Annual Epidemics Research Articles

Universal Vaccines and Vaccine Platforms to Protect against Influenza Viruses in Humans and Agriculture.

Influenza virus infections pose a significant threat to public health due to annual seasonal epidemics and occasional pandemics. Influenza is also associated with significant economic losses in animal production. The most effective way to prevent influenza infections is through vaccination. Current vaccine programs rely heavily on the vaccine's ability to stimulate neutralizing antibody responses to the hemagglutinin (HA) protein. One of the biggest challenges to an effective vaccination program lies on the fact that influenza viruses are ever-changing, leading to antigenic drift that results in escape from earlier immune responses. Efforts toward overcoming these challenges aim at improving the strength and/or breadth of the immune response. Novel vaccine technologies, the so-called universal vaccines, focus on stimulating better cross-protection against many or all influenza strains. However, vaccine platforms or manufacturing technologies being tested to improve vaccine efficacy are heterogeneous between different species and/or either tailored for epidemic or pandemic influenza. Here, we discuss current vaccines to protect humans and animals against influenza, highlighting challenges faced to effective and uniform novel vaccination strategies and approaches.

Neutralizing Antibodies Induced by Gene-Based Hydrodynamic Injection Have a Therapeutic Effect in Lethal Influenza Infection.

The influenza virus causes annual epidemics and occasional pandemics and is thus a major public health problem. Development of vaccines and antiviral drugs is essential for controlling influenza virus infection. We previously demonstrated the use of vectored immune-prophylaxis against influenza virus infection. We generated a plasmid encoding neutralizing IgG monoclonal antibodies (mAbs) against A/PR/8/34 influenza virus (IAV) hemagglutinin (HA). We then performed electroporation of the plasmid encoding neutralizing mAbs (EP) in mice muscles and succeeded in inducing the expression of neutralizing antibodies in mouse serum. This therapy has a prophylactic effect against lethal IAV infection in mice. In this study, we established a new method of passive immunotherapy after IAV infection. We performed hydrodynamic injection of the plasmid encoding neutralizing mAbs (HD) involving rapid injection of a large volume of plasmid-DNA solution into mice via the tail vein. HD could induce neutralizing antibodies in the serum and in several mucosal tissues more rapidly than in EP. We also showed that a single HD completely protected the mice even after infection with a lethal dose of IAV. We also established other isotypes of anti-HA antibody (IgA, IgM, IgD, and IgE) and showed that like anti-HA IgG, anti-HA IgA was also effective at combating upper respiratory tract IAV infection. Passive immunotherapy with HD could thus provide a new therapeutic strategy targeting influenza virus infection.

Predominance of influenza A(H3N2) viruses during the 2016/2017 season in Bulgaria

Influenza viruses are characterised by high variability, which makes them able to cause annual epidemics. The aim of this study is to determine the antigenic and genetic characteristics of influenza viruses circulating in Bulgaria during the 2016/2017 season. The detection and typing/subtyping of influenza viruses were performed using real time RT-PCR. Results of antigenic characterisation, phylogenetic and amino acid sequence analyses of representative influenza strains are presented herein. The 2016/2017 season was characterised by an early start, an exclusive dominance of A(H3N2) viruses accounting for 93 % of total influenza virus detections, and a low circulation of A(H1N1)pdm09 (4.2 %) and type B (2.5 %) viruses. The analysed A(H3N2) viruses belonged to subclades 3C.2a (52 %) and 3C.2a1 (48 %); all studied A(H1N1)pdm09 and B/Victoria-lineage viruses belonged to subclades 6B.1 and 1A, respectively. The amino acid sequence analysis of 56 A(H3N2) isolates revealed the presence of substitutions in 18 positions in haemagglutinin (HA) as compared to the A/Hong Kong/4801/2014 vaccine virus, seven of which occurred in four antigenic sites, together with changes in 23 positions in neuraminidase (NA), and a number of substitutions in internal proteins PB2, PB1, PB1-F2, PA, NP and NS1. Despite the many amino acid substitutions, A(H3N2) viruses remained antigenically similar to the vaccine strain. Substitutions in HA and NA sequences of A(H1N1)pdm09 and B/Victoria-lineage strains were also identified, including in antigenic sites. The results of this study confirm the genetic variability of circulating influenza viruses, particularly A(H3N2), and the need for continued antigenic and molecular surveillance.

Software for Characterizing the Antigenic and Genetic Evolution of Human Influenza Viruses.

Influenza viruses are rapidly evolving pathogens causing annual epidemics and occasional pandemics. The accumulation of amino acid substitutions allows the virus to adapt to changing environments like novel host species or to escape the acquired immunity of the host population. Especially substitutions in the epitope regions of the surface protein HA lead to antigenic change, facilitating the evasion of the host's immune response by the virus and making frequent updates of the vaccine composition necessary. Through the global monitoring of circulating influenza viruses, large amounts of sequence data are generated. Computational biology offers a quick and easy way to analyze these to characterize the genetic and antigenic evolution of influenza viruses. Using sequence data together with antigenic information provided by hemagglutination inhibition (HI) assays and structural information, bioinformatics methods can elucidate evolutionary relationships between isolates, infer amino acid sites or regions of the protein under positive selection, and identify amino acid changes relevant for the antigenic evolution. We here describe a selection of programs used to generate hypotheses about functionally or antigenically important amino acid changes, protein regions, or individual sites that can subsequently be tested in wet-lab experiments or have value for predicting the future evolution of seasonal influenza A viruses.

Current and Next Generation Vaccines Against Influenza

Influenza is an infectious disease. In order to overcome various infectious diseases, many vaccines have been developed so far. Influenza vaccines have played an important role in prevention and control of influenza. However, current influenza vaccines are not perfect. Current influenza vaccines are produced by anticipating influenza viruses that may occur in annual epidemics or pandemics because influenza viruses have characteristic of antigen mutations. Furthermore, current subcutaneous or intramuscular inoculation of vaccine cannot sufficiently induce IgA that plays an important role in defending the entry of pathogens from the mucosa. In order to overcome the drawbacks of these current influenza vaccines, next generation vaccines are under investigation. One candidate is universal influenza vaccine using the antigens that are conserved among influenza virus strains. Another one is mucosal vaccine that can induce IgA on the mucosa of the upper respiratory tract. Here current and next generation influenza vaccines are described.

Четырехвалентные вакцины: путь к снижению бремени гриппа

Annual epidemics of influenza poses a serious risk to health of all mankind. According to WHO estimates, seasonal flu epidemics result in three to five million cases of severe illness and between 250000 and 500 000 deaths worldwide. Seasonal influenza spreads easily, with rapid transmission in crowded areas, it is difficult to protect from it, so vaccination remains the most effective method for preventing infection. For many years, the composition of influenza vaccines included two subtypes A and one type B of influenza viruses. However, since the 2012-2013 season, WHO recommends that the fourth component, the antigens of the second influenza B virus, should be included. The quadrivalent vaccines are expected to provide broader protection against infections caused by influenza B viruses.

Primary Human Influenza B Virus Infection Induces Cross-Lineage Hemagglutinin Stalk-Specific Antibodies Mediating Antibody-Dependent Cellular Cytoxicity.

Influenza A virus (IAV) and influenza B virus (IBV) cause substantial morbidity and mortality during annual epidemics. Two distinct lineages of IBV are distinguished, based on variation in hemagglutinin (HA): B/Victoria/2/87-like (B/Vic) and B/Yamagata/16/88-like (B/Yam). Here, we show that, in humans, primary IBV infection with either lineage induces HA-specific antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. IBV infection induced antibodies specific to the HA head and stalk, but only HA stalk-specific antibodies mediated ADCC efficiently and displayed cross-reactivity with IBV of both lineages. This corresponds to recent findings that 2 points of contact between the effector and target cell (ie, HA and sialic acid, respectively, and the fragment crystallizable [Fc] domain and Fcγ receptor IIIα, respectively) are required for efficient ADCC activity and that antibodies specific for the receptor-binding site located in the head domain of HA therefore fail to mediate ADCC. Potentially, ADCC-mediating antibodies directed to the HA stalk of IBV contribute to cross-protective immunity to IBV of both lineages.

Temporal distribution and genetic variants in influenza A(H1N1)pdm09 virus circulating in Mexico, seasons 2012 and 2013.

The 2012 and 2013 annual influenza epidemics in Mexico were characterized by presenting different seasonal patterns. In 2012 the A(H1N1)pdm09 virus caused a high incidence of influenza infections after a two-year period of low circulation; whereas the 2013 epidemic presented circulation of the A(H1N1)pdm09 virus throughout the year. We have characterized the molecular composition of the Hemagglutinin (HA) and Neuraminidase (NA) genes of the A(H1N1)pdm09 virus from both epidemic seasons, emphasizing the genetic characteristics of viruses isolated from Yucatan in Southern Mexico. The molecular analysis of viruses from the 2012 revealed that all viruses from Mexico were predominantly grouped in clade 7. Strikingly, the molecular characterization of viruses from 2013 revealed that viruses circulating in Yucatan were genetically different to viruses from other regions of Mexico. In fact, we identified the occurrence of two genetic variants containing relevant mutations at both the HA and NA surface antigens. There was a difference on the temporal circulation of each genetic variant, viruses containing the mutations HA-A141T / NA-N341S were detected in May, June and July; whereas viruses containing the mutations HA-S162I / NA-L206S circulated in August and September. We discuss the significance of these novel genetic changes.

Seasonal and pandemic influenza: global fatigue versus global preparedness

Seasonal and pandemic influenza: global fatigue versus global preparedness

Pharmacodynamics, Pharmacokinetics, and Antiviral Activity of BAY 81-8781, a Novel NF-κB Inhibiting Anti-influenza Drug.

Influenza is a respiratory disease that causes annual epidemics. Antiviral treatment options targeting the virus exist, but their efficiency is limited and influenza virus strains easily develop resistance. Thus, new treatment strategies are urgently needed. In the present study, we investigated the anti-influenza virus properties of D,L-lysine acetylsalicylate ⋅ glycine (BAY 81-8781; LASAG) that is approved as Aspirin i.v. for intravenous application. Instead of targeting the virus directly BAY 81-8781 inhibits the activation of the NF-κB pathway, which is required for efficient influenza virus propagation. Using highly pathogenic avian influenza virus strains we could demonstrate that BAY 81-8781 was able to control influenza virus infection in vitro. In the mouse infection model, inhalation of BAY 81-8781 resulted in reduced lung virus titers and protection of mice from lethal infection. Pharmacological studies demonstrated that the oral route of administration was not suitable to reach the sufficient concentrations of BAY 81-8781 for a successful antiviral effect in the lung. BAY 81-8781 treatment of mice infected with influenza virus started as late as 48 h after infection was still effective in protecting 50% of the animals from death. In summary, the data represent a successful proof of the novel innovative antiviral concept of targeting a host cell signaling pathway that is required for viral propagation instead of viral structures.

Multiplex Reverse Transcription-PCR for Simultaneous Surveillance of Influenza A and B Viruses.

Influenza A and B viruses are the causative agents of annual influenza epidemics that can be severe, and influenza A viruses intermittently cause pandemics. Sequence information from influenza virus genomes is instrumental in determining mechanisms underpinning antigenic evolution and antiviral resistance. However, due to sequence diversity and the dynamics of influenza virus evolution, rapid and high-throughput sequencing of influenza viruses remains a challenge. We developed a single-reaction influenza A/B virus (FluA/B) multiplex reverse transcription-PCR (RT-PCR) method that amplifies the most critical genomic segments (hemagglutinin [HA], neuraminidase [NA], and matrix [M]) of seasonal influenza A and B viruses for next-generation sequencing, regardless of viral type, subtype, or lineage. Herein, we demonstrate that the strategy is highly sensitive and robust. The strategy was validated on thousands of seasonal influenza A and B virus-positive specimens using multiple next-generation sequencing platforms.

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral.

Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu®) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic window, coupled with the increasing incidence of drug resistance, calls for the next generation of influenza antivirals. In this study, we discovered hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. Hesperadin inhibits multiple human clinical isolates of influenza A and B viruses with single to submicromolar efficacy, including oseltamivir-resistant strains. Mechanistic studies revealed that hesperadin inhibits the early stage of viral replication by delaying the nuclear entry of viral ribonucleoprotein complex, thereby inhibiting viral RNA transcription and translation as well as viral protein synthesis. Moreover, a combination of hesperadin with oseltamivir shows synergistic antiviral activity, therefore hesperadin can be used either alone to treat infections by oseltamivir-resistant influenza viruses or used in combination with oseltamivir to delay resistance evolution among oseltamivir-sensitive strains. In summary, the discovery of hesperadin as a broad-spectrum influenza antiviral offers an alternative to combat future influenza epidemics and pandemics.

Influenza.

Influenza is an acute viral respiratory disease that affects persons of all ages and is associated with millions of medical visits, hundreds of thousands of hospitalizations, and thousands of deaths during annual winter epidemics of variable severity in the United States. Elderly persons have the highest influenza-associated hospitalization and mortality rates. The primary method of prevention is annual vaccination. Early antiviral treatment has the greatest clinical benefit; otherwise, management includes adherence to recommended infection prevention and control measures as well as supportive care of complications.

Welcome to CRRM2017

On behalf of the entire the international conference Innovations in Cancer Research and Regenerative Medicine 2017 (CRRM2017) Organizing Committee, we would like to extend to you a warm welcome to Ho Chi Minh city, Vietnam to join the 3rd international conference of CRRM. We are very glad to announce that this time, CRRM has made some exciting changes with more plenary sessions, more sessions, more oral invited speakers and especially a day of pre-conference. With two main topics of cancer research and regenerative medicine, this conference has many sessions organized into some parallel sessions with different topics of cancer research and regenerative medicine. By doing so, the audience can arrange their time for networking and speaking to our commercial partners. From the basic science to clinical trials, all sessions at the conference will cover from gene to human body. Therefore, we believe that every session will provide exciting presentations for attendees at all levels from students to scientists/researchers. With this conference, all authors not only share their latest results, but also can publish their works in the reputed journals. That is a reason why the keywords for this conference is Share & Publish. Like many developing countries, Vietnam has no shortage of health challenges, from infectious diseases such as annual flu epidemics to rising rates of unmet and chronic illnesses such as cancers and diabetes. Vietnam also has to contend with increasing drug resistance for killer diseases including AIDS, tuberculosis, and malaria. There is, however, increasing evidence that Vietnamese researchers are tackling the challenges of harnessing biotechnology to improve health care for healthier society as well as advancing the sciences. The biomedicine progresses in Cancer Research, and Regenerative Medicine in Vietnam include gene diagnostics for genetic disorders of human diseases, infectious pathogens; in-vitro production of therapeutic proteins including insulin, IFNs or biosimilar forms of monoclonal antibodies for targeted therapies; biomaterials; cell therapy; stem cell therapy and tissue engineering. In this conference, with 14 sessions of 100 oral presentations and 100 poster presentations, all latest topics of cancer research and regenerative medicine will be covered. New biomarkers of cancers, immunotherapy strategy for cancers and stem cells as well as tissue engineering are hot topics of CRRM2017. In addition to the conference program, there is an extensive set of pre-conference and lunch-on innovation showcases for on 10th and 11th Sept, respectively. We are very grateful for the support from sponsors for the CRRM2017. More vents will be taking place in the exhibition area, and we encourage attendees to take advantage of the opportunities to visit the exhibit booths and corporate symposia. We wish to thank everyone who helped so enthusiastically in the organization of the conference. Our thanks also go out to all of the speakers who have generously agreed to share their research results and experiences at this conference. We hope that you will enjoy this meeting and have a wonderful time here in Ho Chi Minh city, Vietnam.

Development and validation of a house finch interleukin-1\u03b2 (HfIL-1\u03b2) ELISA system

BackgroundA unique clade of the bacterium Mycoplasma gallisepticum (MG), which causes chronic respiratory disease in poultry, has resulted in annual epidemics of conjunctivitis in North American house finches since the 1990s. Currently, few immunological tools have been validated for this songbird species. Interleukin-1β (IL-1β) is a prototypic multifunctional cytokine and can affect almost every cell type during Mycoplasma infection. The overall goal of this study was to develop and validate a direct ELISA assay for house finch IL-1β (HfIL-1β) using a cross-reactive chicken antibody.MethodsA direct ELISA approach was used to develop this system using two different coating methods, carbonate and dehydration. In both methods, antigens (recombinant HfIL-1b or house finch plasma) were serially diluted in carbonate-bicarbonate coating buffer and either incubated at 4 °C overnight or at 60 °C on a heating block for 2 hr. To generate the standard curve, rHfIL-1b protein was serially diluted at 0, 3, 6, 9, 12, 15, 18, 21, and 24 ng/mL. Following blocking and washing, anti-chicken IL-1b polyclonal antibody was added, plates were later incubated with detecting antibodies, and reactions developed with tetramethylbenzidine solution.ResultsA commercially available anti-chicken IL-1β (ChIL-1β) polyclonal antibody (pAb) cross-reacted with house finch plasma IL-1β as well as bacterially expressed recombinant house finch IL-1β (rHfIL-1β) in immunoblotting assays. In a direct ELISA system, rHfIL-1β could not be detected by an anti-ChIL-1β pAb when the antigen was coated with carbonate-bicarbonate buffer at 4°C overnight. However, rHfIL-1β was detected by the anti-ChIL-1β pAb when the antigen was coated using a dehydration method by heat (60°C). Using the developed direct ELISA for HfIL-1β with commercial anti-ChIL-1β pAb, we were able to measure plasma IL-1β levels from house finches.ConclusionsBased on high amino acid sequence homology, we hypothesized and demonstrated cross-reactivity of anti-ChIL-1β pAb and HfIL-1β. Then, we developed and validated a direct ELISA system for HfIL-1β using a commercial anti-ChIL-1β pAb by measuring plasma HfIL-1β in house finches.

Epidemiological characteristics of hand, foot, and mouth disease in Shandong, China, 2009\u20132016

In the past decade, hand, foot, and mouth disease (HFMD) has posed a serious threat to childhood health in China; however, no epidemiological data from large HFMD epidemics have been described since 2013. In the present study, we described the epidemiological patterns of HFMD in Shandong province during 2009–2016 from a large number of symptomatic cases (n = 839,483), including >370,000 HFMD cases since 2013. Our results revealed that HFMD activity has remained at a high level and continued to cause annual epidemics in Shandong province from 2013 onwards. Although the incidence rate was significantly higher in urban areas than in rural areas, no significantly higher case-severity and case-fatality rates were found in urban areas. Furthermore, the seventeen cities of Shandong province could be classified into three distinct epidemiological groups according to the different peak times from southwest (inland) to northeast (coastal) regions. Notably, a replacement of the predominant HFMD circulating agent was seen and non-EVA71/Coxsackievirus A16 enteroviruses became dominant in 2013 and 2015, causing approximately 30% of the severe cases. Our study sheds light on the latest epidemiological characteristics of HFMD in Shandong province and should prove helpful for the prevention and control of the disease in Shandong and elsewhere.

Evolution of Influenza A Virus by Mutation and Re-Assortment.

Influenza A virus (IAV), a highly infectious respiratory pathogen, has continued to be a significant threat to global public health. To complete their life cycle, influenza viruses have evolved multiple strategies to interact with a host. A large number of studies have revealed that the evolution of influenza A virus is mainly mediated through the mutation of the virus itself and the re-assortment of viral genomes derived from various strains. The evolution of influenza A virus through these mechanisms causes worldwide annual epidemics and occasional pandemics. Importantly, influenza A virus can evolve from an animal infected pathogen to a human infected pathogen. The highly pathogenic influenza virus has resulted in stupendous economic losses due to its morbidity and mortality both in human and animals. Influenza viruses fall into a category of viruses that can cause zoonotic infection with stable adaptation to human, leading to sustained horizontal transmission. The rapid mutations of influenza A virus result in the loss of vaccine optimal efficacy, and challenge the complete eradication of the virus. In this review, we highlight the current understanding of influenza A virus evolution caused by the mutation and re-assortment of viral genomes. In addition, we discuss the specific mechanisms by which the virus evolves.

Infective respiratory syncytial virus is present in human cord blood samples and most prevalent during winter months.

BackgroundHuman respiratory syncytial virus (RSV) remains the most common cause of severe lower respiratory tract disease amongst infants, and continues to cause annual epidemics of respiratory disease every winter worldwide. Demonstrating placental transmission of viable RSV in human samples is a major paradigm shift in respiratory routes considered likely for RSV transmission.MethodsDroplet digital PCR (ddPCR) was used to identify RSV present in cord blood mononucleocytes (CBM). CBMs testing positive for RSV were treated with phytohemagglutinin (PHA), PHA and nitric oxide (NO) or PHA, NO and palivizumab, and co-cultured with HeLa cell monolayers. Subsequent immuno-staining for RSV was used to visualize infective viral plaques.ResultsRSV was detected in 26 of 45 samples (57.7%) by ddPCR. CBM’s collected in winter were more likely to test positive for RSV (17/21 samples, risk = 80%, OR = 7.08; 95% CI 1.80–27.80; p = 0.005) compared to non-winter months (9/24 samples, 37.5%). RSV plaques were observed in non-treated and treated co-cultured HeLa monolayers.ConclusionsDemonstrating active RSV in CBMs suggests in utero transmission of infective virus to the fetus without causing overt disease. This is likely to have an important impact on immune development as well as future virus-host interactions, thereby warranting further investigation.

An Informetric Analysis of Studies on Influenza Vaccines and Vaccination

Influenza is one of highly contagious acute virus diseases that primarily affects respiratory ways. Annual seasonal epidemics afflict approximately 15% population worldwide and lead to 250,000–500,000 deaths each year. That is why studies on influenza vaccines and vaccination that prevent spreading of the virus remain highly important. This paper presents the results of informetric analysis of publications on influenza vaccine development and vaccination against influenza based on Web of Science databases. The authors analyzed scholarly output from 2001 to 2015. We detected annual increase in the number of publications since 2002, but the highest interest to influenza vaccination was observed in 2009–2011 years due to emergence of new H1N1 virus. After 2011 we registered decrease in publication activity although this subject area is still in the focus of researchers. Journal original papers and reviews seem to be the main source of information, while a share of conference papers consistently decreased over the analyzed period. United States is a leader in the number of research with 40% of all papers which account for 55% of all citations. Elsevier’s Vaccine is a primary journal publishing nearly 20% of papers; however, results of influenza vaccine development have also been published in extremely authoritative journals including The New England Journal of Medicine, Lancet, Science, British Medical Journal, Nature Medicine, etc. This also highlights the great importance of studies on the analyzed topic. Thus, the paper represents different aspects and trends in influenza vaccine development in the last 15 years using a broad range of bibliometric approaches including citation analysis, collaboration networks, revealing the most active countries studying influenza vaccine development, the most authoritative journals and funding organizations.

Drug resistance in influenza A virus: the epidemiology and management.

Influenza A virus (IAV) is the sole cause of the unpredictable influenza pandemics and deadly zoonotic outbreaks and constitutes at least half of the cause of regular annual influenza epidemics in humans. Two classes of anti-IAV drugs, adamantanes and neuraminidase (NA) inhibitors (NAIs) targeting the viral components M2 ion channel and NA, respectively, have been approved to treat IAV infections. However, IAV rapidly acquired resistance against both classes of drugs by mutating these viral components. The adamantane-resistant IAV has established itself in nature, and a majority of the IAV subtypes, especially the most common H1N1 and H3N2, circulating globally are resistant to adamantanes. Consequently, adamantanes have become practically obsolete as anti-IAV drugs. Similarly, up to 100% of the globally circulating IAV H1N1 subtypes were resistant to oseltamivir, the most commonly used NAI, until 2009. However, the 2009 pandemic IAV H1N1 subtype, which was sensitive to NAIs and has now become one of the dominant seasonal influenza virus strains, has replaced the pre-2009 oseltamivir-resistant H1N1 variants. This review traces the epidemiology of both adamantane- and NAI-resistant IAV subtypes since the approval of these drugs and highlights the susceptibility status of currently circulating IAV subtypes to NAIs. Further, it provides an overview of currently and soon to be available control measures to manage current and emerging drug-resistant IAV. Finally, this review outlines the research directions that should be undertaken to manage the circulation of IAV in intermediate hosts and develop effective and alternative anti-IAV therapies.