-fold) and viral replication capacity in MDCK cells (6.76-fold) compared to wild-type virus. These changes led to enhanced pathogenicity in mice, characterized by severe weight loss, increased mortality, and heightened lung tissue inflammation. The NA N342K mutation likely enhances virus replication and pathogenicity by increasing NA enzyme activity. These findings contribute to understanding the molecular mechanisms underlying influenza B virus pathogenicity and have implications for targeted therapeutic strategies.

While most broadly neutralizing antibodies (bnAb) against Influenza virus target conserved conformational epitopes of the glycoprotein hemagglutinin (HA), Sun et al. characterize a lineage of bnAbs that neutralize group 1 and 2 strains. Structural characterization shows that antibody 28-12 binds a continuous epitope within H3 (group 2) but requires a conformational epitope for H1 (group 1) binding. Comparison of germline-reverted Ab and intermediate mutants provides evidence for an evolutionary adaptation from group 2 to group 1 strain.

Background: Influenza is a global public health problem for its detrimental impact on human health. Annual vaccination is the most effective prevention of influenza infection. Identifying host genetic factors associated with the responsiveness to influenza vaccines can provide clues for developing more effective influenza vaccines. In this study, we aimed to explore whether the single nucleotide polymorphisms in BAT2 are associated with the antibody responses to influenza vaccines.Method: A nested case-control study was conducted in this research. 1968 healthy volunteers were enrolled and 1,582 of them from a Chinese Han population were eligible for further research. According to the hemagglutination inhibition titers of subjects against all influenza vaccine strains, a total of 227 low responders and 365 responders were included in the analysis. Six tag single nucleotide polymorphisms in the coding region of BAT2 were selected and genotyped using the MassARRAY technology platform. Univariable and multivariable analyses were conducted to evaluate the relationship between variants and antibody responses to influenza vaccination.Results: Multivariable logistic regression analysis showed that, compared with the BAT2 rs1046089GG genotype, the GA + AA genotype was correlated with decreased risk of low responsiveness to influenza vaccines after adjusting for gender and age (p = 1.12E-03, OR = .562, 95%CI: .398–.795). rs9366785 GA + AA genotype was associated with a higher risk of low responsiveness to influenza vaccination compared with the GG genotype (p = .003, OR = 1.854, 95%CI: 1.229–2.799). The haplotype consisting of BAT2 rs2280801-rs10885-rs1046089-rs2736158-rs1046080-rs9366785 CCAGAG was correlated with a higher level of antibody response to influenza vaccines compared with haplotype CCGGAG (p < .001, OR = .37, 95%CI: .23–.58).Conclusion: Genetic variants in BAT2 were statistically associated with the immune response to influenza vaccination among the Chinese population. Identifying these variants will provide clues for further research on novel broad-spectrum influenza vaccines, and improve the individualized influenza vaccination scheme.

Circulation of seasonal influenza is the product of complex interplay among multiple drivers, yet characterizing the underlying mechanism remains challenging. Leveraging the diverse seasonality of A(H3N2) virus and abundant climatic space across regions in China, we quantitatively investigated the relative importance of population susceptibility, climatic factors, and antigenic change on the dynamics of influenza A(H3N2) through an integrative modelling framework. Specifically, an absolute humidity driven multiscale transmission model was constructed for the 2013/2014, 2014/2015 and 2016/2017 influenza seasons that were dominated by influenza A(H3N2). We revealed the variable impact of absolute humidity on influenza transmission and differences in the occurring timing and magnitude of antigenic change for those three seasons. Overall, the initial population susceptibility, climatic factors, and antigenic change explained nearly 55% of variations in the dynamics of influenza A(H3N2). Specifically, the additional variation explained by the initial population susceptibility, climatic factors, and antigenic change were at 33%, 26%, and 48%, respectively. The vaccination program alone failed to fully eliminate the summer epidemics of influenza A(H3N2) and non-pharmacological interventions were needed to suppress the summer circulation. The quantitative understanding of the interplay among driving factors on the circulation of influenza A(H3N2) highlights the importance of simultaneous monitoring of fluctuations for related factors, which is crucial for precise and targeted prevention and control of seasonal influenza.

Abstract During the process of the ballistic target's mid‐flight, it is very important to accurately identify the target. The separation of target micro‐Doppler curves and the extraction of characteristic parameters are the key to accurate identification. Aiming at the slow convergence speed of the traditional Fast‐ICA algorithm, this paper proposes an improved Fast‐ICA algorithm, which realizes the separation of the micro‐Doppler curve of the scattering points. On this basis, the trajectory of scattering points in space is analyzed, the expression of the target feature value is established, and the target feature parameters are effectively extracted. According to the results of the simulation experiment, the algorithm can achieve better signal separation and the characteristic parameters of the target are effectively extracted.

Abstract Background School closure is a common mitigation strategy during severe influenza epidemics and pandemics. However, the effectiveness of this strategy remains controversial. In this study, we aimed to explore the effectiveness of school closure on seasonal influenza epidemics in provincial-level administrative divisions (PLADs) with varying urbanization rates in China. Methods This study analyzed influenza surveillance data between 2010 and 2019 provided by the Chinese National Influenza Center. Taking into consideration the climate, this study included a region with 3 adjacent PLADs in Northern China and another region with 4 adjacent PLADs in Southern China. The effect of school closure on influenza transmission was evaluated by the reduction of the effective reproductive number of seasonal influenza during school winter breaks compared with that before school winter breaks. An age-structured Susceptible-Infected-Recovered-Susceptible (SIRS) model was built to model influenza transmission in different levels of urbanization. Parameters were determined using the surveillance data via robust Bayesian method. Results Between 2010 and 2019, in the less urbanized provinces: Hebei, Zhejiang, Jiangsu and Anhui, during school winter breaks, the effective reproductive number of seasonal influenza epidemics reduced 14.6% [95% confidential interval (CI): 6.2–22.9%], 9.6% (95% CI: 2.5–16.6%), 7.3% (95% CI: 0.1–14.4%) and 8.2% (95% CI: 1.1–15.3%) respectively. However, in the highly urbanized cities: Beijing, Tianjin and Shanghai, it reduced only 5.2% (95% CI: -0.7–11.2%), 4.1% (95% CI: -0.9–9.1%) and 3.9% (95% CI: -1.6–9.4%) respectively. In China, urbanization is associated with decreased proportion of children and increased social contact. According to the SIRS model, both factors could reduce the impact of school closure on seasonal influenza epidemics, and the proportion of children in the population is thought to be the dominant influencing factor. Conclusions Effectiveness of school closure on the epidemics varies with the age structure in the population and social contact patterns. School closure should be recommended in the low urbanized regions in China in the influenza seasons. Graphical abstract

Abstract That the high frequency and good replication capacity of strains with reduced susceptibility to neuraminidase inhibitors (NAIs) in highly pathogenic avian influenza H7N9 (HPAI H7N9) virus made it a significance to further study its drug resistance. HPAI H7N9 viruses bearing NA I222L or E119V substitution and two mutations of I222L-E119V as well as their NAIs-sensitive counterpart were generated by reverse genetics for NA inhibition test and replication capability evaluation in vitro. The attenuated H7N9/PR8 recombinant viruses were developed to study the pathogenicity and drug resistance brought by the above substitutions to mice. The IC50 fold change of oseltamivir to HPAI H7N9 with NA222L-119V is 306.34 times than that of its susceptible strain, and 3.5 times than the E119V mutant virus. HPAI H7N9 bearing NA222L-119V had good replication ability with peak value of more than 6log10 TCID50/ml in MDCK cells. H7N9/PR8 virus bearing NA222L-119V substitutions leaded to diffuse pneumonia, significant weight loss and fatality in mice. NA E119V made H7N9/PR8 virus resistant to oseltamivir, and I222L-E119V had synergistic resistance to oseltamivir in mice. Due to the good fitness of drug resistant strains of HPAI H7N9 virus, it is necessary to strengthen drug resistance surveillance and new drug research.

Non-pharmaceutical interventions (NPIs) implemented to interrupt COVID-19 transmission may also impact the spread of other infectious diseases. Here, the authors estimate that influenza activity in China and the United States reduced by up to 80% when NPIs were in place in the 2019–2020 season.

Seasonal influenza A (H3N2) virus has been a concern since its first introduction in humans in 1968. Accumulating antigenic changes in viral hemagglutinin (HA), particularly recent cocirculations of multiple HA genetic clades, allow H3N2 virus evade into humans annually. From 2010, the binding of neuraminidase (NA) to sialic acid made the traditional assay for HA inhibition antibodies (Abs) unsuitable for antigenicity characterization. Here, we investigated the serum anti-NA response in a cohort with a seroconversion of microneutralizing (MN) Abs targeting the circulating strain, A/Singapore/INFIMH-16-0019/2016 (H3N2, 3C.2a1)-like, a virus during 2018/2019 flu seasons. We discovered that MN Ab titers show no difference between children and adults. Nevertheless, higher titers of Abs with NA activity inhibition (NI) activity of 129 and seroconversion rate of 68.42% are presented in children aged 7–17 years (n = 19) and 73.47 and 41.17% in adults aged 21–59 years (n = 17), respectively. The MN Abs generated in children display direct correlations with HA- and NA-binding Abs or NI Abs. The NI activity exhibited cross-reactivity to N2 of H3N2 viruses of 2007 and 2013, commonly with 329-N-glycosylation and E344 in N2, a characteristic of earlier 3C.2a H3N2 virus in 2014. The percentage of such viruses pronouncedly decreased and was even replaced by those dominant H3N2 viruses with E344K and 329 non-glycosylation, which have a significantly low activity to the tested antisera. Our findings suggest that NI assay is a testable assay applied in H3N2 infection in children, and the antigenic drift of current N2 should be considered for vaccine selection.

Influenza A(H1N1)pdm09 virus has remained in a seasonal circulation since being recognized in 2009. Although it followed a mild course in most patients, in others it caused a series of severe clinical illnesses. Epidemiologic studies have implicated that host factors have a major influence on the disease severity of influenza A(H1N1)pdm09 infection. However, an understanding of relevant genetic variations and the underlying mechanisms is still limited. In this present study, we used a host-based whole genome sequencing (WGS) method to comprehensively explore the genetic risk loci associated with severity of influenza A(H1N1)pdm09 infection. From the common single-nucleotide variants (SNVs) analysis, we identified the abnormal nominally significant (P < 1 × 10−4) common SNVs enriched in PTBP3 gene. The results of rare functional SNVs analysis supported that there were several novel candidate genes might confer risk of severe influenza A(H1N1)pdm09 diseases, such as FTSJ3, CPVL, BST2, NOD2 and MAVS. Moreover, our results of gene set based analysis indicated that the HIF-1 transcription factor and IFN-γ pathway might play an important role in the underlying mechanism of severe influenza A(H1N1)pdm09. These findings will increase our knowledge about biological mechanism underlying the severe influenza A(H1N1)pdm09 and facilitate to design novel personalized treatments.

SAR images contain a large amount of noise, and related algorithms will cause high complexity when increasing the accuracy. To overcome this problem, a neural network model based on the attention mechanism was proposed in this paper. The model extracted information in two stages. It gradually extracts high-level features by reducing noise first and then adding hybrid attention. First, use dual-channel one-dimensional convolution to reconstruct the residual shrinkage network to construct a lightweight and efficient feature module, which improved the information extraction of the module with the consumption of a small amount of computing resources. Then, it was used as the backbone for model construction. Subsequently, mixed adaptive pooling was adopted to improve the maximum pooling. After that, dimensionality was reduced by pooling and linear interpolation was used to increase dimensionality, so as to generate feature weights of mixed dimension. Tests were performed on MSTAR dataset. The results showed that compared with the advanced algorithms, the proposed model in this paper can greatly reduce the amount of parameters and complexity while ensuring accuracy. The robustness test demonstrated that the model can effectively identify images with noise being added.

After 56 days without coronavirus disease 2019 (COVID-19) cases, reemergent cases were reported in Beijing, China on June 11, 2020. Here, we report the genetic characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequenced from the clinical specimens of 4 human cases and 2 environmental samples. The nucleotide similarity among six SARS-CoV-2 genomes ranged from 99.98% to 99.99%. Compared with the reference strain of SARS-CoV-2 (GenBank No. NC_045512), all six genome sequences shared the same substitutions at nt241 (C → T), nt3037 (C → T), nt14408 (C → T), nt23403 (A → G), nt28881 (G → A), nt28882 (G → A), and nt28883 (G → C), which are the characteristic nucleotide substitutions of L-lineage European branch I. This was also proved by the maximum likelihood phylogenetic tree based on the full-length genome of SARS-CoV-2. They also have a unique shared nucleotide substitution, nt6026 (C → T), which is the characteristic nucleotide substitution of SARS-CoV-2 in Beijing's Xinfadi outbreak. It is noteworthy that there is an amino acid D614G mutation caused by nt23403 substitution in all six genomes, which may enhance the virus's infectivity in humans and help it become the leading strain of the virus to spread around the world today. It is necessary to continuously monitor the genetic variation of SARS-CoV-2, focusing on the influence of key mutation sites of SARS-CoV-2 on viral transmission, clinical manifestations, severity, and course of disease.

Since coronavirus disease 2019 (COVID-19) might circulate in the following seasons, it is essential to understand how COVID-19 influences other respiratory diseases, especially influenza. In this study, we analyzed the influenza activity from mid-November 2019 to March 2020 in Chinese mainland and found that the influenza season ended much earlier than previous seasons for all subtypes and lineages, which may have resulted from the circulation of COVID-19 and measures such as travel control and personal protection. These findings provide rudimentary knowledge of the co-circulation patterns of the two types of viruses.

Influenza causes a significant disease burden as an acute respiratory infection. Evidence suggests that meteorological factors can influence the spread of influenza; however, the association between these factors and influenza activity remains controversial. In this study, we investigated the impact of temperature on influenza across different regions of China based on the meteorological data and influenza data from 554 sentinel hospitals in 30 provinces and municipalities in China from 2010 to 2017. A distributed lag nonlinear model (DLNM) was used to analyze the exposure lag response of daily mean temperatures to the risk of influenza-like illness (ILI), influenza A (Flu A), and influenza B (Flu B). We found that in northern China, low temperatures increased the risk of ILI, Flu A, and Flu B, while in central and southern China, both low and high temperatures increased the risk of ILI and Flu A, and only low temperatures increased the risk of Flu B. This study suggests that temperature is closely associated with the influenza activity in China. Temperature should be integrated into the current public health surveillance system for highly accurate influenza warnings and the timely implementation of disease prevention and control measures.

Background: The annual death associated with seasonal influenza is 290,000–650,000 globally, which can be effectively reduced by influenza vaccination. However, the protective hemagglutination inhibition (HAI) antibody response to influenza vaccine is affected by many factors, among which single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region can alter the antigen-presenting function of the HLA molecule, thus influencing the process of antibody mounting against vaccine antigen.Methods: Healthy subjects of the Han nationality were recruited and received seasonal trivalent influenza vaccine. Paired serum samples collected on and approximately 28 days after vaccination were tested in parallel by HAI assays. HLA alleles related to the immune response to influenza vaccine reported in the previous literature were summarized, and six corresponding tag SNPs were selected and genotyped using the MassARRAY technology platform.Results: The effects of HLA SNPs on HAI antibody response to influenza vaccine varied with different vaccine antigens. The AA genotype of rs41547618 was correlated with low A/H1N1-specific antibody titer compared with the GG + GA genotype (p = .007). The TT genotype of rs17885382 was correlated with low A/H3N2-specific antibody titer compared with the CC + CT genotype (p = .003). In addition, haplotype consisting of rs41542812—rs17885382—rs2068205—rs41547618—rs6905837—rs9270299—CCTGCA was correlated with non-responsiveness to influenza vaccine (OR = 2.39, 95% CI = 1.02–5.62).Conclusion: HLA SNPs were associated with HAI antibody response to influenza vaccine, which can help in a better understanding of the varied responsiveness to influenza vaccine in the population.

In order to investigate the diagnostic performance characteristics of four phenotypic assays in detecting carbapenem-resistant Enterobacteriaceae (CRE), we collected the CRE strains from infected patients. The results of carbapenemase gene detection, blaKPC-2, blaOXA-23, blaNDM-1, blaNDM-4, blaNDM-5, blaIMP-4, and blaIMP-8, were used as a standard to evaluate the performances of combined disk test (CDT), modified carbapenem inactivation method(mCIM)/EDTA-modified carbapenem inactivation method(eCIM), NG-Test CARBA 5 (CARBA), and color developing immunoassay (CDI). The compliance of phenotype results based on CDT, mCIM/eCIM, CARBA, and CDI with genetic detection results was 94% (231/247), 95% (235/247), 98% (242/247), and 99% (246/247), respectively. CDT demonstrated a low specificity for carbapenemase detection, low negative predictive value (NPV), and low sensitivity for metallo-β-lactamase (79%, 55%, and 88%, respectively); it also failed to accurately detect IMP. The mCIM/eCIM assay had serious problems in detecting OXA-23-like carbapenemases. The sensitivity and specificity of CARBA and CDI were higher than those of the first two methods. However, CARBA did not cover the detection of OXA-23, while CDI cannot detect IMP-8, resulting in low NPVs (70% and 88%, respectively). In conclusion, CARBA and CDI assays are highly accurate except individual rare genes and allow direct genotype detections. CDT and mCIM/eCIM assays are moderately accurate and can only distinguish serine-β-lactamases from metallo-β-lactamases. Laboratories should choose the appropriate method that meets their needs based on its characteristic.

The water content of the foundation soil will change dynamically as a result of rainfall, snowfall, and ground surface evaporation, leading to a significant change in frost heave properties of the foundation soil in cold regions. One-dimensional freezing tests of the Qinghai-Tibet silty clay with three different initial water contents in an open system were carried out using CCD image acquisition technology and computed tomography (CT) scanning technology in combination with the traditional soil freeze-thaw test system. The heat conduct process, cryostructure formation, frost heave development, unfrozen zone consolidation, ice segregation, water migration, and redistribution during soil freezing are studied comprehensively. The results show that increasing the sample’s initial water content will lead to the increase of frozen depth, ladder-like cryostructures in vertical sections, more structural polygons in horizontal sections, and also more obvious ice lens segregation, unfrozen zone consolidation, and water migration during the freezing of soil samples.

Anti-influenza drugs are one of the most critical pathways for control of influenza virus infection. Drugs that have been developed or are developing may function via different mechanisms, and so far, inhibitors of influenza virus polymerase are among the most promising types of drugs. Favipiravir and Baloxavir, also named T-705 and Xofluza respectively, have been approved for influenza treatment in Japan and the United States. Favipiravir effectively and selectively inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses while Baloxavir specifically targets the cap-dependent endonuclease PA of influenza viruses. These two drugs have been suggested as the first candidate drugs for influenza infection treatment, especially for strains resistant to other anti-influenza drugs. This review will focus on the pharmaceutical mechanisms and anti-influenza activity of these two drugs.

The virulence of influenza viruses is a complex multigenic trait. Previous studies about the virulence determinants of influenza viruses mainly focused on amino acid sites, ignoring the influence of nucleotide mutations. In this study, we collected >200 viral strains from 21 subtypes of influenza A viruses with virulence in mammals and obtained over 100 mammalian virulence-related nucleotide sites across the genome by computational analysis. Fifty of these nucleotide sites only experienced synonymous mutations. Experiments showed that synonymous mutations in three high-scoring nucleotide sites, i.e., PB1–2031, PB1–633, and PB1–720, enhanced the pathogenicity of the influenza A(H1N1) viruses in mice. Besides, machine-learning models with accepted accuracy for predicting mammalian virulence of influenza A viruses were built. Overall, this study highlighted the importance of nucleotide mutations, especially synonymous mutations in viral virulence, and provided rapid methods for evaluating the virulence of influenza A viruses. It could be helpful for early warning of newly emerging influenza A viruses.

Bird infections with highly pathogenic avian influenza A(H5N6) viruses have been identified since 2014. With very limited occasion, the virus could sporadically spilled over to infect humans. It has been recognized that all human infections were within southern region of Mainland China until the case reported here in Beijing in Aug. 2019. This was the first human case infected with highly pathogenic avian influenza A(H5N6) virus in northern China. The infection was confirmed by real-time RT-PCR assay. The whole genome sequences were obtained from clinical sample. Genetic characteristics of the virus were identified similar to those of previous avian influenza A(H5N6) viruses, retaining the main features of the avian influenza virus.

ABSTRACTInterferon-induced transmembrane protein 3 (IFITM3) as an antiviral factor can inhibit replication of several viruses including influenza virus. A single-nucleotide polymorphism rs12252-C of IFITM3 results in a truncated IFITM3 protein lacking its first 21 amino acids, which is much higher in the Han Chinese population and associated with severe illness in adults infected with pandemic influenza H1N1/09 virus. To investigate if IFITM3 or IFITM3 rs12252-C could affect the antibody response after influenza vaccination, we detected the haemagglutination inhibition (HI) of 171 healthy young adult volunteers (IFITM3 rs12252-C/C, C/T, T/T carriers) and in an IFITM3-deletion mouse model (Ifitm3-/-) after trivalent inactivated vaccine (TIV) immunization. Seroconversion rates for H1N1, H3N2 and B viruses in IFITM3 rs12252-C/C genotype carriers was lower compared with C/T and T/T donors. Significantly lower levels of specific antibodies to H1N1, H3N2 and B viruses and total IgG were observed in Ifitm3-/- mice. Correspondingly, the numbers of splenic germinal centre (GC) B cells, plasma cells, TIV-specific IgG+ antibody secreting cells and T follicular helper cells in Ifitm3-/- mice were lower compared with wild type mice. However, the number of memory B cells was higher in Ifitm3-/- mice at day 7 after booster. The HI level of Ifitm3-/- mice remained lower than WT mice after third vaccination. Moreover, the transcriptional network regulating GC B cell and plasma cell differentiation was abnormal in Ifitm3-/- mice. Our results indicate that IFITM3 deletion attenuated the antibody response. The mechanism of influenza-IFITM3 interactions affecting the antibody response requires further investigation.

ABSTRACTInfluenza B virus (IBV) is one of the most important human respiratory viruses: it causes approximately one-third of the global influenza-related disease burden each year. However, compared with the several pathogenicity-related molecular markers that have been identified for influenza A virus (IAV), little is known about potential IBV pathogenicity-related markers. Here, although the IBV strain B/Anhui-Tunxi/1528/2014 (AH1528/14) exhibited a more efficient replication ability in vitro and higher pathogenicity in vivo compared with IBV strain B/Anhui-Baohe/127/2015 (AH127/15), only three amino acids differences (HAA390E, NAN342D and PB1V212I) were observed among their full genomes. The contributions of each amino acid difference to the virus pathogenicity were further investigated. Compared with the wild type IBV virus rAH127, the recombinant virus harbouring a single substitution of HAA390E had a similar phenotype, whereas the recombinant virus harbouring PB1V212I replicated to a moderately higher titre in both MDCK cells and in mice. Notably, the virus harbouring NAN342D showed significantly better growth properties in MDCK cells and higher fatality rates in mice. In addition, the presence of NAN342D dramatically enhanced the viral neuraminidase activity. In conclusion, our study identified a novel IBV molecular marker, NAN342D, that could significantly increase the virulence of IBV in mice.

To determine the seroprevalence and seroconversion of avian influenza virus (AIV) antibodies in poultry workers, we conducted a seroepidemiologic study in 7 areas of China during December 2014–April 2016. We used viral isolation and reverse transcription PCR to detect AIVs in specimens from live poultry markets. We analyzed 2,124 serum samples obtained from 1,407 poultry workers by using hemagglutination inhibition and microneutralization assays. We noted seroprevalence of AIV antibodies for subtypes H9N2, H7N9, H6N1, H5N1-SC29, H5N6, H5N1-SH199, and H6N6. In serum from participants with longitudinal samples, we noted seroconversion, with >4-fold rise in titers, for H9N2, H7N9, H6N1, H5N1-SC29, H6N6, H5N6, and H5N1-SH199 subtypes. We found no evidence of H10N8 subtype. The distribution of AIV antibodies provided evidence of asymptomatic infection. We found that AIV antibody prevalence in live poultry markets correlated with increased risk for H7N9 and H9N2 infection among poultry workers.

Background: Although previous studies have proposed leptin plays an important role in energy metabolism as well as in immune response, the effects of leptin-related genes on influenza vaccine-induced immune response remain unexplored. In this study, we aimed to investigate the potential association of leptin gene (LEP), leptin receptor gene (LEPR), and peroxisome proliferator activated receptor gamma gene (PPARG) polymorphisms with humoral immune response to influenza vaccine.Methods: Based on the seroconversion to influenza vaccine, 227 low-responders and 365 responders were selected in this study, and 11 candidate single nucleotide polymorphisms (SNPs) were genotyped using the MassARRAY technology platform. Univariate and multivariate logistic regression analyses were used to explore the association of SNPs in LEP, LEPR, and PPARG with humoral immune response to influenza vaccine. We also conducted a stratified analysis by gender to further clarify this association. The haplotypes analysis was performed using SNPStats.Results: Significant differences were observed in the genotypic distribution of PPARG rs17793951 between the two groups (p = 0.001), and the PPARG rs17793951 AG + GG genotype was associated with a higher risk of low responsiveness to influenza vaccine adjusted for gender and age (additive genetic model: OR = 2.94, 95% CI = 1.67–5.19, dominant genetic model: OR = 2.81, 95% CI = 1.61–4.92). No significant association of other SNPs in LEP and LEPR with immune response to influenza vaccine was found. The stratified analysis found the gender difference in the association of LEPR and PPARG variants with immune response to influenza vaccine. We found that LEPR rs6673591 GA + AA genotype was correlated with low responsiveness to influenza vaccine only in males (OR = 1.96, 95% CI = 1.05–3.67), and PPARG rs17793951 AG + GG genotype was associated with low responsiveness to influenza vaccine in females (OR = 3.28, 95% CI = 1.61–6.67). Compared with the CGGAGGC haplotype composed of LEPR rs1327118, rs7602, rs1137101, rs1938489, rs6673591, rs1137100, and rs13306523, the CAAAAAC haplotype was positively correlated with immune response of influenza vaccine (OR = 0.34, 95% CI = 0.15–0.77). Haplotype TG comprised of PPARG rs796313 and rs17793951 was associated with a 2.85-fold increased risk of low responsiveness to influenza vaccine.Conclusion: Our study identified that PPARG rs17793951 variants were significantly associated with the immune response to influenza vaccine.

Background Understanding the transmission source, pattern, and mechanism of infectious diseases is essential for targeted prevention and control. Though it has been studied for many years, the detailed transmission patterns and drivers for the seasonal influenza epidemics in China remain elusive. Methods In this study, utilizing a suite of epidemiological and genetic approaches, we analyzed the updated province-level weekly influenza surveillance, sequence, climate, and demographic data between 1 April 2010 and 31 March 2018 from continental China, to characterize detailed transmission patterns and explore the potential initiating region and drivers of the seasonal influenza epidemics in China. Results An annual cycle for influenza A(H1N1)pdm09 and B and a semi-annual cycle for influenza A(H3N2) were confirmed. Overall, the seasonal influenza A(H3N2) virus caused more infection in China and dominated the summer season in the south. The summer season epidemics in southern China were likely initiated in the “Lingnan” region, which includes the three most southern provinces of Hainan, Guangxi, and Guangdong. Additionally, the regions in the south play more important seeding roles in maintaining the circulation of seasonal influenza in China. Though intense human mobility plays a role in the province-level transmission of influenza epidemics on a temporal scale, climate factors drive the spread of influenza epidemics on both the spatial and temporal scales. Conclusion The surveillance of seasonal influenza in the south, especially the “Lingnan” region in the summer, should be strengthened. More broadly, both the socioeconomic and climate factors contribute to the transmission of seasonal influenza in China. The patterns and mechanisms revealed in this study shed light on the precise forecasting, prevention, and control of seasonal influenza in China and worldwide.

BackgroundAnnual vaccination is the most effective prevention of influenza infection. Up to now, a series of studies have demonstrated the role of genetic variants in regulating the antibody response to influenza vaccine. However, among the Chinese population, the relationship between genetic factors and the responsiveness to influenza vaccination has not been clarified through genome-wide association study (GWAS).MethodA total of 1,968 healthy volunteers of Chinese descent were recruited and 1,582 of them were available for the subsequent two-stage analysis. In the discovery stage, according to our inclusion criteria, 123 of 1,582 subjects were selected as group 1 and received whole-genome sequencing to identify potential variants and genes. In the verification stage, 29 candidate variants identified by GWAS were selected for further validation in 481 subjects in group 2. Besides, we also analyzed nine variants from previously published reports in our study.ResultsMultivariate logistic regression analysis showed that compared with the TT genotype of ZBTB46 rs2281929, the TC + CC genotype was associated with a lower risk of low responsiveness to influenza vaccination adjusted for gender and age (Group 2: P = 7.75E-05, OR = 0.466, 95%CI = 0.319–0.680; Combined group: P = 1.18E-06, OR = 0.423, 95%CI = 0.299–0.599). In the combined group, IQGAP2 rs2455230 GC + CC genotype was correlated with a lower risk of low responsiveness to influenza vaccination compared with the GG genotype (P = 8.90E-04, OR = 0.535, 95%CI = 0.370–0.774), but the difference was not statistically significant in group 2 (P = 0.008). The antibody fold rises of subjects with ZBTB46 rs2281929 TT genotype against H1N1, H3N2,and B were all significantly lower than that of subjects with TC + CC genotype (P < 0.001). Compared with IQGAP2 rs2455230 GC + CC carriers, GG carriers had lower antibody fold rises to H1N1 (P = 0.001) and B (P = 0.032). The GG genotype of rs2455230 tended to be correlated with lower antibody fold rises (P = 0.096) against H3N2, but the difference was not statistically significant. No correlation was found between nine SNPs from previously published reports and the serological response to influenza vaccine in our study.ConclusionOur study identified two novel candidate missense variants, ZBTB46 rs2281929 and IQGAP2 rs2455230, were associated with the immune response to influenza vaccination among the Chinese population. Identifying these variants will provide more evidence for future research and improve the individualized influenza vaccination program.

Vaccination is currently the most effective way to protect against influenza viruses. This study presents PREDAC (PREDict Antigenic Cluster), a sequence-based computational method to model antigenic clusters of influenza viruses. PREDAC could improve vaccine recommendations for influenza viruses and has been used to support the influenza vaccine strain recommendations at the Chinese National Influenza Center. Moreover, a PREDAC server which includes tools for the prediction of antigenic variants and antigenic clusters of both influenza A and B viruses was built and made publicly available at http://www.computationalbiology.cn/home/. PREDAC could not only facilitate systematic studies of the antigenic evolution of influenza viruses but also provide user-friendly tools for vaccine strain recommendations for influenza viruses.

Aims The virus is common in patients with viral pneumonia. However, the viral etiology and clinical features of patients with viral pneumonia in China remain unclear. The main purpose of this study was to analyze the viral causes and epidemiology of patients with viral pneumonia in Beijing, which can significantly improve the pertinence and accuracy of clinical treatment of the disease. Methods Firstly, 1539 respiratory specimens of pneumonia (oropharyngeal swabs, nasopharyngeal swabs, saliva samples and bronchoalveolar lavage fluid) were collected from 19 hospitals in Beijing from September 2015 to August 2018. Then, TaqMan low-density microfluidic chip technology was used to detect viral pneumonia specimens in 1539 respiratory tract specimens of pneumonia and determine the types of viral bacteria in them. Lastly, the analysis of demographic, clinical and etiological data of patients with viral pneumonia was performed. Results The results showed that among the 1539 respiratory tract specimens with pneumonia, 760 were detected as viral pneumonia specimens, with a positive rate of 49.4%. Among which, 467 were infected with mono-viral and 293 were infected with multi-viral. Influenza A virus (Flu A), mycoplasma pneumoniae (MPn), Ebola virus (EBV) and herpes simplex virus type 1 (HSV-1) were the major viral components in the samples of these patients. Furthermore, these viral species were significantly associated with sample sources, onset season and certain clinical characteristics. Discussion Our findings may provide corresponding treatment strategies for viral pneumonia patients infected with specific viruses.

Abstract Background Human infection with avian influenza H7N9 virus was first reported in 2013. Since the fifth epidemic, a highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. Several potential NAI resistance sites have been found in human cases. However, the drug susceptibility and replication ability of HPAI H7N9 virus with such substitutions have not yet been studied. Methods Thirty-three HPAI H7N9 virus strains were isolated from human cases in China, and then sequences were analyzed to identify potential NAI resistance sites. Recombinant influenza viruses were generated to evaluate the effect of NA amino acid substitutions on NAI (oseltamivir or zanamivir) susceptibility and viral replication efficiency in MDCK cells. Results Four potential NAI resistance sites, R292 K, E119V, A246T or H274Y, were screened. All four substitutions conferred either reduced or highly reduced susceptibility to oseltamivir or zanamivir. 292 K not only highly reduced the susceptibility of HPAI H7N9 to oseltamivir but also induced an increase in the IC50 of zanamivir. 119 V or 274Y conferred reduced susceptibility of HPAI H7N9 to oseltamivir. Additionally, 246 T conferred reduced susceptibility to zanamivir. All tested NAI-resistant viruses were capable of replication in MDCK cells. The virus yields of rg006-NA292K were lower than those of rg006-NA292R at 24, 48, 72 and 96 h postinfection (P

Mutations of influenza virus associated with adaptation occurring during passage in embryonated chicken eggs could result in antigenic change or reduced vaccine effectiveness. In this study, we investigated the mutations of influenza A(H1N1)pdm09 egg isolates from the Chinese National Influenza Surveillance Network between 2009 and 2016. Thirteen mutations were identified in the hemagglutinin (HA) protein from viruses passaged in eggs, in comparing to those in cells. After scanning public database, four mutations, D127E, L191I, D222G/N and Q223R in HA1, which may alter the receptor-binding specificity, were observed frequently. Although the A(H1N1)pdm09 virus has evolved in human for nearly ten years, most egg-cultured viruses acquired one or more further mutations. Using the egg isolates for influenza surveillance requires extra caution because of these selected mutations, and their impacts on antigenicity and receptor-binding property need further evaluation. Currently, most of the influenza vaccines are produced using egg isolates, particularly in China. Thus, there is an urge to promote the establishment of an alternative influenza vaccine production platform.

Abstract Background Since 2008, avian influenza surveillance in poultry-related environments has been conducted annually in China. Samples have been collected from environments including live poultry markets, wild bird habitats, slaughterhouses, and poultry farms. Multiple subtypes of avian influenza virus have been identified based on environmental surveillance, and an H1N8 virus was isolated from the drinking water of a live poultry market. Methods Virus isolation was performed by inoculating influenza A-positive specimens into embryonated chicken eggs. Next-generation sequencing was used for whole-genome sequencing. A solid-phase binding assay was performed to test the virus receptor binding specificity. Trypsin dependence plaque formation assays and intravenous pathogenicity index tests were used to evaluate virus pathogenicity in vitro and in vivo, respectively. Different cell lines were chosen for comparison of virus replication capacity. Results According to the phylogenetic trees, the whole gene segments of the virus named A/Environment/Fujian/85144/2014(H1N8) were of Eurasian lineage. The HA, NA, PB1, and M genes showed the highest homology with those of H1N8 or H1N2 subtype viruses isolated from local domestic ducks, while the PB2, PA, NP and NS genes showed high similarity with the genes of H7N9 viruses detected in 2017 and 2018 in the same province. This virus presented an avian receptor binding preference. The plaque formation assay showed that it was a trypsin-dependent virus. The intravenous pathogenicity index (IVPI) in chickens was 0.02. The growth kinetics of the A/Environment/Fujian/85144/2014(H1N8) virus in different cell lines were similar to those of a human-origin virus, A/Brisbane/59/2007(H1N1), but lower than those of the control avian-origin and swine-origin viruses. Conclusions The H1N8 virus was identified in avian influenza-related environments in China for the first time and may have served as a gene carrier involved in the evolution of the H7N9 virus in poultry. This work further emphasizes the importance of avian influenza virus surveillance, especially in live poultry markets (LPMs). Active surveillance of avian influenza in LPMs is a major pillar supporting avian influenza control and response.

Abstract The emergence of severe acute respiratory syndrome (SARS) underscored the importance of influenza detection and response in China. From 2004, the Chinese National Influenza Center (CNIC) and the United States Centers for Disease Control and Prevention (USCDC) initiated Cooperative Agreements to build capacity in influenza surveillance in China. From 2004 to 2014, CNIC and USCDC collaborated on the following activities: 1) developing human technical expertise in virology and epidemiology in China; 2) developing a comprehensive influenza surveillance system by enhancing influenza-like illness (ILI) reporting and virological characterization; 3) strengthening analysis, utilization and dissemination of surveillance data; and 4) improving early response to influenza viruses with pandemic potential. Since 2004, CNIC expanded its national influenza surveillance and response system which, as of 2014, included 408 laboratories and 554 sentinel hospitals. With support from USCDC, more than 2500 public health staff from China received virology and epidemiology training, enabling > 98% network laboratories to establish virus isolation and/or nucleic acid detection techniques. CNIC established viral drug resistance surveillance and platforms for gene sequencing, reverse genetics, serologic detection, and vaccine strains development. CNIC also built a bioinformatics platform to strengthen data analysis and utilization, publishing weekly on-line influenza surveillance reports in English and Chinese. The surveillance system collects 200,000–400,000 specimens and tests more than 20,000 influenza viruses annually, which provides valuable information for World Health Organization (WHO) influenza vaccine strain recommendations. In 2010, CNIC became the sixth WHO Collaborating Centre for Influenza. CNIC has strengthened virus and data sharing, and has provided training and reagents for other countries to improve global capacity for influenza control and prevention. The collaboration’s successes were built upon shared mission and values, emphasis on long-term capacity development and sustainability, and leadership commitment.

ABSTRACTThe spread of influenza A/H3N2 variants possessing the hemagglutinin 121 K mutation and the unexpectedly high incidence of influenza in the 2017–2018 northern hemisphere influenza season have raised serious concerns about the next pandemic. We summarized the national surveillance data of seasonal influenza in China and identified marked differences in influenza epidemics between northern and southern China, particularly the predominating subtype and the presence of an additional summer peak in southern China. Notably, a minor spring peak of influenza caused by a different virus subtype was also observed. We also revealed that the 3C.2a lineage was dominant from the summer of 2015 to the end of the 2015–2016 peak season in China, after which the 3C.2a2 lineage predominated despite the importation and co-circulation of the 121 K variants of 3C.2a1 and 3C.2a3 lineages at the global level. Finally, an analysis based on genetic distances revealed a delay in A/H3N2 vaccine strain update. Overall, our results highlight the complicated circulation pattern of seasonal influenza in China and the necessity for a timely vaccine strain update worldwide.

ABSTRACTIt has recently been proposed that the Eurasian avian-like H1N1 (EA H1N1) swine influenza virus (SIV) is one of the most likely zoonotic viruses to cause the next influenza pandemic. Two main genotypes EA H1N1 viruses have been recognized to be infected humans in China. Our study finds that one of the genotypes JS1-like viruses are avirulent in mice. However, the other are HuN-like viruses and are virulent in mice. The molecular mechanism underlying this difference shows that the NP gene determines the virulence of the EA H1N1 viruses in mice. In addition, a single substitution, Q357K, in the NP protein of the EA H1N1 viruses alters the virulence phenotype. This substitution is a typical human signature marker, which is prevalent in human viruses but rarely detected in avian influenza viruses. The NP-Q357K substitution is readily to be occurred when avian influenza viruses circulate in pigs, and may facilitate their infection of humans and allow viruses also carrying NP-357K to circulate in humans. Our study demonstrates that the substitution Q357K in the NP protein plays a key role in the virulence phenotype of EA H1N1 SIVs, and provides important information for evaluating the pandemic risk of field influenza strains.

Abstract Background Bacterial co-infection of patients suffering from influenza pneumonia is a key element that increases morbidity and mortality. The occurrence of Acinetobacter baumannii co-infection in patients with avian influenza A (H7N9) virus infection has been described as one of the most prevalent bacterial co-infections. However, the clinical and laboratory features of this entity of H7N9 and A. baumannii co-infection have not been systematically investigated. Methods We collected clinical and laboratory data from laboratory-confirmed H7N9 cases co-infected by A. baumannii. H7N9 patients without bacterial co-infection and patients with A. baumannii-related pneumonia in the same hospital during the same period were recruited as controls. The antibiotic resistance features and the corresponding genome determinants of A. baumannii and the immune responses of the patients were tested through the respiratory and peripheral blood specimens. Results Invasive mechanical ventilation was the most significant risk factor for the nosocomial A. baumannii co-infection in H7N9 patients. The co-infection resulted in severe clinical manifestation which was associated with the dysregulation of immune responses including deranged T-cell counts, antigen-specific T-cell responses and plasma cytokines. The emergence of genome variations of extensively drug-resistant A. baumannii associated with acquired polymyxin resistance contributed to the fatal outcome of a co-infected patient. Conclusions The co-infection of H7N9 patients by extensively drug-resistant A. baumannii with H7N9 infection is an important issue which deserves attention. The dysfunctions of immune responses were associated with the co-infection and were correlated with the disease severity. These data provide useful reference for the diagnosis and treatment of H7N9 infection.

Background: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. Methods: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. Results: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p 80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. Conclusion: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.