Measures for control of influenza

Influenza viruses cause recurring illnesses among individuals and recurring epidemics among populations. The major effective control measure for preventing infection and illness is inactivated vaccine, which can prevent influenza illnesses and their complications when given before exposure to the virus. While inactivated vaccine is effective for preventing influenza in most individuals, recommendations for its use focus on the prevention of severe disease and death among those who are at high risk of complications. Live attenuated cold-adapted influenza vaccines are nearing availability. They are given by nasal spray and are particularly effective for preventing influenza among young children, but also for preventing influenza among young adults, and enhancing protection against influenza when given with inactivated vaccine to elderly persons. The antiviral agents amantadine and rimantadine are related compounds that are effective for the prevention and treatment of influenza A virus infections and illnesses. Disadvantages are the rapid development of resistance during treatment and CNS adverse effects with amantadine. These drugs are also effective for outbreak control. Ribavirin is an antiviral given by small particle aerosol that is approved for the treatment of respiratory syncytial virus disease; it is also effective for the treatment of influenza. Two new antiviral agents inhibit influenza viral neuraminidase activity; one is given by inhalation or intranasally (zanamivir) and the other orally (GS4104). The former is free of adverse effects, while the latter induces nausea and vomiting in some individuals. Both are effective for the prevention as well as the treatment of influenza A and B illnesses. Thus, various measures for preventing and treating influenza are nearing availability. Their optimal use should further improve the control of influenza in individuals and populations as well as permit efforts to prevent community epidemics.     

新型抗病毒RNA聚合酶PA亚基抑制剂临床研究进展

流行性感冒（简称流感）是流感病毒引起的对人类健康危害较重的呼吸道传染病。目前抗流感药物的应用主要面临病毒耐药性和对高致病性流感病毒的效价低的问题,如M2离子通道抑制剂和神经氨酸酶抑制剂存在药效低、时间窗口窄和耐药性等缺点。近来的抗流感药物研发的靶点聚焦于病毒RNA聚合酶。流感病毒RNA聚合酶是病毒在宿主细胞内完成复制和转录过程的关键酶,其中PA亚基通过内切酶活性为流感病毒的转录过程提供引物,成为潜在抗流感药物靶点。本文总结了以PA亚基内切酶为靶点的抗流感药物研究进展,旨在为开发安全有效的新型抗病毒RNA聚合酶抑制剂提供参考。     

基于流感发病机制的药物研究进展

流行性感冒简称流感,经飞沫或接触在人或动物之间传播的RNA流感病毒感染所致,流感病毒在宿主体内复制扩散引发机体过度免疫反应造成一些呼吸道、消化道甚至休克等症状,其强传染性一直对公共健康构成威胁。筛选新的抗流感药物并解释其作用机制已成为当前研究的热点,本文根据流感发病机制就抗流感药物进行分类总结,归纳近现代及在未来有抗流感开发前景的中药、化药及中西药联用,以期为抗流感新药的研发提供参考依据。     

New small-molecule drug design strategies for fighting resistant influenza A

Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two main treatment strategies–vaccination and small molecule anti-influenza drugs are currently available. As an effective vaccine usually takes at least 6 months to develop, anti-influenza small molecule drugs are more effective for the first line of protection against the virus during an epidemic outbreak, especially in the early stage. Two major classes of anti-influenza drugs currently available are admantane-based M2 protein blockers (amantadine and rimantadine) and neuraminidase (NA) inhibitors (oseltamivir, zanamivir, and peramivir). However, the continuous evolvement of influenza A virus and the rapid emergence of resistance to current drugs, particularly to amantadine, rimantadine, and oseltamivir, have raised an urgent need for developing new anti-influenza drugs against resistant forms of influenza A virus. In this review, we first give a brief introduction of the molecular mechanisms behind resistance, and then discuss new strategies in small-molecule drug development to overcome influenza A virus resistance targeting mutant M2 proteins and neuraminidases, and other viral proteins not associated with current drugs.KEY WORDS: Influenza A virus, Drug discovery, Resistance, M2 ion channel, Neuraminidase     

Recent Patents on development of nucleic acid-based antiviral drugs against seasonal and pandemic influenza virus infections

Influenza viruses are etiological agents of deadly flu that continue to pose global health threats, and have caused global pandemics that killed millions of people worldwide. The global crisis involving the avian H5N1 influenza provides compelling reasons to accelerate fast track development of novel antiviral drugs against the potential pandemic virus. The availability of neuraminidase inhibitors such as oseltamivir (tamiflu) improves our ability to defend against influenza viruses, but the incidences of tamiflu-resistance are rising rapidly. Nucleic acid-based antiviral drugs are promising classes of experimental antiviral drugs that have been shown in pre-clinical studies to be effective against seasonal and avian influenza viruses. The potency and versatility of these drugs make them potential candidates to be used in seasonal and pandemic influenza scenarios. The review will assess the recent patents, research and development of antisense oligonucleotides, small interfering RNA, immunomodulating RNA for the prevention and treatment of influenza infection.     

CpG oligodeoxynucleotides protect against the 2009 H1N1 pandemic influenza virus infection in a murine model

The 2009 H1N1 influenza virus pandemic poses a global public health threat, and there is a critical need for antiviral drugs for pandemic control. CpG oligodeoxynucleotides have strong immunostimulatory properties and are expected to be used as prophylactic agents to protect against microbial infections. The present study evaluated the efficacy of synthetic CpG oligodeoxynucleotide (ODN) 1826 against pandemic H1N1 virus infection in a murine model. A single injection of 15 μg ODN 1826 intraperitoneally prior to virus challenge inhibits virus replication in lungs, reduces lung lesions and prevents mortality in mice, indicating CpG ODNs as a possible strategy for future influenza pandemics control.     

Controlling influenza by inhibiting the virus's neuraminidase

Despite the fact that influenza is a disease which affects millions of people, sometimes with fatal consequences. there has not, until recently, been any drug effective against all strains. Vaccines may be relatively or totally ineffective, so drugs are needed. Random screening of many thousands of compounds by pharmaceutical companies has resulted in only two compounds, amantadine and rimantidine, which target the M2 ion channel on the virus. These drugs have major disadvantages. Knowledge of the crystal structure of influenza virus neuraminidase, on the other hand, has allowed the rational design of four "plug-drugs" which bind to the active site of flu neuraminidase and stop replication of the virus. Two of these compounds. Relenza and Tamiflu, are now being used worldwide and, although effective when used properly, suffer from problems of delivery. They need to be given very soon after infection to be effective, they only inhibit the influenza virus and none of the other respiratory agents which cause flu-like symptoms, and they are very expensive.     

Neuraminidase inhibitors for the treatment and prevention of influenza

The impact of influenza virus infection is estimated to run into billions of dollars worldwide. Vaccination plays a key role in prevention; however, vaccines do not provide complete protection against influenza due to the constant mutation of the virus responsible. Unlike amantadine and rimantadine, which are only effective against influenza A, the new neuraminidase inhibitors zanamivir (Relenza), GlaxoSmithKline) and oseltamivir (Tamiflu), Gilead/Roche) are potent and specific inhibitors of influenza types A and B and have minimal side effects. The greatest benefit is derived if treatment commences as soon as possible after symptoms develop. In order for these inhibitors to have a significant impact on the disease, clinicians and the general public need to be made more aware of the symptoms of influenza and the availability of these new drugs.     

DNA-based influenza vaccines: evaluating their potential to provide universal protection

The recent outbreaks of the H5N1 and H1N1 pandemic influenza have highlighted the importance of developing fast, effective therapeutic strategies to prevent and/or limit the spread of future influenza outbreaks. Although current vaccines against influenza are generally effective, several limitations, including those associated with the amount of available vaccine, the time to vaccine production and vaccine efficacy, may encumber a mass vaccination strategy and effective targeting against future outbreaks. This feature review discusses the prospects of SynCon-derived DNA vaccines against influenza; such vaccines are expected to be effective at targeting many currently circulating influenza virus strains, as well as potentially targeting strains that may be associated with future outbreaks. Because of advantages associated with safety, time to production and ease of production, as well as the generation of more effective immune responses, influenza DNA vaccines provide a promising potential solution to a global medical concern.     

Reconstruction of the 1918 pandemic influenza virus: how revealing the molecular secrets of the virus responsible for the worst pandemic in recorded history can guide our response to future influenza pandemics

There is an ever-present threat that a pandemic will result from the emergence of a new influenza strain to which humans have little immunity. In 1957 and 1968, new influenza viruses emerged into the human population and spread globally. Those pandemics were associated with high rates of illness and mortality, but both paled in comparison with the influenza pandemic of 1918. Reconstruction of the 1918 pandemic virus and studies to elucidate the exceptional virulence of the virus will be important steps toward understanding virulent influenza strains. One approach has been to reconstruct recombinant viruses, in which genes of the 1918 virus are replaced with genes from contemporary human influenza viruses in attempts to understand which of the eight virus gene segments contribute to its high virulence. The identification of the precise pandemic virus genes associated with replication may help elucidate virulence factors for other influenza viruses with pandemic potential and, thereby, help identify targets for drug intervention. An important role of antiviral drugs during an influenza pandemic will be to slow virus replication and subsequent spread while an appropriate vaccine is in production. The topics included in this review highlight areas of active research into the understanding of what made the 1918 pandemic influenza virus so virulent and transmissible. Such research is being done with the hope that the knowledge gained will allow the world to better prepare for and respond to future influenza pandemics.     

Neuraminidase inhibitors for the treatment and prevention of influenza

The impact of influenza virus infection is estimated to run into billions of dollars worldwide. Vaccination plays a key role in prevention; however, vaccines do not provide complete protection against influenza due to the constant mutation of the virus responsible. Unlike amantadine and rimantadine, which are only effective against influenza A, the new neuraminidase inhibitors zanamivir (Relenza^®, GlaxoSmithKline) and oseltamivir (Tamiflu^®, Gilead/Roche) are potent and specific inhibitors of influenza types A and B and have minimal side effects. The greatest benefit is derived if treatment commences as soon as possible after symptoms develop. In order for these inhibitors to have a significant impact on the disease, clinicians and the general public need to be made more aware of the symptoms of influenza and the availability of these new drugs.     

Strategy in structure-based drug design for influenza A virus targeting M2 channel proteins

The 2009 influenza A virus pandemic, with high level of drug resistance reported, has highlighted the urgent need of more effective anti-influenza drugs. M2 channel proteins on the influenza A virus membrane have emerged as an efficient structure-based drug design target since variety of M2 channel protein structures were constructed by different experiment methods to generate the high resolution of crystal, solution NMR and solid-state NMR structure. In an effort to facilitate the future design of M2 channel inhibitors, the binding modes of 200 Adamantane-based drugs in four different types of M2 channel protein structures were evaluated by the critical interactions in terms of ligand binding affinity. The molecular docking results and statistic testing of binding affinity showed that the effect of each representative type from M2 channel protein structures was significantly different. Moreover, pharmacophore analysis revealed that there are two mechanisms of binding interactions to critical residues, Ser31 in holo structures and Ala30 in apo structures, respectively. Molecular docking studies, drug-like filters, and structure-based pharmacophore approaches successfully led us identifying the final hits reduced the false positives and false negatives in strategy of designing new potential group of future M2 channel inhibitors.     

The potential use of influenza virus as an agent for bioterrorism

Influenza A virus has been responsible for widespread human epidemics because it is readily transmitted from humans to humans by aerosol. Recent events have highlighted the potential of influenza A virus as a bioterrorist weapon: the high virulence of the influenza A virus that infected people in Hong Kong in 1997; and the development of laboratory methods to generate influenza A viruses by transfection of DNAs without a helper virus. Antiviral drugs that are directed at functions shared by all influenza A viruses constitute the best line of defense against a bioterrorist attack. Consequently, new antiviral drugs need to be developed, and the few currently available antiviral drugs should be stockpiled.     

Respiratory viral infections in the elderly

Viral respiratory infections represent a significant challenge for those interested in improving the health of the elderly. Influenza continues to result in a large burden of excess morbidity and mortality. Two effective measures, inactivated influenza vaccine, and the antiviral drugs rimantadine and amantadine, are currently available for control of this disease. Inactivated vaccine should be given yearly to all of those over the age of 65, as well as younger individuals with high-risk medical conditions and individuals delivering care to such persons. Live, intranasally administered attenuated influenza vaccines are also in development, and may be useful in combination with inactivated vaccine in the elderly. The antiviral drugs amantadine and rimantadine are effective in the treatment and prevention of influenza A, although rimantadine is associated with fewer side-effects. Recently, the inhaled neuraminidase inhibitor zanamivir, which is active against both influenza A and B viruses, was licensed for use in uncomplicated influenza. The role of this drug in treatment and prevention of influenza in the elderly remains to be determined. Additional neuraminidase inhibitors are also being developed. In addition, to influenza, respiratory infections with respiratory syncytial virus, parainfluenza virus, rhinovirus, and coronavirus have been identified as potential problems in the elderly. With increasing attention, it is probable that the impact of these infections in this age group will be more extensively documented. Understanding of the immunology and pathogenesis of these infections in elderly adults is in its infancy, and considerable additional work will need to be performed towards development of effective control measures.     

The 2009 influenza pandemic: promising lessons for antiviral therapy for future outbreaks

The influenza A virus is the main circulating influenza virus in the human population. It can cause disease also in birds and other mammals and is responsible for annual epidemics and occasional pandemics. The most known and deadly pandemic was the "Spanish flu" (influenza type A/H1N1), which struck the human population between 1918 and 1919, with probably the heaviest toll ever recorded in terms of human lives. The most recent flu pandemic, caused in 2009 by the swine-origin reassortant virus (pH1N1), has raised several critical issues in terms of our preparedness in responding fast to new pandemic influenza strains. Probably, the most instructive lesson that has been learned from the 2009 pandemic, was that the speed of manufacturing and distributing an effective vaccine will not be able to keep up with the pace of a rapidly spreading pandemic virus, failing to grant accessibility to the vaccine for a significant percentage of the susceptible population, before the onset of the pandemic peak. Thus, our first and most effective line of defense against a pandemic influenza virus, particularly in the early phases, are the antiviral drugs. Here we analyze our current understanding of the influenza pandemic viruses, in general, and of the pH1N1 in particular, along with the most recent approaches being pursued to design new anti-influenza drugs.     

Recent anti-influenza strategies in multivalent sialyloligosaccharides and sialylmimetics approaches

Sialic acid-containing oligosaccharides expressed on the respiratory tract epithelial cell surface are involved in influenza virus infection in both virus attaching and detaching processes. Therefore, inhibition of sialic acid-binding processes provides rational anti-influenza strategies. Previous exploring efforts using monosaccharide sialic acid-bearing macromolecules provided proof of concept for multivalent hemagglutinin inhibition. However, the monosaccharide sialic acid cannot account for the molecular determinant of virus receptor-binding specificity in the context of the whole sialyloligosaccharide receptor. On the other hand, neuraminidase inhibition efforts using sialylmimetics have resulted into two antiinfluenza drugs, zanamivir and oseltamivir, which have been shown to reduce both the severity and duration of influenza illness. Nevertheless, the usage of monomeric sialylmimetics requires relatively large amounts of expensive compounds, which may also induce virus resistance and side effect. Therefore, it is critical to develop new antiinfluenza drugs and improve the current antiinfluenza drugs. This review highlights recent explorations of multivalent sialyloligosaccharides-based influenza virus adhesion inhibition strategy and multivalent sialylmimetics-based influenza virus detachment inhibition strategy for these efforts.     

Avian influenza: a review.

PURPOSE: A review of the avian influenza A/H5N1 virus, including human cases, viral transmission, clinical features, vaccines and antivirals, surveillance plans, infection control, and emergency response plans, is presented. SUMMARY: The World Health Organization (WHO) considers the avian influenza A/H5N1 virus a public health risk with pandemic potential. The next human influenza pandemic, if caused by the avian influenza A/H5N1 virus, is estimated to have a potential mortality rate of more than a hundred million. Outbreaks in poultry have been associated with human transmission. WHO has documented 258 confirmed human infections with a mortality rate greater than 50%. Bird-to-human transmission of the avian influenza virus is likely by the oral-fecal route. The most effective defense against an influenza pandemic would be a directed vaccine to elicit a specific immune response toward the strain or strains of the influenza virus. However, until there is an influenza pandemic, there is no evidence that vaccines or antivirals used in the treatment or prevention of such an outbreak would decrease morbidity or mortality. Surveillance of the bird and human populations for the highly pathogenic H5N1 is being conducted. Infection-control measures and an emergency response plan are discussed. CONCLUSION: Avian influenza virus A/H5N1 is a public health threat that has the potential to cause serious illness and death in humans. Understanding its pathology, transmission, clinical features, and pharmacologic treatments and preparing for the prevention and management of its outbreak will help avoid its potentially devastating consequences.     

Recent strategies in the search for new anti-influenza therapies

Influenza is a highly contagious, acute upper respiratory tract disease caused by influenza virus, a member of the Orthomyxoviridae family. The viral particles have two surface antigens, haemagglutinin and sialidase (neuraminidase) that extensively decorate the surface of the virus and have been implicated in viral attachment and fusion, and the release of virion progeny, respectively. The receptor for haemagglutinin is the terminal sialic acid residue of host cell surface sialyloligosaccharides, while sialidase catalyses the hydrolysis of terminal sialic acid residues from sialyloligosaccharides. Extensive crystallographic studies of both these proteins have revealed that the residues that interact with the sialic acid are strictly conserved. Therefore, these proteins make attractive targets for the design of drugs to halt the progression of the virus. Recent successful efforts in the search for new cures for influenza have led to the development of three clinically-useful anti-influenza drugs. All three are potent, selective inhibitors of influenza virus A and B sialidase. Strategies for the development of haemagglutinin inhibitors have also been devised.     

Antiviral drugs in influenza: an adjunct to vaccination in some situations

(1) Influenza is a common acute respiratory disease due to a virus that causes annual seasonal epidemics. Three major pandemics occurred in the 20th century, in 1918-1919, 1957 and 1968, mainly due to genetic variants of type A influenza virus. (2) In temperate regions the incidence of hospitalisation increases during annual influenza epidemics. More than 90% of deaths linked to influenza involve people over 65 years of age. (3) The clinical manifestations of influenza virus infection are non specific. The main complications are secondary bacterial respiratory tract infections (especially pneumonia); those most at risk are people over 65, infants less than one year old, and people with underlying chronic disorders (pulmonary, cardiac, renal or metabolic) or immune deficiencies. (4) Vaccination is the main preventive measure. During most years the vaccine strain closely matches the epidemic strain. In relative terms, vaccination of people over 65 reduces the number of deaths linked to influenza by about 80%, hospitalisation and pneumonia by about 50%, and symptomatic influenza by about 30%. Yearly vaccination is recommended for younger people with serious chronic disease. (5) Three antiviral drugs are currently approved in France for prevention or treatment of influenza: amantadine and the neuraminidase inhibitors zanamivir and oseltamivir. (6) Efficacy of antiviral drugs has not been evaluated in comparative randomised trials in which death and influenza complications were the primary outcome measures. (7) A systematic review of 20 comparative randomised trials involving about 2500 healthy people showed that amantadine reduced the frequency of flu-like syndromes by about 7% in absolute terms (26.3% versus 33.1% with placebo). Zanamivir and oseltamivir have only been shown to reduce the frequency of serologically confirmed episodes of influenza (0.4% to 2.5%, compared to 4.4% to 14.9% with placebo). (8) In a randomised placebo-controlled trial of oseltamivir, involving 548 institutionalised subjects over 65 years of age, more than 80% of whom had been vaccinated, respiratory tract infections were less frequent in the oseltamivir group, but the relevance of this result is undermined by the small number of observed cases. (9) Efficacy of antiviral drugs on avian influenza (bird flu) was studied during a 2003 Dutch outbreak due to a type A/H7N7 virus. Among the 38 exposed persons who were treated, about 3% developed symptoms, compared with about 10% of 52 exposed persons who refused treatment (p = 0.38). The low statistical power and the lack of randomisation rule out any firm conclusions on preventive effects. (10) The three antiviral drugs have different profiles of adverse effects and drug interactions. Amantadine carries a risk of neuropsychological, atropinic and dopaminergic adverse effects, and can interact with drugs that have similar effects. Zanamivir carries a risk of life-threatening bronchospasm. Oseltamivir was approved relatively recently and its full spectrum of adverse effects is not yet known; its main adverse effects appear to be mild gastrointestinal disturbances, although a few cases of serious cutaneous reactions have been reported. (11) In vitro resistance to the three drugs has been demonstrated, but the possible clinical and epidemiological consequences are unclear. (12) In situations warranting antiviral therapy for the prevention of influenza, oseltamivir, at a dose of 75 mg/day for 10 days, is the drug with the best risk-benefit balance. Its use should be limited to situations where a major potential benefit exists in order to avoid selection for resistant strains. (13) Testing of oseltamivir in children is limited. Oseltamivir should be avoided during pregnancy, because of evidence that it may harm the unborn child. (14) In practice, the use of antiviral drugs in otherwise healthy adults and children is not generally recommended. (15) Despite the lack of convincing data regarding the efficacy of oseltamivir in preventing complications of influenza, its effect on documented infections suggests it may be useful for unvaccinated individuals who are at high risk of infection and severe complications. Under these conditions, treatment should be started within 48 hours after contact with a person who has flu-like symptoms during a seasonal epidemic; residents in institutions in which influenza cases occur may also qualify for preventive treatment. Other preventive measures should also be used, including immediate vaccination, case isolation, use of face masks, and more frequent hand washing. (16) During seasonal influenza epidemics due to viral strains against which the current vaccine is of limited effectiveness, the utility, target populations and optimal duration of preventive antiviral treatment must be determined by examining the groups most at risk and the severity of complications. (17) Most flu-like syndromes are not due to the influenza virus, and the preventive effect of antiviral drugs on complications in persons at risk has not yet been demonstrated. (18) In practice, antiviral drugs are not an alternative to influenza vaccination, but may be a useful adjunct in some situations. It is best to limit their use to short-term prophylaxis of vulnerable persons in situations where the risk of contracting influenza virus infection is high.