Last data update: May 28, 2024. (Total: 46864 publications since 2009)
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Query Trace: Cox NJ [original query] |
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Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010
Fiore AE , Uyeki TM , Broder K , Finelli L , Euler GL , Singleton JA , Iskander JK , Wortley PM , Shay DK , Bresee JS , Cox NJ . MMWR Recomm Rep 2010 59 1-62 This report updates the 2009 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8] and CDC. Use of influenza A (H1N1) 2009 monovalent vaccine---recommendations of the Advisory Committee on Immunization Practices [ACIP], 2009. MMWR 2009;58:[No. RR-10]). The 2010 influenza recommendations include new and updated information. Highlights of the 2010 recommendations include 1) a recommendation that annual vaccination be administered to all persons aged >or=6 months for the 2010-11 influenza season; 2) a recommendation that children aged 6 months--8 years whose vaccination status is unknown or who have never received seasonal influenza vaccine before (or who received seasonal vaccine for the first time in 2009-10 but received only 1 dose in their first year of vaccination) as well as children who did not receive at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine regardless of previous influenza vaccine history should receive 2 doses of a 2010-11 seasonal influenza vaccine (minimum interval: 4 weeks) during the 2010--11 season; 3) a recommendation that vaccines containing the 2010-11 trivalent vaccine virus strains A/California/7/2009 (H1N1)-like (the same strain as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; 4) information about Fluzone High-Dose, a newly approved vaccine for persons aged >or=65 years; and 5) information about other standard-dose newly approved influenza vaccines and previously approved vaccines with expanded age indications. Vaccination efforts should begin as soon as the 2010-11 seasonal influenza vaccine is available and continue through the influenza season. These recommendations also include a summary of safety data for U.S.-licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates or supplements that might be required during the 2010-11 influenza season also will be available at this website. Recommendations for influenza diagnosis and antiviral use will be published before the start of the 2010-11 influenza season. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information. |
Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009
Fiore AE , Shay DK , Broder K , Iskander JK , Uyeki TM , Mootrey G , Bresee JS , Cox NJ . MMWR Recomm Rep 2009 58 1-52 This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]). Information on vaccination issues related to the recently identified novel influenza A H1N1 virus will be published later in 2009. The 2009 seasonal influenza recommendations include new and updated information. Highlights of the 2009 recommendations include 1) a recommendation that annual vaccination be administered to all children aged 6 months-18 years for the 2009-10 influenza season; 2) a recommendation that vaccines containing the 2009-10 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; and 3) a notice that recommendations for influenza diagnosis and antiviral use will be published before the start of the 2009-10 influenza season. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Approximately 83% of the United States population is specifically recommended for annual vaccination against seasonal influenza; however, <40% of the U.S. population received the 2008-09 influenza vaccine. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates or supplements that might be required during the 2009-10 influenza season also can be found at this website. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information. |
Global Influenza Surveillance and Response System: 70 years of responding to the expected and preparing for the unexpected
Ziegler T , Moen A , Zhang W , Cox NJ . Lancet 2022 400 (10357) 981-982 When a cluster of respiratory viral infections occurs, early recognition by clinicians linked to a global network is essential for rapid identification of the causal pathogen and subsequent risk assessment and public health response. Crucial to this process are sentinel physician and hospital networks where samples are collected from patients with febrile respiratory infections; trained laboratory staff to identify the causative pathogen; and epidemiologists and public health staff to collect data and evaluate pathogen spread and disease severity in susceptible populations. |
Influenza virus NS1- C/EBPβ gene regulatory complex inhibits RIG-I transcription.
Kumari R , Guo Z , Kumar A , Wiens M , Gangappa S , Katz JM , Cox NJ , Lal RB , Sarkar D , Fisher PB , Garcia-Sastre A , Fujita T , Kumar V , Sambhara S , Ranjan P , Lal SK . Antiviral Res 2020 176 104747 Influenza virus non-structural protein 1 (NS1) counteracts host antiviral innate immune responses by inhibiting Retinoic acid inducible gene-I (RIG-I) activation. However, whether NS1 also specifically regulates RIG-I transcription is unknown. Here, we identify a CCAAT/Enhancer Binding Protein beta (C/EBPbeta) binding site in the RIG-I promoter as a repressor element, and show that NS1 promotes C/EBPbeta phosphorylation and its recruitment to the RIG-I promoter as a C/EBPbeta/NS1 complex. C/EBPbeta overexpression and siRNA knockdown in human lung epithelial cells resulted in suppression and activation of RIG-I expression respectively, implying a negative regulatory role of C/EBPbeta. Further, C/EBPbeta phosphorylation, its interaction with NS1 and occupancy at the RIG-I promoter was associated with RIG-I transcriptional inhibition. These findings provide an important insight into the molecular mechanism by which influenza NS1 commandeers RIG-I transcriptional regulation and suppresses host antiviral responses. |
65 years of influenza surveillance by a World Health Organization-coordinated global network
Ziegler T , Mamahit A , Cox NJ . Influenza Other Respir Viruses 2018 12 (5) 558-565 The 1918 devastating influenza pandemic left a lasting impact on influenza experts and the public, and the importance of global influenza surveillance was soon recognized. The World Health Organization (WHO) Global Influenza Surveillance Network (GISN) was founded in 1952 and renamed to Global Influenza Surveillance and Response System in 2011 upon the adoption by the World Health Assembly, of the Pandemic Influenza Preparedness Framework for the Sharing of Influenza Viruses and Access to Vaccines and Other Benefits ("PIP Framework"). The importance of influenza surveillance had been recognized and promoted by experts prior to the years leading up to the establishment of WHO. In the 65 years of its existence, the Network has grown to comprise 143 National Influenza Centers recognized by WHO, 6 WHO Collaborating Centers, 4 Essential Regulatory Laboratories, and 13 H5 Reference Laboratories. The Network has proven its excellence throughout these 65 years, providing detailed information on circulating seasonal influenza viruses, as well as immediate response to the influenza pandemics in 1957, 1968, and 2009, and to threats caused by animal influenza viruses and by zoonotic transmission of coronaviruses. For its central role in global public health, the Network has been highly recognized by its many partners and by international bodies. Several generations of world-renowned influenza scientists have brought the Network to where it is now and they will take it forward to the future, as influenza will remain a preeminent threat to humans and to animals. |
Progress in vaccine-preventable and respiratory infectious diseases - first 10 Years of the CDC National Center for Immunization and Respiratory Diseases, 2006-2015
Schuchat A , Anderson LJ , Rodewald LE , Cox NJ , Hajjeh R , Pallansch MA , Messonnier NE , Jernigan DB , Wharton M . Emerg Infect Dis 2018 24 (7) 1178-1187 The need for closer linkages between scientific and programmatic areas focused on addressing vaccine-preventable and acute respiratory infections led to establishment of the National Center for Immunization and Respiratory Diseases (NCIRD) at the Centers for Disease Control and Prevention. During its first 10 years (2006-2015), NCIRD worked with partners to improve preparedness and response to pandemic influenza and other emergent respiratory infections, provide an evidence base for addition of 7 newly recommended vaccines, and modernize vaccine distribution. Clinical tools were developed for improved conversations with parents, which helped sustain childhood immunization as a social norm. Coverage increased for vaccines to protect adolescents against pertussis, meningococcal meningitis, and human papillomavirus-associated cancers. NCIRD programs supported outbreak response for new respiratory pathogens and oversaw response of the Centers for Disease Control and Prevention to the 2009 influenza A(H1N1) pandemic. Other national public health institutes might also find closer linkages between epidemiology, laboratory, and immunization programs useful. |
Selection of antigenically advanced variants of seasonal influenza viruses
Li C , Hatta M , Burke DF , Ping J , Zhang Y , Ozawa M , Taft AS , Das SC , Hanson AP , Song J , Imai M , Wilker PR , Watanabe T , Watanabe S , Ito M , Iwatsuki-Horimoto K , Russell CA , James SL , Skepner E , Maher EA , Neumann G , Klimov AI , Kelso A , McCauley J , Wang D , Shu Y , Odagiri T , Tashiro M , Xu X , Wentworth DE , Katz JM , Cox NJ , Smith DJ , Kawaoka Y . Nat Microbiol 2016 1 (6) 16058 Influenza viruses mutate frequently, necessitating constant updates of vaccine viruses. To establish experimental approaches that may complement the current vaccine strain selection process, we selected antigenic variants from human H1N1 and H3N2 influenza virus libraries possessing random mutations in the globular head of the haemagglutinin protein (which includes the antigenic sites) by incubating them with human and/or ferret convalescent sera to human H1N1 and H3N2 viruses. We also selected antigenic escape variants from human viruses treated with convalescent sera and from mice that had been previously immunized against human influenza viruses. Our pilot studies with past influenza viruses identified escape mutants that were antigenically similar to variants that emerged in nature, establishing the feasibility of our approach. Our studies with contemporary human influenza viruses identified escape mutants before they caused an epidemic in 2014-2015. This approach may aid in the prediction of potential antigenic escape variants and the selection of future vaccine candidates before they become widespread in nature. |
Divergent seasonal patterns of influenza types A and B across latitude gradient in tropical Asia
Saha S , Chadha M , Shu Y , Lijie W , Chittaganpitch M , Waicharoen S , Lindblade KA , Phengta V , Phonekeo D , Corwin A , Touch S , Buchy P , Lin R , Low C , Kheong CC , Yusof AB , Tandoc A 3rd , Roque V Jr , Arguelles V , Dawood FS , Moen A , Widdowson MA , Cox NJ , Lal RB . Influenza Other Respir Viruses 2016 10 (3) 176-84 METHODS: We analyzed influenza surveillance data from nine countries around southern and southeastern Asia spanning latitudinal gradient from equatorial to temperate zones to further characterize influenza type specific seasonality in the region. We calculated proportion of positives by month out of positives during that year and adjust for variation in samples tested and positivity in these countries. RESULTS: Influenza A epidemics were identified between November-March during winters in areas lying above 30o N latitude; during monsoon months of June-November in areas between 10o -30o N latitude, and no specific seasonality for influenza A virus circulation in areas lying closer to the equator. Influenza B circulation coincided with influenza A circulation in areas lying above 30o N latitude; however in areas south of 30o N Asia, influenza B circulated year round at 3-8% of annual influenza B positives during most months with less pronounced peaks during post-monsoon period. CONCLUSION: Even though influenza B circulates round the year in most areas of the tropical southern and southeastern Asia region, the most appropriate time for influenza vaccination would be prior to the monsoon season conferring protection against influenza A and B peaks using the most recent WHO recommended vaccine. This article is protected by copyright. All rights reserved. |
Human Heat shock protein 40 (Hsp40/DnaJB1) promotes influenza A virus replication by assisting nuclear import of viral ribonucleoproteins.
Batra J , Tripathi S , Kumar A , Katz JM , Cox NJ , Lal RB , Sambhara S , Lal SK . Sci Rep 2016 6 19063 A unique feature of influenza A virus (IAV) life cycle is replication of the viral genome in the host cell nucleus. The nuclear import of IAV genome is an indispensable step in establishing virus infection. IAV nucleoprotein (NP) is known to mediate the nuclear import of viral genome via its nuclear localization signals. Here, we demonstrate that cellular heat shock protein 40 (Hsp40/DnaJB1) facilitates the nuclear import of incoming IAV viral ribonucleoproteins (vRNPs) and is important for efficient IAV replication. Hsp40 was found to interact with NP component of IAV RNPs during early stages of infection. This interaction is mediated by the J domain of Hsp40 and N-terminal region of NP. Drug or RNAi mediated inhibition of Hsp40 resulted in reduced nuclear import of IAV RNPs, diminished viral polymerase function and attenuates overall viral replication. Hsp40 was also found to be required for efficient association between NP and importin alpha, which is crucial for IAV RNP nuclear translocation. These studies demonstrate an important role for cellular chaperone Hsp40/DnaJB1 in influenza A virus life cycle by assisting nuclear trafficking of viral ribonucleoproteins. |
Development of framework for assessing influenza virus pandemic risk
Trock SC , Burke SA , Cox NJ . Emerg Infect Dis 2015 21 (8) 1372-8 Although predicting which influenza virus subtype will cause the next pandemic is not yet possible, public health authorities must continually assess the pandemic risk associated with animal influenza viruses, particularly those that have caused infections in humans, and determine what resources should be dedicated to mitigating that risk. To accomplish this goal, a risk assessment framework was created in collaboration with an international group of influenza experts. Compared with the previously used approach, this framework, named the Influenza Risk Assessment Tool, provides a systematic and transparent approach for assessing and comparing threats posed primarily by avian and swine influenza viruses. This tool will be useful to the international influenza community and will remain flexible and responsive to changing information. |
Global circulation patterns of seasonal influenza viruses vary with antigenic drift.
Bedford T , Riley S , Barr IG , Broor S , Chadha M , Cox NJ , Daniels RS , Gunasekaran CP , Hurt AC , Kelso A , Klimov A , Lewis NS , Li X , McCauley JW , Odagiri T , Potdar V , Rambaut A , Shu Y , Skepner E , Smith DJ , Suchard MA , Tashiro M , Wang D , Xu X , Lemey P , Russell CA . Nature 2015 523 (7559) 217-20 Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour. |
Strengthening the influenza vaccine virus selection and development process: Report of the 3rd WHO Informal Consultation for Improving Influenza Vaccine Virus Selection held at WHO headquarters, Geneva, Switzerland, 1-3 April 2014.
Ampofo WK , Azziz-Baumgartner E , Bashir U , Cox NJ , Fasce R , Giovanni M , Grohmann G , Huang S , Katz J , Mironenko A , Mokhtari-Azad T , Sasono PM , Rahman M , Sawanpanyalert P , Siqueira M , Waddell AL , Waiboci L , Wood J , Zhang W , Ziegler T . Vaccine 2015 33 (36) 4368-82 Despite long-recognized challenges and constraints associated with their updating and manufacture, influenza vaccines remain at the heart of public health preparedness and response efforts against both seasonal and potentially pandemic influenza viruses. Globally coordinated virological and epidemiological surveillance is the foundation of the influenza vaccine virus selection and development process. Although national influenza surveillance and reporting capabilities are being strengthened and expanded, sustaining and building upon recent gains has become a major challenge. Strengthening the vaccine virus selection process additionally requires the continuation of initiatives to improve the timeliness and representativeness of influenza viruses shared by countries for detailed analysis by the WHO Global Influenza Surveillance and Response System (GISRS). Efforts are also continuing at the national, regional, and global levels to better understand the dynamics of influenza transmission in both temperate and tropical regions. Improved understanding of the degree of influenza seasonality in tropical countries of the world should allow for the strengthening of national vaccination policies and use of the most appropriate available vaccines. There remain a number of limitations and difficulties associated with the use of HAI assays for the antigenic characterization and selection of influenza vaccine viruses by WHOCCs. Current approaches to improving the situation include the more-optimal use of HAI and other assays; improved understanding of the data produced by neutralization assays; and increased standardization of serological testing methods. A number of new technologies and associated tools have the potential to revolutionize influenza surveillance and response activities. These include the increasingly routine use of whole genome next-generation sequencing and other high-throughput approaches. Such approaches could not only become key elements in outbreak investigations but could drive a new surveillance paradigm. However, despite the advances made, significant challenges will need to be addressed before next-generation technologies become routine, particularly in low-resource settings. Emerging approaches and techniques such as synthetic genomics, systems genetics, systems biology and mathematical modelling are capable of generating potentially huge volumes of highly complex and diverse datasets. Harnessing the currently theoretical benefits of such bioinformatics ("big data") concepts for the influenza vaccine virus selection and development process will depend upon further advances in data generation, integration, analysis and dissemination. Over the last decade, growing awareness of influenza as an important global public health issue has been coupled to ever-increasing demands from the global community for more-equitable access to effective and affordable influenza vaccines. The current influenza vaccine landscape continues to be dominated by egg-based inactivated and live attenuated vaccines, with a small number of cell-based and recombinant vaccines. Successfully completing each step in the annual influenza vaccine manufacturing cycle will continue to rely upon timely and regular communication between the WHO GISRS, manufacturers and regulatory authorities. While the pipeline of influenza vaccines appears to be moving towards a variety of niche products in the near term, it is apparent that the ultimate aim remains the development of effective "universal" influenza vaccines that offer longer-lasting immunity against a broad range of influenza A subtypes. |
Identification of Influenza A/PR/8/34 Donor Viruses Imparting High Hemagglutinin Yields to Candidate Vaccine Viruses in Eggs.
Johnson A , Chen LM , Winne E , Santana W , Metcalfe MG , Mateu-Petit G , Ridenour C , Hossain MJ , Villanueva J , Zaki SR , Williams TL , Cox NJ , Barr JR , Donis RO . PLoS One 2015 10 (6) e0128982 One of the important lessons learned from the 2009 H1N1 pandemic is that a high yield influenza vaccine virus is essential for efficient and timely production of pandemic vaccines in eggs. The current seasonal and pre-pandemic vaccine viruses are generated either by classical reassortment or reverse genetics. Both approaches utilize a high growth virus, generally A/Puerto Rico/8/1934 (PR8), as the donor of all or most of the internal genes, and the wild type virus recommended for inclusion in the vaccine to contribute the hemagglutinin (HA) and neuraminidase (NA) genes encoding the surface glycoproteins. As a result of extensive adaptation through sequential egg passaging, PR8 viruses with different gene sequences and high growth properties have been selected at different laboratories in past decades. The effect of these related but distinct internal PR8 genes on the growth of vaccine viruses in eggs has not been examined previously. Here, we use reverse genetics to analyze systematically the growth and HA antigen yield of reassortant viruses with 3 different PR8 backbones. A panel of 9 different HA/NA gene pairs in combination with each of the 3 different lineages of PR8 internal genes (27 reassortant viruses) was generated to evaluate their performance. Virus and HA yield assays showed that the PR8 internal genes influence HA yields in most subtypes. Although no single PR8 internal gene set outperformed the others in all candidate vaccine viruses, a combination of specific PR8 backbone with individual HA/NA pairs demonstrated improved HA yield and consequently the speed of vaccine production. These findings may be important both for production of seasonal vaccines and for a rapid global vaccine response during a pandemic. |
Development of influenza A(H7N9) candidate vaccine viruses with improved hemagglutinin antigen yield in eggs
Ridenour C , Johnson A , Winne E , Hossain J , Mateu-Petit G , Balish A , Santana W , Kim T , Davis C , Cox NJ , Barr JR , Donis RO , Villanueva J , Williams TL , Chen LM . Influenza Other Respir Viruses 2015 9 (5) 263-70 BACKGROUND: The emergence of avian influenza A(H7N9) virus in poultry causing zoonotic human infections was reported on March 31, 2013. Development of A(H7N9) candidate vaccine viruses (CVV) for pandemic preparedness purposes was initiated without delay. Candidate vaccine viruses were derived by reverse genetics using the internal genes of A/Puerto/Rico/8/34 (PR8). The resulting A(H7N9) CVVs needed improvement because they had titers and antigen yields that were suboptimal for vaccine manufacturing in eggs, especially in a pandemic situation. METHODS: Two CVVs derived by reverse genetics were serially passaged in embryonated eggs to improve the hemagglutinin (HA) antigen yield. The total viral protein and HA antigen yields of six egg-passaged CVVs were determined by the BCA assay and isotope dilution mass spectrometry (IDMS) analysis, respectively. CVVs were antigenically characterized by hemagglutination inhibition (HI) assays with ferret antisera. RESULTS: Improvement of total viral protein yield was observed for the six egg-passaged CVVs; HA quantification by IDMS indicated approximately a two-fold increase in yield of several egg-passaged viruses as compared to that of the parental CVV. Several different amino acid substitutions were identified in the HA of all viruses after serial passage; however HI tests indicated that the antigenic properties of two CVVs remained unchanged. CONCLUSIONS: If influenza A(H7N9) viruses were to acquire sustained human to human transmissibility, the improved HA yield of the egg-passaged CVVs generated in this study could expedite vaccine manufacturing for pandemic mitigation. |
Use of highly pathogenic avian influenza A(H5N1) gain-of-function studies for molecular-based surveillance and pandemic preparedness.
Davis CT , Chen LM , Pappas C , Stevens J , Tumpey TM , Gubareva LV , Katz JM , Villanueva JM , Donis RO , Cox NJ . mBio 2014 5 (6) Zoonotic influenza viruses circulating in poultry and swine pose an ever present threat to human health. In particular, the rapid geographical expansion of highly pathogenic avian influenza (HPAI) A(H5N1) throughout Asia and then into Europe, the Middle East, and Africa during the 2000s galvanized the global community in an attempt to control this rapidly growing threat. Despite successful control efforts in some countries, the virus remains endemic in poultry in at least six countries and continues to cause human illness and deaths as well as countless outbreaks in birds. During the past decade, 668 cases and 393 deaths were detected and reported to the World Health Organization (WHO) (1). During the 17 years since human infections with HPAI A(H5N1) were first identified in Hong Kong, Special Administrative Region, People’s Republic of China, in 1997, these viruses have evolved substantially through mutation and reassortment, resulting in multiple divergent genotypes and clades (2). | Ongoing H5N1 circulation has appropriately resulted in a focus on sequencing viral genomes to understand the evolution of these viruses and the significance of observed genetic changes. Expanded laboratory capacity for high-throughput Sanger sequencing and recent technological advances, such as next-generation sequencing and parallel computing, have revolutionized the quantity, quality, and availability of gene sequences and our ability to quickly and accurately analyze these data (3). Consequently, the number of animal and human influenza virus sequences available in publically accessible databases has dramatically increased over the years, as have the bioinformatics tools required for efficient investigation (4, 5). These advances in laboratory and analytical methods provide strong incentives to utilize molecular data for pandemic risk assessment of zoonotic influenza viruses at the animal-human interface (6). |
H7N9: preparing for the unexpected in influenza
Jernigan DB , Cox NJ . Annu Rev Med 2014 66 361-71 In the years prior to 2013, avian influenza A H7 viruses were a cause of significant poultry mortality; however, human illness was generally mild. In March 2013, a novel influenza A(H7N9) virus emerged in China as an unexpected cause of severe human illness with 36% mortality. Chinese and other public health officials responded quickly, characterizing the virus and identifying more than 400 cases through use of new technologies and surveillance tools made possible by past preparedness and response efforts. Genetic sequencing, glycan-array receptor-binding assays, and ferret studies reveal theH7N9 virus to have increased binding to mammalian respiratory cells and to have mutations associated with higher virus replication rates and illness severity. New risk-assessment tools indicate H7N9 has the potential for further mammalian adaptation with possible human-to-human transmission. Vigilant virologic and epidemiologic surveillance are needed to monitor H7N9 and detect other unexpected novel influenza viruses that may emerge. Expected final online publication date for the Annual Review of Medicine Volume 66 is January 14, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. |
Updated preparedness and response framework for influenza pandemics
Holloway R , Rasmussen SA , Zaza S , Cox NJ , Jernigan DB . MMWR Recomm Rep 2014 63 1-9 The complexities of planning for and responding to the emergence of novel influenza viruses emphasize the need for systematic frameworks to describe the progression of the event; weigh the risk of emergence and potential public health impact; evaluate transmissibility, antiviral resistance, and severity; and make decisions about interventions. On the basis of experience from recent influenza responses, CDC has updated its framework to describe influenza pandemic progression using six intervals (two prepandemic and four pandemic intervals) and eight domains. This updated framework can be used for influenza pandemic planning and serves as recommendations for risk assessment, decision-making, and action in the United States. The updated framework replaces the U.S. federal government stages from the 2006 implementation plan for the National Strategy for Pandemic Influenza (US Homeland Security Council. National strategy for pandemic influenza: implementation plan. Washington, DC: US Homeland Security Council; 2006. Available at http://www.flu.gov/planning-preparedness/federal/pandemic-influenza-implementatio n.pdf). The six intervals of the updated framework are as follows: 1) investigation of cases of novel influenza, 2) recognition of increased potential for ongoing transmission, 3) initiation of a pandemic wave, 4) acceleration of a pandemic wave, 5) deceleration of a pandemic wave, and 6) preparation for future pandemic waves. The following eight domains are used to organize response efforts within each interval: incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination. Compared with the previous U.S. government stages, this updated framework provides greater detail and clarity regarding the potential timing of key decisions and actions aimed at slowing the spread and mitigating the impact of an emerging pandemic. Use of this updated framework is anticipated to improve pandemic preparedness and response in the United States. Activities and decisions during a response are event-specific. These intervals serve as a reference for public health decision-making by federal, state, and local health authorities in the United States during an influenza pandemic and are not meant to be prescriptive or comprehensive. This framework incorporates information from newly developed tools for pandemic planning and response, including the Influenza Risk Assessment Tool and the Pandemic Severity Assessment Framework, and has been aligned with the pandemic phases restructured in 2013 by the World Health Organization. |
Characterization of drug-resistant influenza A(H7N9) variant viruses isolated from an oseltamivir-treated patient in Taiwan
Marjuki H , Mishin VP , Chesnokov AP , Jones J , De La Cruz JA , Sleeman K , Tamura D , Nguyen HT , Wu HS , Chang FY , Liu MT , Fry AM , Cox NJ , Villanueva JM , Davis CT , Gubareva LV . J Infect Dis 2014 211 (2) 249-57 BACKGROUND: Patients contracting influenza A(H7N9) often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for A(H7N9) is limited. METHODS: Four NA variants of A/Taiwan/1/2013 (H7N9) virus containing a single substitution (NA-E119 V, NA-I222 K, NA-I222R or NA-R292 K), recovered from an oseltamivir-treated patient, were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice and ferrets. RESULTS: NA-R292 K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119 V, NA-I222 K and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222 K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA-R292 K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of the NA-I222 K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292 K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract, but produced only mild illness. NA-R292 K virus, showed reduced replicative fitness in this animal model. CONCLUSIONS: Our data highlight challenges in assessment of replicative fitness of H7N9 NA variants emerged in NAI-treated patients. |
Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) - United States, 2014-15 influenza season
Grohskopf LA , Olsen SJ , Sokolow LZ , Bresee JS , Cox NJ , Broder KR , Karron RA , Walter EB . MMWR Morb Mortal Wkly Rep 2014 63 (32) 691-7 This report updates the 2013 recommendations by the Advisory Committee on Immunization Practices (ACIP) regarding use of seasonal influenza vaccines. Updated information for the 2014-15 influenza season includes 1) antigenic composition of U.S. seasonal influenza vaccines; 2) vaccine dose considerations for children aged 6 months through 8 years; and 3) a preference for the use, when immediately available, of live attenuated influenza vaccine (LAIV) for healthy children aged 2 through 8 years, to be implemented as feasible for the 2014-15 season but not later than the 2015-16 season. Information regarding issues related to influenza vaccination not addressed in this report is available in the 2013 ACIP seasonal influenza recommendations. |
Pandemic preparedness and the Influenza Risk Assessment Tool (IRAT)
Cox NJ , Trock SC , Burke SA . Curr Top Microbiol Immunol 2014 385 119-36 Influenza infections have resulted in millions of deaths and untold millions of illnesses throughout history. Influenza vaccines are the cornerstone of influenza prevention and control. Recommendations are made by the World Health Organization (WHO) 6-9 months in advance of the influenza season regarding what changes, if any, should be made in the formulation of seasonal influenza vaccines. This allows time to manufacture, test, distribute, and administer vaccine prior to the beginning of the influenza season. At the same time experts also consider which viruses not currently circulating in the human population, but with pandemic potential, pose the greatest risk to public health. Experts may conclude that one or more of these viruses are of enough concern to warrant development of a high-growth reassortant candidate vaccine virus. Subsequently, national authorities may determine that a vaccine should be manufactured, tested in clinical trials, and even stockpiled in some circumstances. The Influenza Risk Assessment Tool (IRAT) was created in an effort to develop a standardized set of elements that could be applied for decision making when evaluating pre-pandemic viruses. The tool is a simple, additive model, based on multi-attribute decision analysis . The ultimate goal is to identify an appropriate candidate vaccine virus and prepare a human vaccine before the virus adapts to infect and efficiently transmit in susceptible human populations. This pre-pandemic preparation allows production of vaccine-a strategy that could save lives and mitigate illness during a pandemic. |
Influenza A viral nucleoprotein interacts with cytoskeleton scaffolding protein alpha-actinin-4 for viral replication
Sharma S , Mayank AK , Nailwal H , Tripathi S , Patel JR , Bowzard JB , Gaur P , Donis RO , Katz JM , Cox NJ , Lal RB , Farooqi H , Sambhara S , Lal SK . FEBS J 2014 281 (13) 2899-914 Influenza A virus (IAV), similar to other viruses, exploits the machinery of human host cells for its survival and replication. We identified alpha-actinin-4, a host cytoskeletal protein, as an interacting partner of IAV nucleoprotein (NP). We confirmed this interaction using co-immunoprecipitation studies, first in a coupled in vitro transcription-translation assay and then in cells either transiently co-expressing the two proteins or infected with whole IAV. Importantly, the NP-actinin-4 interaction was observed in several IAV subtypes, including the 2009 H1N1 pandemic virus. Moreover, immunofluorescence studies revealed that both NP and actinin-4 co-localized largely around the nucleus and also in the cytoplasmic region of virus-infected A549 cells. Silencing of actinin-4 expression resulted in not only a significant decrease in NP, M2 and NS1 viral protein expression, but also a reduction of both NP mRNA and viral RNA levels, as well as viral titers, 24 h post-infection with IAV, suggesting that actinin-4 was critical for viral replication. Furthermore, actinin-4 depletion reduced the amount of NP localized in the nucleus. Treatment of infected cells with wortmannin, a known inhibitor of actinin-4, led to a decrease in NP mRNA levels and also caused the nuclear retention of NP, further strengthening our previous observations. Taken together, the results of the present study indicate that actinin-4, a novel interacting partner of IAV NP, plays a crucial role in viral replication and this interaction may participate in nuclear localization of NP and/or viral ribonucleoproteins. |
Characterization of reverse genetics-derived cold-adapted master donor virus A/Leningrad/134/17/57 (H2N2) and reassortants with H5N1 surface genes in a mouse model.
Isakova-Sivak I , Chen LM , Bourgeois M , Matsuoka Y , Voeten JT , Heldens JG , van den Bosch H , Klimov A , Rudenko L , Cox NJ , Donis RO . Clin Vaccine Immunol 2014 21 (5) 722-31 Live attenuated influenza vaccines offer significant advantages over subunit or split inactivated vaccines to mitigate an eventual influenza pandemic, including simpler manufacturing process and more cross-protective immune responses. Using an established reverse genetics (rg) system for wild type A/Leningrad/134/1957 and cold-adapted (ca) A/Leningrad/134/17/1957 (Len17) master donor virus (MDV) we produced and characterized three rg H5N1 reassortant viruses carrying modified HA and intact NA genes from either A/Vietnam/1203/2004 (H5N1, VN1203, clade 1) or A/Egypt/321/2007 (H5N1, EG321, clade 2) viruses. A mouse model of infection was used to determine the infectivity and tissue tropism of the parent wt viruses as compared to the ca master donor viruses as well as the H5N1 resassortants. All ca viruses showed reduced replication in lungs and enhanced replication in nasal epithelium. In addition, the H5N1 HA and NA enhanced replication in lungs unless it was restricted by the internal genes of the ca MDV. Mice inoculated twice four weeks apart with the H5N1 reassortant LAIV candidate viruses developed serum HI and IgA antibody titers to the homologous and heterologous viruses consistent with protective immunity. These animals remained healthy after challenge inoculation with a lethal dose with homologous or heterologous wt H5N1 HPAI. The profiles of viral replication in respiratory tissues, immunogenicity and protective efficacy characteristics of the two ca H5N1 candidate LAIV warrant further development into a vaccine for human use. |
Structural stability of influenza A(H1N1)pdm09 virus hemagglutinins
Yang H , Chang JC , Guo Z , Carney PJ , Shore DA , Donis RO , Cox NJ , Villanueva JM , Klimov AI , Stevens J . J Virol 2014 88 (9) 4828-38 The non-covalent interactions that mediate trimerization of the influenza hemagglutinin (HA) are important determinants of its biological activities. Recent studies have demonstrated that mutations in the HA trimer interface affect the thermal and pH sensitivities of HA, suggesting a possible impact on vaccine stability (Farnsworth et al. 2011. Vaccine 29:: 1529-1533). We used size exclusion chromatography analysis of recombinant HA ectodomain to compare the differences among recombinant trimeric HA proteins from early 2009 pandemic H1N1 viruses, which dissociate to monomers, with those of more recent virus HAs that can be expressed as trimers. We analyzed differences amongst the HA sequences and identified inter-molecular interactions mediated by the residue at position 374 (HA0 numbering) of the HA2 sub-domain as critical for HA trimer stability. Crystallographic analyses of HA from the recent H1N1 virus A/Washington/5/2011 highlight the structural basis for this observed phenotype. It remains to be seen whether more recent viruses with this mutation will yield more stable vaccines in the future. IMPORTANCE: Hemagglutinins from the early 2009 H1N1 pandemic viruses are unable to maintain a trimeric complex when expressed in a recombinant system. However HAs from 2010 and 2011 strains are more stable and our work highlights the improvement in stability can be attributed to an E47K substitution in the HA2 subunit of the stalk that emerged naturally in the circulating viruses. |
Pandemic influenza planning, United States, 1978-2008
Iskander J , Strikas RA , Gensheimer KF , Cox NJ , Redd SC . Emerg Infect Dis 2013 19 (6) 879-85 During the past century, 4 influenza pandemics occurred. After the emergence of a novel influenza virus of swine origin in 1976, national, state, and local US public health authorities began planning efforts to respond to future pandemics. Several events have since stimulated progress in public health emergency planning: the 1997 avian influenza A(H5N1) outbreak in Hong Kong, China; the 2001 anthrax attacks in the United States; the 2003 outbreak of severe acute respiratory syndrome; and the 2003 reemergence of influenza A(H5N1) virus infection in humans. We outline the evolution of US pandemic planning since the late 1970s, summarize planning accomplishments, and explain their ongoing importance. The public health community's response to the 2009 influenza A(H1N1)pdm09 pandemic demonstrated the value of planning and provided insights into improving future plans and response efforts. Preparedness planning will enhance the collective, multilevel response to future public health crises. |
Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin
Tripathi S , Batra J , Cao W , Sharma K , Patel JR , Ranjan P , Kumar A , Katz JM , Cox NJ , Lal RB , Sambhara S , Lal SK . Cell Death Dis 2013 4 (3) e562 Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through beta-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process. |
Global concerns regarding novel influenza A (H7N9) virus infections
Uyeki TM , Cox NJ . N Engl J Med 2013 368 (20) 1862-4 Severe disease in humans caused by a novel influenza A virus that is distinct from circulating human influenza A viruses is a seminal event. It might herald sporadic human infections from an animal source - e.g., highly pathogenic avian influenza (HPAI) A (H5N1) virus; or it might signal the start of an influenza pandemic - e.g., influenza A(H1N1)pdm09 virus. Therefore, the discovery of novel influenza A (H7N9) virus infections in three critically ill patients reported in the Journal by Gao and colleagues is of major public health significance. Chinese scientists are to be congratulated for the apparent speed with which . . . |
Pathogenesis, transmissibility, and ocular tropism of a highly pathogenic avian influenza A (H7N3) virus associated with human conjunctivitis
Belser JA , Davis CT , Balish A , Edwards LE , Zeng H , Maines TR , Gustin KM , Martinez IL , Fasce R , Cox NJ , Katz JM , Tumpey TM . J Virol 2013 87 (10) 5746-54 H7 subtype influenza A viruses, responsible for numerous outbreaks in land-based poultry in Europe and the Americas, have caused over 100 cases of confirmed or presumed human infection over the last decade. The emergence of a highly pathogenic avian influenza H7N3 virus in poultry throughout the state of Jalisco, Mexico, resulting in two cases of human infection, prompted us to examine the virulence of this virus [A/Mexico/InDRE7218/2012 (MX/7218)] and related avian H7 subtype viruses in mouse and ferret models. Several high and low pathogenicity H7N3 and H7N9 viruses replicated efficiently in the respiratory tract of mice without prior adaptation following intranasal inoculation, but only MX/7218 virus caused lethal disease in this species. H7N3 and H7N9 viruses were also detected in the mouse eye following ocular inoculation. Virus from both H7N3 and H7N9 subtypes replicated efficiently in the upper and lower respiratory tract of ferrets, however, only MX/7218 virus infection caused clinical signs and symptoms and was capable of transmission to naive ferrets in a direct contact model. Similar to other highly pathogenic H7 viruses, MX/7218 replicated to high titers in human bronchial epithelial cells, yet downregulated numerous genes related to NF-kappaB-mediated signaling transduction. These findings indicate that the recently isolated North American lineage H7 subtype virus associated with human conjunctivitis is capable of causing severe disease in mice and spreading to naive contact ferrets, while concurrently retaining the ability to replicate within ocular tissue allowing the eye to serve as a portal of entry. |
Transmission studies resume for avian flu
Fouchier RA , Garcia-Sastre A , Kawaoka Y , Barclay WS , Bouvier NM , Brown IH , Capua I , Chen H , Compans RW , Couch RB , Cox NJ , Doherty PC , Donis RO , Feldmann H , Guan Y , Katz JM , Kiselev OI , Klenk HD , Kobinger G , Liu J , Liu X , Lowen A , Mettenleiter TC , Osterhaus AD , Palese P , Peiris JS , Perez DR , Richt JA , Schultz-Cherry S , Steel J , Subbarao K , Swayne DE , Takimoto T , Tashiro M , Taubenberger JK , Thomas PG , Tripp RA , Tumpey TM , Webby RJ , Webster RG . Science 2013 339 (6119) 520-1 In January 2012, influenza virus researchers from around the world announced a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals (1). We declared a pause to this important research to provide time to explain the public health benefits of this work, to describe the measures in place to minimize possible risks, and to enable organizations and governments around the world to review their policies (for example, on biosafety, biosecurity, oversight, and communication) regarding these experiments. | During the past year, the benefits of this important research have been explained clearly in publications (2-7) and meetings (8-10). Measures to mitigate possible risks of the work have been detailed (11-13). The World Health Organization has released recommendations on laboratory biosafety for those conducting this research (14), and relevant authorities in several countries have reviewed the biosafety, biosecurity, and funding conditions under which further research would be conducted on the laboratory-modified H5N1 viruses (10, 15-17). Thus, acknowledging that the aims of the voluntary moratorium have been met in some countries and are close to being met in others, we declare an end to the voluntary moratorium on avian flu transmission studies. |
Development of an influenza virologic risk assessment tool
Trock SC , Burke SA , Cox NJ . Avian Dis 2012 56 1058-61 Influenza pandemics pose a continuous risk to human and animal health and may engender food security issues worldwide. As novel influenza A virus infections in humans are identified, pandemic preparedness strategies necessarily involve decisions regarding which viruses should be included for further studies and mitigation efforts. Resource and time limitations dictate that viruses determined to pose the greatest risk to public or animal health should be selected for further research to fill information gaps and, potentially, for development of vaccine candidates that could be put in libraries, manufactured and stockpiled, or even administered to protect susceptible populations of animals or people. A need exists to apply an objective, science-based risk assessment to the process of evaluating influenza viruses. During the past year, the Centers for Disease Control and Prevention began developing a tool to evaluate influenza A viruses that are not circulating in the human population but pose a pandemic risk. The objective is to offer a standardized set of considerations to be applied when evaluating prepandemic viruses. The tool under consideration is a simple, additive model, based on multiattribute decision analysis. The model includes elements that address the properties of the virus itself and population attributes, considers both veterinary and human findings, and integrates both laboratory and field observations. Additionally, each element is assigned a weight such that all elements are not considered of equal importance within the model. |
So many questions, so little time
Donis RO , Cox NJ . J Infect Dis 2012 207 (2) 208-10 Fifteen years have elapsed since the first human infections with H5N1 highly pathogenic avian influenza (HPAI) virus were detected in Hong Kong SAR, China [1, 2]. Many of these human infections were fatal and represented the first documented outbreak of severe disease due to HPAI viruses. The hallmark of these H5N1 viruses is their hemagglutinin genes inherited from A/goose/Guangdong/1996, a virus first detected during an outbreak in domestic geese in China. Who could have predicted the current H5N1 situation in 1997? As of August 2012, H5N1 viruses of this lineage have caused 607 reported human cases (358 fatal), the culling of 400 million birds, and have become entrenched in poultry populations on 2 continents [3, 4]. Early expectations were that this virus would be eliminated quickly and become extinct after local bird populations were decimated by the outbreak or culled, thus recapitulating the experience with dozens of HPAI outbreaks in poultry in many countries during the past century. Rather than becoming extinct, these H5N1 viruses spread to 60 countries on 3 continents by 2006 [3]. The alarm caused by the far-ranging geographic expansion of H5N1 galvanized governments to invest resources in avian disease control. Despite many effective local and regional infection control programs in recent years, H5N1 is considered to be endemic in poultry in many countries, including Indonesia, Bangladesh, China, Vietnam, and Egypt [3]. Several of these countries also report the highest numbers of human infection. Most HPAI H5N1 human infections reported to the World Health Organization by public health authorities since 1997 were acquired by direct or indirect contact with infected birds. |
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