The evolutionary emergence of pandemic influenza

Pandemic influenza remains a serious public health threat and the processes involved in the evolutionary emergence of pandemic influenza strains remain incompletely understood. Here, we develop a stochastic model for the evolutionary emergence of pandemic influenza, and use it to address three main questions. (i) What is the minimum annual number of avian influenza virus infections required in humans to explain the historical rate of pandemic emergence? (ii) Are such avian influenza infections in humans more likely to give rise to pandemic strains if they are driven by repeated cross-species introductions, or by low-level transmission of avian influenza viruses between humans? (iii) What are the most effective interventions for reducing the probability that an influenza strain with pandemic potential will evolve? Our results suggest that if evolutionary emergence of past pandemics has occurred primarily through viral reassortment in humans, then thousands of avian influenza virus infections in humans must have occurred each year for the past 250 years. Analyses also show that if there is epidemiologically significant variation among avian influenza virus genotypes, then avian virus outbreaks stemming from repeated cross-species transmission events result in a greater likelihood of a pandemic strain evolving than those caused by low-level transmission between humans. Finally, public health interventions aimed at reducing the duration of avian virus infections in humans give the greatest reduction in the probability that a pandemic strain will evolve.     

禽流感:一种人畜共患病

禽流感 (AvianInfluenza ,AI)是严重危害畜牧业与人类健康的一种传染性疾病。多年来在世界上许多国家和地区都发生过此病 ,危害严重 ,经济损失巨大。禽流感病毒可感染多种动物 ,包括人、猪、马、鲸、海豹和雪貂。禽流感病毒经变异或基因重组 ,已具备感染人的能力 ,有可能成为人类新型流感流行的潜在病原。本文对与禽流感病毒相关的流感疫情进行历史性的回顾 ,并对其人畜共患机制做了初步探讨     

Innovations in modeling influenza virus infections in the laboratory

Respiratory viruses represent one of the most substantial infectious disease burdens to the human population today, and in particular, seasonal and pandemic influenza viruses pose a persistent threat to public health worldwide. In recent years, advances in techniques used in experimental research have provided the means to better understand the mechanisms of pathogenesis and transmission of respiratory viruses, and thus more accurately model these infections in the laboratory. Here, we briefly review the model systems used to study influenza virus infections, and focus particularly on recent advances that have increased our knowledge of these formidable respiratory pathogens.     

Killer-cell immunoglobulin-like receptors (KIR) in severe A (H1N1) 2009 influenza infections

Introduction of a novel influenza virus into the human population leads to the occurrence of pandemic events, such as the one caused by pandemic influenza A (H1N1) 2009 virus. The severity of infections caused by this virus in young adults was greater than that observed in patients with seasonal influenza. Fatal cases have been associated with an abnormal innate, proinflammatory immune response. A critical role for natural killer cells during the initial responses to influenza infections has been suggested. In this study, we assessed the association of killer-cell immunoglobulin-like receptors (KIRs) with disease severity by comparing KIR gene content in patients with mild and severe pandemic influenza virus infections to a control group. We found that activator (KIR3DS1 and KIR2DS5) and inhibitory (KIR2DL5) genes, encoded in group B haplotypes containing the cB01, cB03 and tB01 motifs, are associated with severe pandemic influenza A (H1N1) 2009 infections. Better understanding of how genetic variability contributes to influenza virus pathogenesis may help to the development of immune intervention strategies aiming at controlling the severity of disease.     

From lethal virus to life-saving vaccine: developing inactivated vaccines for pandemic influenza

Over the past eight years, cases of human infection with highly pathogenic avian influenza viruses have raised international concern that we could be on the brink of a global influenza pandemic. Many of these human infections have proved fatal and if the viruses had been able to transmit efficiently from person to person, the effects would have been devastating. How can we arm ourselves against this pandemic threat when these viruses are too dangerous to use in conventional vaccine production? Recent technological developments (reverse genetics) have allowed us to manipulate the influenza virus genome so that we can construct safe, high-yielding vaccine strains. However, the transition of reverse-genetic technologies from the research laboratory to the manufacturing environment has presented new challenges for vaccine manufacturers as well as veterinary and public health authorities.     

New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and Therapeutic Efficacy in Ferrets

Background

The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class.

Methodology/Principal Findings

We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage.

Conclusions/Significance

These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.     

Pathogenesis of avian influenza (H7) virus infection in mice and ferrets: enhanced virulence of Eurasian H7N7 viruses isolated from humans

Before 2003, only occasional case reports of human H7 influenza virus infections occurred as a result of direct animal-to-human transmission or laboratory accidents; most of these infections resulted in conjunctivitis. An increase in isolation of avian influenza A H7 viruses from poultry outbreaks and humans has raised concerns that additional zoonotic transmissions of influenza viruses from poultry to humans may occur. To better understand the pathogenesis of H7 viruses, we have investigated their ability to cause disease in mouse and ferret models. Mice were infected intranasally with H7 viruses of high and low pathogenicity isolated from The Netherlands in 2003 (Netherlands/03), the northeastern United States in 2002-2003, and Canada in 2004 and were monitored for morbidity, mortality, viral replication, and proinflammatory cytokine production in respiratory organs. All H7 viruses replicated efficiently in the respiratory tracts of mice, but only Netherlands/03 isolates replicated in systemic organs, including the brain. Only A/NL/219/03 (NL/219), an H7N7 virus isolated from a single fatal human case, was highly lethal for mice and caused severe disease in ferrets. Supporting the apparent ocular tropism observed in humans following infection with viruses of the H7 subtype, both Eurasian and North American lineage H7 viruses were detected in the mouse eye following ocular inoculation, whereas an H7N2 virus isolated from the human respiratory tract was not. Therefore, in general, the relative virulence and cell tropism of the H7 viruses in these animal models correlated with the observed virulence in humans.     

Incidence of avian flu worldwide and in the Russian Federation. Improvement of surveillance and control of influenza during preparation for potential pandemic

Problem of influenza and acute respiratory virus infections (ARVI) remains one of the most urgent medical and socio-economic issues in despite of certain achievements in vaccine and chemoprophylaxis. In Russia influenza and ARVI account for up to 90% of the total annual incidence of infectious disease (up to 30 million of sick people; 45-60% of them are children). Economic damage, caused by influenza and ARVI, makes around 86% of total economic damage, caused by infectious diseases. WHO predicts that in the years coming a new antigenic influenza virus will appear, which can lead to development of large pandemia with 4-5 times increase in disease incidence and 5-10 times increase in death rate. During 2005 some changes in animal influenza epidemiology were registered. New cases of people infections are detected, the virus has spread to some new countries. Avian influenza is a high contagious virus infection that can affect all bird species. For birds influenza is enteral infection, it severely affects parenchymatous organs, especially spleen, and lungs. By now it is known that carriers of avian influenza virus H5N1 can be all known species of wild waterfowl and near-water birds. Poultry is highly susceptible to many stocks of influenza virus H5N1, death rate reaches 100%. At that hens, especially chickens, are most susceptible. From January 2004 to 24th November 2005 in the world there were detected 131 cases of influenza, caused by virus A/H5N1/, 68 of them (51%) ended in lethal outcome (Vietnam--92 cases, Thailand--21 cases, Cambodia--4, Indonesia--11, China--3). Most of the described cases of avian influenza resulted from direct contact with infected birds (handling bird internal organs is especially dangerous). In frozen meat of infected birds the virus can remain for about one year. Heating kills virus (no cases of infection caused by use for food of poultry products were detected). In order to prevent wide ranging spread of infection over Russia it is necessary to organize medical monitoring of sea ships, aircraft and train crews, arriving from the countries where influenza H5N1 cases were detected, in case of need to arrange raids to outlets and markets to detect poultry and poultry products brought from these countries. In Russia it is necessary to prepare a reserve of vaccine strains of viruses--potential causative agent of pandemic, including H5N1 and H7N7, that can start to vaccine reproduction immediately in case of pandemic.     

New infections: myths and reality

New contemporary data about new infectious diseases of XXI century are presented. Data on morbidity and mortality from severe acute respiratory syndrome (SARS, atypical pneumonia) and avian influenza are analyzed and compared with World Health Organization data on human influenza. Biologic characteristics of avian influenza virus A/H5N1 are discussed as well as possibility of its human-to-human transmission. Principles of SARS and avian influenza infections transmission as zoonoses are described as well as mechanisms of transmission impeding their ability to infect humans. It has been argued that SARS should be regarded as contagious infection, whereas avian influenza - as non-contagious. Features of all stages of epidemic process of these infections are analyzed.     

What about the ducks? An alternative vaccination strategy.

Like most emerging disease threats, avian influenza is a zoonotic disease maintained in nature by wildlife. In this case, the reservoir of infection is migratory waterfowl, primarily ducks. Rather than trying to vaccinate most of the world's human population in response to the threat of an avian influenza pandemic, it might be more prudent to vaccinate key reservoir wildlife species from which pandemic strains evolve. This strategy would require a much more intensive research effort to understand the evolution of avian influenza viruses in nature, but it would be far less costly than any of the alternatives. Research priorities for emerging zoonoses, such as new strains of avian influenza viruses, should be re-evaluated with an emphasis on ways to intervene at their source, the natural reservoir hosts from which they originate, rather than focusing up on human-based interventions, which are too often too late.     

Biological and epidemiological aspects of influenza virus H5N1 in context of India

Since 1997, highly pathogenic avian influenza (HPAI) H5N1 virus crossed the species barriers from birds to humans and caused fatal disease, leading to great speculation about a possible influenza pandemic. This subtype is characterized by its pathogenicity in a large number of animal species and resistance to older class of antiviral drugs. At present, two out of three general conditions for the onset of pandemic have been met, emergence of new virus; and its ability to replicate in humans causing serious illness. Next influenza pandemic might be due to human to human transmission. This review addresses the biological and epidemiological aspects of influenza in context of India.     

季节性流感病毒与其他病原混合或继发感染的研究进展与思考

流感病毒包括甲(A)、乙(B)、丙(C)和丁(D)四种型。人流行性感冒是由甲型和乙型季节性流感病毒引起的一种急性呼吸道传染病。流感病毒感染患者主要表现出呼吸道症状,严重时可以导致肺炎。此外,与其他病毒、细菌和支原体等病原体混合或继发感染时,会增加流感患者的重症率和死亡率。近几年,流感病毒与其他病原协同感染的病例有增加趋势。本文归纳总结了流感病毒与其他病原混合及继发感染的研究现状,希望为流感病毒复杂感染情况的临床诊断和治疗方案的制定提供线索。     

The emergence of pandemic influenza viruses

Pandemic influenza has posed an increasing threat to public health worldwide in the last decade. In the 20th century, three human pandemic influenza outbreaks occurred in 1918, 1957 and 1968, causing significant mortality. A number of hypotheses have been proposed for the emergence and development of pandemic viruses, including direct introduction into humans from an avian origin and reassortment between avian and previously circulating human viruses, either directly in humans or via an intermediate mammalian host. However, the evolutionary history of the pandemic viruses has been controversial, largely due to the lack of background genetic information and rigorous phylogenetic analyses. The pandemic that emerged in early April 2009 in North America provides a unique opportunity to investigate its emergence and development both in human and animal aspects. Recent genetic analyses of data accumulated through long-term influenza surveillance provided insights into the emergence of this novel pandemic virus. In this review, we summarise the recent literature that describes the evolutionary pathway of the pandemic viruses. We also discuss the implications of these findings on the early detection and control of future pandemics.     

Catastrophes after crossing species barriers

Probably the most tragic examples of virus infections that have caused the deaths of many millions of people in the past century were the influenza and AIDS pandemics. These events occurred as a direct result of the introduction of animal viruses into the human population. Similarly, mass mortalities among aquatic and terrestrial mammals were caused by the introduction of viruses into species in which they had not previously been present. It seems paradoxical that at a time when we have managed to control or even eradicate major human virus infections like polio and smallpox we are increasingly confronted with new or newly emerging virus infections of humans and animals. A complex mix of social, technological and ecological changes, and the ability of certain viruses to adapt rapidly to a changing environment, seems to be at the basis of this phenomenon. Extensive diagnostic and surveillance networks, as well as novel vaccine- and antiviral development strategies should provide us with the safeguards to limit its impact.     

The genesis of a pandemic influenza virus

Pandemic influenza viruses pose a significant threat to public health worldwide. In a recent Nature paper, Taubenberger et al. (2005) now report remarkable similarities between the polymerase genes of the influenza virus that caused the 1918 Spanish influenza pandemic and those of avian influenza viruses. Meanwhile, Tumpey et al. (2005) reporting in Science show that the reconstructed 1918 Spanish influenza virus kills mice faster than any other influenza virus so far tested.     

Adaptation of Pandemic H2N2 Influenza A Viruses in Humans

The 1957 A/H2N2 influenza virus caused an estimated 2 million fatalities during the pandemic. Since viruses of the H2 subtype continue to infect avian species and pigs, the threat of reintroduction into humans remains. To determine factors involved in the zoonotic origin of the 1957 pandemic, we performed analyses on genetic sequences of 175 newly sequenced human and avian H2N2 virus isolates and all publicly available influenza virus genomes.     

Prioritizing Zoonoses: A Proposed One Health Tool for Collaborative Decision-Making

Emerging and re-emerging zoonotic diseases pose a threat to both humans and animals. This common threat is an opportunity for human and animal health agencies to coordinate across sectors in a more effective response to zoonotic diseases. An initial step in the collaborative process is identification of diseases or pathogens of greatest concern so that limited financial and personnel resources can be effectively focused. Unfortunately, in many countries where zoonotic diseases pose the greatest risk, surveillance information that clearly defines burden of disease is not available. We have created a semi-quantitative tool for prioritizing zoonoses in the absence of comprehensive prevalence data. Our tool requires that human and animal health agency representatives jointly identify criteria (e.g., pandemic potential, human morbidity or mortality, economic impact) that are locally appropriate for defining a disease as being of concern. The outcome of this process is a ranked disease list that both human and animal sectors can support for collaborative surveillance, laboratory capacity enhancement, or other identified activities. The tool is described in a five-step process and its utility is demonstrated for the reader.     

Pandemic swine influenza virus (H1N1): A threatening evolution

“Survival of the fittest” is an old axiom laid down by the great evolutionist Charles Darwin and microorganisms seem to have exploited this statement to a great extent. The ability of viruses to adapt themselves to the changing environment has made it possible to inhabit itself in this vast world for the past millions of years. Experts are well versed with the fact that influenza viruses have the capability to trade genetic components from one to the other within animal and human population. In mid April 2009, the Centers for Disease Control and Prevention and the World Health Organization had recognized a dramatic increase in number of influenza cases. These current 2009 infections were found to be caused by a new strain of influenza type A H1N1 virus which is a re-assortment of several strains of influenza viruses commonly infecting human, avian, and swine population. This evolution is quite dependent on swine population which acts as a main reservoir for the reassortment event in virus. With the current rate of progress and the efforts of heath authorities worldwide, we have still not lost the race against fighting this virus. This article gives an insight to the probable source of origin and the evolutionary progress it has gone through that makes it a potential threat in the future, the current scenario and the possible measures that may be explored to further strengthen the war against pandemic.     

重组金丝雀痘病毒载体疫苗研制进展

金丝雀痘病毒（canarypox virus,CNPV）引起的雀痘是一种禽类传染性疾病。CNPV感染后可在宿主体内诱导细胞、体液和黏膜免疫应答,经过改造可开发为一种候选疫苗载体,其可表达病毒和寄生虫的多种蛋白,因此,研制重组CNPV载体疫苗进行免疫预防具有重要的经济意义。国外学者已构建了多种类似疫苗,如马流感病毒（equine influenza virus,EIV）、犬瘟热病毒（canine distemper virus,CDV）、麻疹病毒（measles virus,MV）、尼帕病毒（Nipah virus,NiV）、艾滋病毒（human immunodeficiency virus type 1,HIV?1）、非洲马病病毒4型（African horse sickness virus type 4,AHSV?4）、蓝舌病毒17型（bluetongue virus serotype 17,BTV?17）、丙型肝炎病毒（hepatitis C virus,HCV）、巨细胞病毒（cytomelovirus,CMV）、狂犬病毒（rabies virus）和婴儿利什曼原虫（Leishmania infantum）等。概述了CNPV载体介导的病原体疫苗的构建及其免疫机制等方面的研制现状,旨在为病毒和寄生虫病的免疫预防提供理论依据。