Different Subtypes Of Influenza Research Articles

In silico design of a broad-spectrum multiepitope vaccine against influenza virus

Influenza remains a global health concern due to its potential to cause pandemics as a result of rapidly mutating influenza virus strains. Existing vaccines often struggle to keep up with these rapidly mutating flu viruses. Therefore, the development of a broad-spectrum peptide vaccine that can stimulate an optimal antibody response has emerged as an innovative approach to addressing the influenza threat. In this study, an immunoinformatic approach was employed to rapidly predict immunodominant epitopes from different antigens, aiming to develop an effective multiepitope influenza vaccine (MEV). The immunodominant B-cell linear epitopes of seasonal influenza strains hemagglutinin (HA) and neuraminidase (NA) were predicted using an antibody-peptide microarray, involving a human cohort including vaccinees and infected patients. On the other hand, bioinformatics tools were used to predict immunodominant cytotoxic T-cell (CTL) and helper T-cell (HTL) epitopes. Subsequently, these epitopes were evaluated by various immunoinformatic tools. Epitopes with high antigenicity, high immunogenicity, non-allergenicity, non-toxicity, as well as exemplary conservation were then connected in series with appropriate linkers and adjuvants to construct a broad-spectrum MEV. Moreover, the structural analysis revealed that the MEV candidates exhibited good stability, and the docking results demonstrated their strong affinity to Toll-like receptors 4 (TLR4). In addition, molecular dynamics simulation confirmed the stable interaction between TLR4 and MEVs. Three injections with MEVs showed a high level of B-cell and T-cell immune responses according to the immunological simulations in silico. Furthermore, in-silico cloning was performed, and the results indicated that the MEVs could be produced in considerable quantities in Escherichia coli (E. coli). Based on these findings, it is reasonable to create a broad-spectrum MEV against different subtypes of influenza A and B viruses in silico.

Establishment of a rapid method for detection of influenza A/B virus' antigens

This study aims to develop a rapid and convenient test card for simultaneous detection of influenza A and influenza B viruses using quantum dot-based immunochromatographic assay. The test card consists of a test strip and a plastic casing. The test strip is composed of absorbent paper, a buffer pad, nitrocellulose membrane (NC membrane), sample pad, quantum dot-labeled antibody pad, and polyvinyl chloride (PVC) board. The NC membrane is coated with mouse monoclonal antibodies against influenza A and influenza B viruses for the T lines (test lines), and reference proteins A and B for the C line (control line). The quantum dot-labeled antibody pad contains mouse monoclonal antibody-quantum dot conjugates against influenza A and influenza B viruses. The results showed that the detection limit of the test card for both viruses ranged from 1.51 ×102 to 2.71×103 TCID50/ml, indicating its sensitivity for accurate detection of influenza A and influenza B viruses without being affected by various variants. The test card exhibited specific reactions with different subtypes of influenza A and influenza B virus culture fluids and showed no cross-reactivity with adenovirus, novel coronavirus, Mycoplasma pneumoniae, respiratory syncytial virus, Staphylococcus aureus, and other pathogens. Overall, the sensitivity and specificity of the test card for simultaneous detection of influenza A and influenza B viruses meet the requirements for clinical use. It offers the advantages of simplicity, rapidity, and no requirement for special equipment, enabling quick auxiliary diagnosis to prevent disease transmission.

Synthesis and evaluation of alkoxy-substituted enamides against influenza A virus in vitro and in vivo

Alkoxy-substituted enamides are often used as synthetic intermediates due to their special reactivity. To the best our knowledge, the biological activity of alkoxy-substituted amines has never been reported so far. We have synthesized a series of alkoxy-substituted enamides to study their anti-influenza A virus activity in vitro and in vivo. Among these compounds, compound E-2o had the best antiviral activity (EC50 = 2.76 ± 0.67 μM) and low cytotoxicity (CC50 = 662.87 ± 24.85 μM). The mechanism of action of this compound was preliminarily explored by us. It alleviated the cytopathic effects and cell death caused by different subtypes of influenza A virus. Different drug delivery methods and timed dosing experiments had shown that E-2o had the best therapeutic effect and mainly played a role in the early stages of virus replication. The expansion of influenza viruses in cells was inhibited by reducing ROS accumulation, cell apoptosis, and autophagy. Alkoxy-substituted enamide E-2o reduced the production of interferon and other pro-inflammatory factors in the RIG-Ⅰ pathway and its downstream NF-κB was induced by influenza A virus in vitro and in vivo. It avoided damage in the mice which was caused by excessive inflammatory factors. In addition, the weight loss and lung lesion damage in mice caused by influenza virus were improved by compound E-2o. Therefore, Alkoxy-substituted enamide E-2o could inhibit the replication of influenza viruses in vivo and in vitro, and has the potential to be developed into a drug for treating influenza.

Mutations at site 207 of influenza a virus NS1 protein switch its function in regulating RIG-I-like receptors mediated antiviral responses

RIG-I-like receptors (RLRs), retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), are pattern recognition receptors through which cells initially sense pathogenic RNA and trigger interferon (IFN) signaling. Herein, we report that interferon induced protein 35 (IFI35) activates the ring finger protein 125 (RNF125)-UbcH5c-dependent degradation of RLRs and represses the recognition by RIG-I and MDA5 of viral RNA to inhibit innate immunity. Furthermore, IFI35 binds selectively to different subtypes of influenza A virus (IAV) nonstructural protein 1 (NS1) with asparagine residue207 (N207). Functionally, the NS1(N207)-IFI35 interaction restores the activity of RLRs, and IAV with NS1(non-N207) showed high pathogenicity in mice. Big data analysis showed that the 21st century pandemic IAV are almost all characterized by NS1 protein with non-N207. Collectively, our data uncovered the mechanism of IFI35 restricting the activation of RLRs and provides a new drug target comprising the NS1 protein of different IAV subtypes.

Effectiveness of intravenous peramivir for the treatment of influenza A/H3N2 and influenza B/Victoria in hospitalized children

ObjectiveTo optimize the medication administered to children with influenza, we evaluated the effectiveness of peramivir in hospitalized children with influenza A/H3N2 and influenza B/Victoria. MethodsA retrospective study was conducted from October 2019 to March 2020 in children aged 29 days to 18 years with influenza A/H3N2 or B/Victoria. A total of 97 patients were enrolled and treated with intravenous infusion of peramivir. ResultsThe duration of influenza virus nucleic acid positivity in the influenza A/H3N2 group (3 days) was shorter than that in the influenza B/Victoria group (4 days) (P = 0.008). The remission time of fever symptoms in the influenza A/H3N2 group was 14 h, which was significantly shorter than that in the influenza B/Victoria group (26 h) (P = 0.042). In the 6–18 years age group, the median duration of virus nucleic acid positivity for children with influenza B/Victoria (4 days) was longer than that for children with influenza A/H3N2 (2 days) (P = 0.005). The incidence of adverse drug reactions (ADRs) with peramivir in the influenza A/H3N2 group and the influenza B/Victoria group was 2.04% (n = 1/49) and 4.17% (n = 2/48), respectively (P = 0.617). ConclusionsA difference in the effectiveness of peramivir against different subtypes of influenza was observed. Compared to those infected with influenza B/Victoria, the children infected with influenza A/H3N2 experienced a significantly shorter duration of influenza virus nucleic acid positivity and remission time of fever symptoms.

Expression of Influenza M2e-NP Recombinant Fusion Protein in Escherichia coli BL21 (DE3) and Its Binding to Antibodies

The current influenza vaccines only confer protection against the circulating influenza subtypes, therefore universal vaccines are needed to prevent upcoming influenza outbreaks caused by emerging influenza subtypes. The extracellular domain of influenza A M2 protein (M2e) is highly conserved among different subtypes of influenza A viruses, and it is able to elicit protective immunity against the viruses. The influenza nucleoprotein (NP) was used to display the M2e in this study due to its promising T-cell response and adjuvanticity. The M2e gene was fused to the 5'-end of the NP gene and then cloned into pRSET B vector. The DNA sequencing analysis revealed six point mutations in the M2e-NP fusion gene, including one mutation in the M2e peptide and five mutations in the NP. The mutations were reverted using PCR site-directed mutagenesis. The recombinant plasmids (pRSET B-M2e-NP and pRSET B-mM2e-NP) were introduced into Escherichia coli (E. coli) BL21 (DE3) for protein expression. The mutated and non-mutated proteins were subsequently expressed and named mM2e-NP and M2e-NP, respectively. The expression of mM2e-NP and M2e-NP was not affected by the mutations. The binding of anti-M2e antibody to the purified native mM2e-NP and M2e-NP also remained active. However, when the anti-NP antibody was tested, the signal produced by mM2e-NP was very weak. The results implied that the amino acid changes in the NP had adversely impacted on the conformation of mM2e-NP and subsequently affected the antibody binding. In light of the remarkable antibody binding to the M2e-NP fusion protein, this study highly recommends the potential of M2e-NP as a universal influenza vaccine candidate.

Nanoparticles based on artificial self-assembling peptide and displaying M2e peptide and stalk HA epitopes of influenza A virus induce potent humoral and T-cell responses and protect against the viral infection

The extracellular domain of the M2 protein (M2e) and conserved region of the second subunit of the hemagglutinin (HA2) could be used for the development of broad-spectrum vaccines against influenza A. Here we obtained and characterized recombinant mosaic proteins containing tandem copies of M2e and HA2 fused to an artificial self-assembling peptide (SAP). The inclusion of SAP peptides in the fusion proteins enabled their self-assembly in vitro into spherical particles with a size of 30-50 nm. Intranasal immunization of mice with these particles without additional adjuvants induced strong humoral immune response against M2e and the whole virus. Particles carrying both M2e and HA2 induced antigen-specific multifunctional CD4+ effector memory T cells. Immunization provided high protection of mice against the lethal challenge with different subtypes of influenza A virus. The obtained self-assembling nanoparticles can be used to develop a universal influenza vaccine.

In silico design of a multi-epitope peptide construct as a potential vaccine candidate for Influenza A based on neuraminidase protein.

Designing an effective vaccine against different subtypes of Influenza A virus is a critical issue in the field of medical biotechnology. At the current study, a novel potential multi-epitope vaccine candidate based on the neuraminidase proteins for seven subtypes of Influenza virus was designed, using the in silico approach. Potential linear B-cell and T-cell binding epitopes from each neuraminidase protein (N1, N2, N3, N4, N6, N7, N8) were predicted by in silico tools of epitope prediction. The selected epitopes were joined by three different linkers, and physicochemical properties, toxicity, and allergenecity were investigated. The final multi-epitope construct was modeled using GalaxyWEB server, and the molecular interactions with immune receptors were investigated and the immune response simulation assay was performed. A multi-epitope construct with GPGPGPG linker with the lowest allergenicity and highest stability was selected. The molecular docking assay indicated the interactions with immune system receptors, including HLA1, HLA2, and TLR-3. Immune response simulation detected both humoral and cellular response, including the elevated count of B-cells, T-cell, and Nk-cells.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40203-021-00095-w.

The Effects of Genetic Variation on H7N9 Avian Influenza Virus Pathogenicity.

Since the H7N9 avian influenza virus emerged in China in 2013, there have been five seasonal waves which have shown human infections and caused high fatality rates in infected patients. A multibasic amino acid insertion seen in the HA of current H7N9 viruses occurred through natural evolution and reassortment, and created a high pathogenicity avian influenza (HPAI) virus from the low pathogenicity avian influenza (LPAI) in 2017, and significantly increased pathogenicity in poultry, resulting in widespread HPAI H7N9 in poultry, which along with LPAI H7N9, contributed to the severe fifth seasonal wave in China. H7N9 is a novel reassorted virus from three different subtypes of influenza A viruses (IAVs) which displays a great potential threat to public health and the poultry industry. To date, no sustained human-to-human transmission has been recorded by the WHO. However, the high ability of evolutionary adaptation of H7N9 and lack of pre-existing immunity in humans heightens the pandemic potential. Changes in IAVs proteins can affect the viral transmissibility, receptor binding specificity, pathogenicity, and virulence. The multibasic amino acid insertion, mutations in hemagglutinin, deletion and mutations in neuraminidase, and mutations in PB2 contribute to different virological characteristics. This review summarized the latest research evidence to describe the impacts of viral protein changes in viral adaptation and pathogenicity of H7N9, aiming to provide better insights for developing and enhancing early warning or intervention strategies with the goal of preventing highly pathogenic IAVs circulation in live poultry, and transmission to humans.

Influenza A Virus in Swine: Epidemiology, Challenges and Vaccination Strategies.

Influenza A viruses cause acute respiratory infections in swine that result in significant economic losses for global pig production. Currently, three different subtypes of influenza A viruses of swine (IAV-S) co-circulate worldwide: H1N1, H3N2, and H1N2. However, the origin, genetic background and antigenic properties of those IAV-S vary considerably from region to region. Pigs could also have a role in the adaptation of avian influenza A viruses to humans and other mammalian hosts, either as intermediate hosts in which avian influenza viruses may adapt to humans, or as a “mixing vessel” in which influenza viruses from various origins may reassort, generating novel progeny viruses capable of replicating and spreading among humans. These potential roles highlight the importance of controlling influenza A viruses in pigs. Vaccination is currently the main tool to control IAV-S. Vaccines containing whole inactivated virus (WIV) with adjuvant have been traditionally used to generate highly specific antibodies against hemagglutinin (HA), the main antigenic protein. WIV vaccines are safe and protect against antigenically identical or very similar strains in the absence of maternally derived antibodies (MDAs). Yet, their efficacy is reduced against heterologous strains, or in presence of MDAs. Moreover, vaccine-associated enhanced respiratory disease (VAERD) has been described in pigs vaccinated with WIV vaccines and challenged with heterologous strains in the US. This, together with the increasingly complex epidemiology of SIVs, illustrates the need to explore new vaccination technologies and strategies. Currently, there are two different non-inactivated vaccines commercialized for swine in the US: an RNA vector vaccine expressing the HA of a H3N2 cluster IV, and a bivalent modified live vaccine (MLV) containing H1N2 γ-clade and H3N2 cluster IV. In addition, recombinant-protein vaccines, DNA vector vaccines and alternative attenuation technologies are being explored, but none of these new technologies has yet reached the market. The aim of this article is to provide a thorough review of the current epidemiological scenario of IAV-S, the challenges faced in the control of IAV-S infection and the tools being explored to overcome those challenges.

Comparable Disease Severity by Influenza Virus Subtype in the Acute Respiratory Infection Consortium Natural History Study.

Since the influenza A/H1N1 pandemic of 2009 to 2010, numerous studies have described the clinical course and outcome of the different subtypes of influenza (A/H1N1, A/H3N2, and B). A recent systematic literature review concluded that there were no appreciable differences in either clinical presentation or disease severity among these subtypes, but study parameters limit the applicability of these results to military populations. We sought to evaluate differences in disease severity among influenza subtypes in a cohort of healthy, primarily outpatient adult U.S. Department of Defense beneficiaries. From 2009 to 2014, we enrolled otherwise healthy adults age 18 to 65years with influenza-like illness in an observational cohort study based in 5 U.S. military medical centers. Serial nasopharyngeal swabs were collected for determination of etiology and viral shedding by polymerase chain reaction. The presence and severity of symptoms was assessed by interview and patient diary. Over a 5-year period, a total of 157 adults with laboratory-confirmed influenza and influenza subtype were enrolled. Of these, 69 (44%) were positive for influenza A(H1N1), 69 (44%) for influenza A(H3N2), and 19 (12%) for influenza B. About 61% were male, 64% were active duty military personnel, and 72% had received influenza vaccine in the past 8months. Almost 10% were hospitalized with influenza. Seasonal influenza virus distribution among enrollees mirrored that of nationwide trends each year of study. Individuals with A/H1N1 had upper respiratory composite scores that were lower than those with A/H3N2. Multivariate models indicated that individuals with A(H1N1) and B had increased lower respiratory symptom scores when compared to influenza A(H3N2) (A[H1N1]: 1.51 [95% CI 0.47, 2.55]; B: 1.46 [95% CI 0.09, 2.83]), whereas no other differences in symptom severity scores among influenza A(H1N1), influenza A(H3N2), and influenza B infection were observed. Overall, influenza season (maximum in 2012-2013 season) and female sex of the participant were found to be associated with increased influenza symptom severity. Our study of influenza in a cohort of otherwise healthy, outpatient adult Department of Defense beneficiaries over 5 influenza seasons revealed few differences between influenza A(H1N1), influenza A(H3N2), and influenza B infection with respect to self-reported disease severity or clinical outcomes. This study highlights the importance of routine, active, and laboratory-based surveillance to monitor ongoing trends and severity of influenza in various populations to inform prevention measures.

Universal anti-influenza vaccines based on viral HA2 and M2e antigens.

Aquatic birds are the main reservoir of influenza A viruses (IAVs). These viruses can infect humans repeatedly and cause acute respiratory disease with potential of spread in the form of epidemics. In addition, avian influenza viruses that overcome the interspecies barrier and adapt to humans can cause a world-wide pandemic with severe consequences to human health. Therefore, scientists are focused on the development of a "universal" vaccine with a broad protective efficacy, i.e. against different subtypes of influenza A viruses and not only against the currently co-circulating human epidemic strains. Nowadays, several new vaccine design strategies have been described. Most of them utilize the conserved stem part of influenza surface glycoprotein hemagglutinin (HA) or the ectodomain of M2 (M2e) protein with proton-channel activity. A comparison of the efficacy of novel vaccines and their protective mechanisms against influenza infection is discussed in this review and should be considered for the construction of the most effective broadly protective vaccine with minimal side effects. This is the essential goal in influenza virus research today, especially when the infection with new human coronavirus SARS-CoV-2 can interfere with the course of influenza virus infection. Keywords: influenza A virus; HA2 gp; M2 ectodomain; universal vaccine.

Image processing techniques represent innovative tools for comparative analysis of proteins

Different bioinformatic and data-mining approaches have been used for the analysis of proteins. Here, we describe a novel, robust, and reliable approach for comparative analysis of a large number of proteins by combining Image Processing Techniques and Convolutional Deep Neural Network (IPT-CNN). As proof of principle, we used IPT-CNN to predict different subtypes of Influenza A virus (IAV). Over 8000 sequences of surface proteins haemagglutinin (HA) and neuraminidase (NA) from different IAV subtypes were used to create polynomial or binary vector datasets. The datasets were then converted into binary images. Analysis of these images enabled the classification of IAV subtypes with 100% accuracy and, compared to non-image-based approaches, within a shorter time frame. The proteome-based IPT-CNN approach described here may be used for analysis and proteome-based classification of other proteins.

Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation.

Influenza A viruses have regularly jumped to new host species to cause epidemics or pandemics, an evolutionary process that involves variation in the viral traits necessary to overcome host barriers and facilitate transmission. Mice are not a natural host for influenza virus but are frequently used as models in studies of pathogenesis, often after multiple passages to achieve higher viral titers that result in clinical disease such as weight loss or death. Here, we examine the processes of influenza A virus infection and evolution in mice by comparing single nucleotide variations of a human H1N1 pandemic virus, a seasonal H3N2 virus, and an H3N2 canine influenza virus during experimental passage. We also compared replication and sequence variation in wild-type mice expressing N-glycolylneuraminic acid (Neu5Gc) with those seen in mice expressing only N-acetylneuraminic acid (Neu5Ac). Viruses derived from plasmids were propagated in MDCK cells and then passaged in mice up to four times. Full-genome deep sequencing of the plasmids, cultured viruses, and viruses from mice at various passages revealed only small numbers of mutational changes. The H3N2 canine influenza virus showed increases in frequency of sporadic mutations in the PB2, PA, and NA segments. The H1N1 pandemic virus grew well in mice, and while it exhibited the maintenance of some minority mutations, there was no clear evidence for adaptive evolution. The H3N2 seasonal virus did not establish in the mice. Finally, there were no clear sequence differences associated with the presence or absence of Neu5Gc.IMPORTANCE Mice are commonly used as a model to study the growth and virulence of influenza A viruses in mammals but are not a natural host and have distinct sialic acid receptor profiles compared to humans. Using experimental infections with different subtypes of influenza A virus derived from different hosts, we found that evolution of influenza A virus in mice did not necessarily proceed through the linear accumulation of host-adaptive mutations, that there was variation in the patterns of mutations detected in each repetition, and that the mutation dynamics depended on the virus examined. In addition, variation in the viral receptor, sialic acid, did not affect influenza virus evolution in this model. Overall, our results show that while mice provide a useful animal model for influenza virus pathology, host passage evolution will vary depending on the specific virus tested.

Different Subtypes of Influenza Viruses Target Different Human Proteins and Pathways Leading to Different Pathogenic Phenotypes.

Different subtypes of influenza A viruses (IAVs) cause different pathogenic phenotypes after infecting human bodies. Analysis of the interactions between viral proteins and the host proteins may provide insights into the pathogenic mechanisms of the virus. In this paper, we found that the same proteins (nucleoprotein and neuraminidase) of H1N1 and H5N1 have different impacts on the NF-κB activation. By further examining the virus–host protein–protein interactions, we found that both NP and NA proteins of the H1N1 and H5N1 viruses target different host proteins. These results indicate that different subtypes of influenza viruses target different human proteins and pathways leading to different pathogenic phenotypes.

Detecting virus-specific effects on post-infection temporal gene expression

BackgroundDifferent types of viruses have different envelope proteins, and may have their shared or distinctive host-virus interactions which result in various post-infection effects in humans and animals. These effects often do not appear at once but take time to unfold. To characterize the virus-specific effects, we applied a Multivariate Polynomial Time-dependent Genetic Association (MPTGA) method, previously proposed for detecting differences in temporal gene expression traits, to test for the differences in mouse lung transcriptome response to infection of different subtypes of influenza A viruses.ResultsWe compared two methods: the Multivariate Polynomial Time-dependent Genetic Association (MPTGA) method, and the conventional modified t-test, to study the virus-specific effects on mouse lung gene expression. Both methods found H3N2 to be the most different virus among the three viruses tested, with the largest number of genes with H3N2-specific effects. However, the MPTGA method demonstrated much higher power of detection, and the detected genes with virus-specific effects showed better biological relevance.ConclusionsTranscriptome response to virus infection is dynamic. MPTGA which leverages temporal gene expression traits showed increased power in detecting biologically relevant virus-specific effects comparing with conventional t-test method.

Heterosubtypic cross-protection correlates with cross-reactive interferon-gamma-secreting lymphocytes in the ferret model of influenza

An effective universal vaccine for influenza will likely need to induce virus-specific T-cells, which are the major mediator of heterosubtypic cross-protection between different subtypes of influenza A virus. In this study we characterise the cell-mediated immune response in ferrets during heterosubtypic protection induced by low-dose H1N1 virus infection against an H3N2 virus challenge, given 4 weeks later. Although the ferrets were not protected against the infection by H3N2 virus, the duration of virus shedding was shortened, and clinical disease was markedly reduced. No cross-reactive neutralizing antibodies were detected, but cross-reactive interferon-gamma-secreting T cells were detected in the circulation prior to H3N2 challenge. These T-cells peaked at 11 days post-H1N1 infection, and were strongly induced in blood and in lung following H3N2 infection. The rapid induction of interferon-gamma-secreting cells in ferrets previously infected with H1N1 virus, but not in naïve ferrets, suggests induction of memory T-cells. These results are in accord with the observations that pre-existing cross-reactive T-cells correlate with protection in humans and have implications for outbreak modelling and universal vaccine design.

Predictors of fatality in influenza A virus subtype infections among inpatients in the 2015–2016 season

BackgroundInfection with the influenza A virus can cause severe disease and mortality. The effect of the different subtypes of influenza on morbidity and mortality is not yet known in Turkey. The aim of this study was to describe the predictors of fatality related to influenza A infection among hospitalized patients in Istanbul during the 2015–2016 influenza season, and to detail the differences between infections caused by H3N2 and H1N1. MethodsThis was a multicenter study performed by the Istanbul Respiratory Infections Study Group of The Turkish Society of Clinical Microbiology and Infectious Diseases (KLİMİK), among patients hospitalized for influenza in Istanbul during the 2015–2016 influenza season. ResultsA total of 222 patients hospitalized with laboratory-confirmed influenza during the 2015–2016 season were included in the study, of whom 25 (11.2%) died. The fatality rate was significantly higher among patients older than 65 years of age and those with chronic heart and kidney diseases (p<0.001), chronic neurological diseases (p=0.009), and malignancies (p=0.021). Thrombocyte counts were lower in those who died than in those who survived (p<0.004). The median alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatinine phosphokinase, and C-reactive protein levels were higher among fatal cases. In the multivariate analysis for the prediction of fatality, being >65years old (odds ratio (OR) 6.9, 95% confidence interval (CI) 2.07–23.08, p=0.002), being infected with influenza A(H3N2) (OR 4.2, 95% CI 1.27–14.38, p=0.019), and a 1-day delay in antiviral use (OR 1.28, 95% CI 1.01–1.63, p=0.036) were found to be associated with an increased likelihood of fatality. ConclusionsThe case fatality rate of influenza A(H3N2) was significantly higher than that of influenza A(H1N1). Detection of the infection, allowing the opportunity for the early use of antiviral agents, was found to be important for the prevention of fatality. The vaccination should be prioritized for at-risk groups.

Influenza infections in Australia 2009\u20132015: is there a combined effect of age and sex on susceptibility to virus subtypes?

BackgroundInfluenza is a global infectious disease with a large burden of illness and high healthcare costs. Those who experience greater burden of disease include younger and older people, and pregnant women. Although there are known age and sex susceptibilities, little is known about how the interaction of age and sex may affect a population’s vulnerability to infection with different subtypes of influenza virus.MethodsLaboratory-confirmed cases of influenza notified between 1 January 2009 and 31 December 2015 obtained from the Australian Government National Notifiable Diseases Surveillance System Influenza Public Data Set were analysed by age, sex and virus subtype. Age standardised notification rates per 100,000 population were calculated separately for females and males and used to generate female-to-male ratios with 95% confidence intervals for influenza A and B, and for virus subtypes A(H1N1)pdm09 and A(H3N2).Results334,560 notifications for influenza A (all notifications), A(H1N1)pmd09, A(H3N2) and B subtypes from a total of 335,414 influenza notifications were analysed. Male notification rates were significantly higher for the 0 to 4 years old age group regardless of virus type or subtype; and higher for those aged 0 to 14 years and those 85 years and older for influenza types A and B and subtype A(H1N1)pdm09. Female notification rates were significantly higher for A(H1N1)pdm09 in those aged 15 to 54 years, for Type A and sub-type A(H3N2) in those aged 15 to 69 years, and for Influenza B in those aged 20 to 74 years.ConclusionsWe observed a female dominance in notification rates throughout the adult age groups, which could possibly be related to health seeking behaviours. However, differences in health seeking behaviours cannot explain the variations observed across virus subtypes in the particular age groups with higher female notifications. Depending on their age, females may be more susceptible to certain subtypes of influenza virus. These observations suggest that there is an interaction between age and sex on susceptibility to influenza infection which varies by the subtype of the virus. The inclusion of pregnancy and menopausal status in surveillance data may assist development of targeted public health approaches during the emergence of new subtypes of influenza virus. Targeted vaccination campaigns may need to take into consideration specific age and sex groups who have a greater susceptibility to influenza infection as well as those who experience a greater burden of illness.

A Century of Influenza: Is the World Prepared for the Next Pandemic?

A Century of InfluenzaIs the World Prepared for the Next Pandemic? Michael A Stoto (bio), Normand LeBlanc (bio), Nellie Darling (bio), Julia Gasior (bio), Mikaela Harmsen (bio), and Casey Zipfel (bio) Over the last century, four international public health crises challenged global health-systems and severely damaged communities. Influenza pandemics, or influenza epidemics that spread throughout the world, all stemmed from changing subtypes of the influenza A virus. Although its unassuming popular name—the "flu"—sometimes minimizes public perception of the threat, influenza is a complex, constantly changing threat, and globalization has created both benefits and new challenges for global health-systems in combating it. Despite all we know about the virus' structure, transmissibility, and epidemiology, there is still much to be discovered in order to combat its potential for causing death and global disruption. Leading up to the centennial of the 1918 "Great Influenza," which caused up to 100 million deaths worldwide, public health officials reviewed and commissioned historical analyses. These studies focused on the following: [End Page 163] • Reconstructing the pathogen's epidemiological characteristics as well as the temporal and geographic spread of the pandemic, including its social and health consequences • Understanding the impact and effectiveness of non-pharmaceutical interventions and other population-based control strategies in various US cities • Identifying parameters and other assumptions for pandemic influenza models, which were subsequently used to assess prevention and control strategies This research, along with studies of other 20th-century pandemics, informed global, federal, state, and local preparation for a possible avian influenza pandemic in the 2000s. It was also used to guide the response to the 2009 H1N1 pandemic, which was far different in character from the 1918 pandemic and the expected avian influenza pandemic. Today, this research continues to guide pandemic planning at both the national and global levels. In order to apply findings from research and to gain further insight into possible responses to a global pandemic in the 21st century, we conducted a simulation exercise of a hypothetical, but realistic, pandemic influenza today. Approximately thirty Georgetown medical, graduate, and undergraduate students played the roles of global, national, and local officials as well as medical advisors responding to a pandemic. The exercise included two phases, each of which ended with a presentation by the student participants to a panel of "decision-makers" from public health and other sectors. The simulation highlighted several areas that were key to the simulation, that would likely also arise in the case of an influenza pandemic today: identifying epidemiological characteristics of the novel pandemic strain, coordinating globally in accord with the International Health Regulations, implementing a Public Health Emergency of International Concern, applying non-pharmaceutical interventions, assessing availability and distribution of medical countermeasures, maintaining standards of care in a crisis, and communicating risk information locally. Global Health Challenges The first phase of the simulation focused on global issues following the emergence of a new subtype of influenza in Vietnam. Several unusual influenza cases were identified in rural Vietnam with a high fatality rate. It was initially unclear if the influenza cases were part of the normal influenza season or whether they were due to a novel strain with pandemic potential. Different subtypes of influenza are characterized by proteins on the surface of the virus.1 A novel influenza subtype arises when the proteins on the surface of the virus combine in new ways. It is important to distinguish whether the influenza cases in Vietnam were due to a novel subtype that could cause a pandemic because often large groups of the population tend to be immunologically naive to novel subtypes, meaning that people do not have immunity because they have never been previously infected by the novel subtype. If the novel subtype is easily spread from human to human, the result could be a pandemic, in which the pathogen can rapidly spread throughout the world. Furthermore, if the novel subtype is highly virulent, meaning that the virus causes severe disease and high rates of death, the result can be catastrophic. Currently, there are several subtypes of avian influenza that could potentially result in the next influenza pandemic.2 Fortunately, these viruses are currently not easily transmissible between humans. Yet, if they...