动物细胞培养技术在流感疫苗研发中的应用进展

流感是由流感病毒引发的急性呼吸道传染病,每年可引起季节性流行。疫苗接种是预防和控制流感流行和大流行期间病毒感染的主要方法,目前流感疫苗生产主要仍依赖鸡胚培养技术,但近年来,使用动物细胞基质代替鸡胚培养已成为流感疫苗技术创新的重要趋势。随着贴壁培养及无血清全悬浮培养等培养技术在生物制药领域的发展,已有多种动物细胞系用于流感疫苗生产。本文简要综述近年来动物细胞培养技术在流感疫苗研发中的应用进展。     

流感病毒表位疫苗的研究进展

流感是由流感病毒引起的高度传染性疾病.流感病毒分为甲、乙、丙3个型.其中甲型和乙型流感病毒导致了大多数人类感染病例,并造成全球流感季节性流行和大流行.现有流感疫苗的缺陷直接推进了新型流感疫苗的研制.通过适当表位设计的新型疫苗可以刺激机体产生特异性抗体和CTL,从而达到预防和治疗的目的 .这类疫苗对于多个流感毒株都有效.目前需要对这类疫苗作进一步研究,确定并解决具体使用中的一系列问题,使其达到最好的免疫效果和适用范围,以应对流感这个全球性的健康威胁.     

通用流感疫苗研发进展

流感病毒感染在世界范围内引起较高的发病率和死亡率。接种流感疫苗是预防和控制流感病毒感染及其严重并发症的有效手段,但由于流感病毒抗原的变异性,导致疫苗毒株与当年的流行毒株的抗原性并不完全匹配,造成流感疫苗的有效性降低,不能有效预防季节性和大流行流感,因此研发通用疫苗成为当前的主要趋势。本文综述了流感疫苗的发展及通用流感疫苗的研发平台,为未来新型流感疫苗的设计和开发提供参考。     

甲型流感病毒交叉免疫的研究进展

流感是重大的公共卫生问题,可发生全球大流行.研制安全有效的流感疫苗对控制流感至关重要.然而,由于流感病毒的交叉免疫及其机制尚未完全阐明,对研制疫苗带来不利影响.对甲型流感病毒交叉免疫的深入研究必将有助于更好地研制流感疫苗,对预防和控制甲型流感具有重要意义.此文对甲型流感病毒交叉免疫、免疫机制、不同亚型免疫的评价等研究进展进行综述.     

基于流感病毒保守抗原的广谱流感疫苗研究进展

流感是由流感病毒感染引起的严重急性呼吸道传染病,接种流感疫苗是预防流感最经济、安全且有效的措施。目前广泛应用的传统流感疫苗的保护效果受到疫苗株与流行株表面抗原匹配程度的明显影响,难以有效应对因流感病毒发生抗原漂移或抗原转换而产生的无法预料的流行或大流行。因而开发能够诱导广谱和持久免疫的广谱流感疫苗是新型流感疫苗研发的重要方向。流感病毒基质、核蛋白和血凝素茎部结构域作为流感病毒的保守抗原,是当前广谱流感疫苗的主要靶抗原。此文就近年来基于流感病毒保守抗原的广谱流感疫苗的抗原选择、免疫保护制剂、临床研究进展做一综述。     

流感病毒血凝素在多种系统中表达的研究进展

流感疫苗是预防流感病毒感染最有效的方法。传统灭活流感疫苗通过在鸡胚中培养病毒后经纯化获得。流感每年都会发生季节性流行,流感病毒高度多变的特性使生产有效疫苗成为一项挑战。为了克服流感疫苗生产对鸡胚的依赖,需要开发新的流感疫苗生产策略。由于血凝素是流感病毒主要表面抗原之一,重组血凝素亚单位疫苗为流感疫苗的生产提供了一个方案。本文将对流感病毒血凝素在大肠埃希菌、毕赤酵母、昆虫细胞、哺乳动物细胞多种系统中表达的研究进行综述。     

欧盟批准新型流感疫苗Fluenz Tetra上市

<正>2013年12月6日,阿斯利康公司宣布,欧盟(EC)批准流感疫苗Fluenz Tetra上市。Fluenz Tetra是一种喷鼻剂型四价减毒活流感疫苗,经鼻腔给药,适用于用于24个月至18岁青少年和儿童群体,用于季节性流感的预防。Fluenz Tetra包含2株A型流感病毒株和2株B型流感病毒株,能够针对B型流感提供更广泛的保护。在欧洲流行的流感病毒株     

抗流感小分子药物研究进展

流感病毒种类多、变异快,是对人类健康威胁最大的呼吸道病毒。季节性流感每年均会造成地区性疫情,大流行流感每隔几年导致全球性的流感大暴发,高致病性禽流感病情凶险,死亡率高。而流感病毒极高的基因重配效率严重影响了流感疫苗的效果。因此,抗流感药物成为流感疫情防控的核心手段。随着金刚烷胺、金刚乙胺的长期使用和作为动物饲料添加剂,季节性流感和新发流感病毒对其几乎全部耐药,而随着奥司他韦的广泛使用,流感病毒对神经氨酸酶抑制剂耐药也存在潜在的趋势,加快推进新型抗流感药物研发迫在眉睫。本文从流感病毒感染复制周期入手,对近年来抗流感药物新靶点、新药物实体进行综述,并重点阐述处于临床研究阶段的抗流感新药品种。     

流感疫苗的不良反应报告

流行性感冒(简称流感)是由流感病毒引起的急性呼吸道传染病,是全球范围的严重公共卫生问题,经常引起地方性流行,但有时也会引起世界性大流行。我国是流感的高发区,每年均有不同程度流行,严重威胁人民健康。1957年以来发生的3次世界性流感大流行的新亚型均首发于我国。国外在流感疫苗的研发及应用方面取得了巨大进展,预防效果明显提高,流感疫苗已成为降低流感发病率及病死率的主要措施。流感疫苗是在鸡胚中培养,经裂解、灭活、纯化后应用。近年来,国内流感疫苗也逐步普及应用,其安全性越来越受到人们的关注,有关流感疫苗不良反应的报道也屡见…     

山西省2014—2015年度流感监测结果分析

<正>引起流感的病原为流感病毒,流感病毒因表面抗原频繁变异而不断引起新的流行,历史上曾经发生过多次世界性大流行。流感监测能掌握流感动态变化规律、明确流行株并及早现变异株,为预测和推荐流感疫苗毒株提供依据,是预防控制流感的关键措施,也是早期预测预警流感疫情的重要基础[1]。山西省于2005年加入全国流感监测网络实施半年监测;2009年甲型H1N1流感大流行期间扩大监测网络并实行全年监测,目前流感监测哨点医院及网络实验室已遍布全省     

Should expectant mothers be vaccinated against flu? A safety review

Introduction: Pregnant women have a higher risk of serious complications from influenza than non-pregnant women of reproductive age. This increased risk has been noted both during pandemic and inter-pandemic influenza seasons. However, although vaccination against flu is recommended at any trimesters by international and national policies, vaccine coverage remains low in pregnant women, possibly due to patient and healthcare providers’ concern about the safety of the vaccine.

Areas covered: This review addresses the effectiveness and safety of seasonal and adjuvanted and non-adjuvanted pandemic 2009 A/H1N1 influenza vaccine.

Expert opinion: Available data suggest no evidence of an increased risk for any adverse event for both mothers and fetuses after vaccination against flu during pregnancy. These results are important when considering the potential of maternal immunization against flu as a public health intervention to protect both the mother and her infant against serious infectious disease.     

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.     

A/H5N1 prepandemic influenza vaccine (whole virion, vero cell-derived, inactivated) [Vepacel®

The influenza A subtype H5N1 virus is a likely causative agent for the next human influenza pandemic. Pandemic influenza vaccine production can begin only after a novel pandemic virus emerges. Cell-based vaccine production has advantages over conventional egg-based methods, allowing more rapid large-scale vaccine production. A reliable Vero cell culture system is available for pandemic and prepandemic influenza vaccine production. Prepandemic influenza vaccines are an important component of influenza pandemic preparedness plans, as their targeted use in the pandemic alert period or early in a pandemic is likely to mitigate the consequences of an influenza outbreak. Vepacel? is a prepandemic influenza vaccine (whole virion, Vero cell-derived, inactivated) containing antigen of H5N1 strain A/Vietnam/1203/2004 and is approved for use in the EU. Clinical immunogenicity studies with the vaccine have demonstrated good rates of functional neutralizing antibody responses against the vaccine strain (A/Vietnam/1203/2004), meeting established immunogenicity criteria for seasonal influenza vaccines, and cross-reactivity against H5N1 strains from other clades. In phase I/II and III studies, a heterologous (A/Indonesia/05/2005) booster vaccine administered to healthy adult and elderly volunteers 6-24 months after the two-dose priming vaccine (A/Vietnam/1203/2004) regimen induced good immunogenic responses against both H5N1 strains, demonstrating strong immunological memory. Broadly similar, albeit less robust, responses were observed in two special risk cohorts of immunocompromised and chronically ill patients. In general, adverse events observed in clinical immunogenicity studies with H5N1 vaccine (A/Vietnam/1203/2004) were similar to those reported with non-adjuvanted, inactivated, seasonal influenza vaccines.     

季节性流感疫苗接种对大流行流感的影响研究

加拿大研究发现,季节性流感疫苗接种增加2009年大流行甲型流感(H1N1)感染的危险性,而澳大利亚研究未能证实这个发现.雪貂实验结果表明,以前的季节性流感感染能防御大流行甲型流感(H1N1),但以前的季节性流感疫苗接种则不能.模型研究显示,流感感染可导致对不同亚型的暂时性免疫.这些观察可以解释加拿大和澳大利亚的不一致发...     

Pandemics, avian influenza A (H5N1), and a strategy for pharmacists

Epidemics of influenza occur annually and account for more morbidity in the developed world than all other respiratory diseases combined. On average, 36,000 Americans die from influenza or its complications each year. Pandemics occur when influenza viruses undergo either antigenic drift or antigenic shift that results in a new viral strain that infects humans, when they are capable of sustained transmission from person-to-person, and when they are introduced in populations with little or no preexisting immunity. The influenza pandemic of 1918 caused an estimated 20-40 million deaths worldwide. An avian influenza A (H5N1) virus, currently circulating in Asia, has pandemic potential. However, no evidence currently exists that a pandemic is occurring. Pharmacists are uniquely positioned to initiate nearterm practice changes that may positively impact both seasonal and potential pandemic morbidity and mortality. Pharmacists must be immunization advocates and provide pharmaceutical care that includes evaluation of immunization status. Increasing immunization to prevent invasive pneumococcal disease, as well as seasonal influenza immunization, is encouraged. A pandemic vaccine represents the most effective strategy to mitigate the effects of a pandemic. Antiviral agents represent a treatment bridge until a pandemic-specific vaccine is available. The neuraminidase inhibitors oseltamivir and zanamivir are active against H5N1, although oseltamivir resistance has been reported. Advances in vaccine research, development, and production through the use of reverse-genetics systems represent the most effective technology to rapidly produce a pandemic influenza vaccine.     

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.     

清新县甲型H1N1流感流行因素分析

[目的]通过系统监测调查,及时掌握我县甲型H1N1流感的疫情动态和流行规律,分析其流行因素,为我县完善甲型H1N1流感的防控工作提供科学依据.[方法]在清新县中部、南部、北部地区选择6个镇作为监测点,抽取普通人群静脉血,用酶联免疫试验检测甲型H1N1 IgG抗体进行血清学调查,同时以面对面问卷方式进行流行病学调查.[结果]共调查1325人,甲型H1N1流感抗体阳性190人,阳性率为14.34％;我县甲型H1N1流感病毒感染以轻症患者和隐性感染者为主;生活聚集性人群甲型H1N1IgG抗体高于非聚集人群(P＜0.05),甲型H1N1流感疫苗接种率为2.49％,免疫效果为57.58％;感冒患者就诊率为70.66％;甲型H1N1确诊0例.[结论]疫苗接种率及免疫效果、医疗诊断的准确率、生活聚集人群的易感性、以轻症感染和隐性感染为主的感染状况是影响我县甲型H1N1流感流行的主要因素,应加强人群甲型H1N1流感疫苗的接种,加强对临床医生甲型H1N1流感知识的培训,幼托机构、学校等聚集性场所仍然是我县甲型H1N1流感防控的重点场所.     

MF59 adjuvanted seasonal and pandemic influenza vaccines

MF59-adjuvanted seasonal trivalent inactivated (ATIV) vaccine licensed since 1997 and MF59-adjuvanted pandemic H1N1 vaccines have been distributed to approximately 80M persons. Addition of the emulsion adjuvant to inactivated vaccine formulations provides for higher levels of antibody to the viral hemagglutinin (HA) in less responsive older adults, infants and children which, in the case of the pandemic vaccine, allowed only 3.75 μg of the HA to be immunogenic. The adjuvant also stimulates production of more broadly-reactive antibodies against strains that are mismatched to those in the vaccine, a potential advantage in the face of perennial influenza virus antigenic drift. In a field trial, ATIV was 89% efficacious in preventing laboratory-confirmed influenza in 6-<72 month old children, 81% more efficacious than the unadjuvanted control split vaccine while, in older adults, ATIV reduced community-acquired pneumonia and influenza hospitalizations in adults >65 years old by 23% compared to unadjuvanted vaccine, in an observational study. The effectiveness of MF59 adjuvanted split pandemic H1N1 vaccine was 74% overall. Unadjuvanted pandemic vaccine was poorly immunogenic in HIV-infected persons, whereas their responses to MF59-adjuvanted vaccine were similar to those of healthy controls. Analyses of the clinical trials and pharmacovigilance databases and observational studies have shown that while MF59-adjuvanted influenza vaccines are more locally reactogenic, they have not been associated with an increased risk for various adverse effects (AE) of special interest, including unsolicited neurological or autoimmune events.     

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     

Simplifying Influenza Vaccination During Pandemics: Sublingual Priming and Intramuscular Boosting of Immune Responses with Heterologous Whole Inactivated Influenza Vaccine

The best approach to control the spread of influenza virus during a pandemic is vaccination. Yet, an appropriate vaccine is not available early in the pandemic since vaccine production is time consuming. For influenza strains with a high pandemic potential like H5N1, stockpiling of vaccines has been considered but is hampered by rapid antigenic drift of the virus. It has, however, been shown that immunization with a given H5N1 strain can prime the immune system for a later booster with a drifted variant. Here, we investigated whether whole inactivated virus (WIV) vaccine can be processed to tablets suitable for sublingual (s.l.) use and whether s.l. vaccine administration can prime the immune system for a later intramuscular (i.m.) boost with a heterologous vaccine. In vitro results demonstrate that freeze-drying and tableting of WIV did not affect the integrity of the viral proteins or the hemagglutinating properties of the viral particles. Immunization experiments revealed that s.l. priming with WIV (prepared from the H5N1 vaccine strain NIBRG-14) 4 weeks prior to i.m. booster immunization with the same virus strongly enhanced hemagglutination-inhibition (HI) titers against NIBRG-14 and the drifted variant NIBRG-23. Moreover, s.l. (and i.m.) immunization with NIBRG-14 also primed for a subsequent heterologous i.m. booster immunization with NIBRG-23 vaccine. In addition to HI serum antibodies, s.l. priming enhanced lung and nose IgA responses, while i.m. priming enhanced lung IgA but not nose IgA levels. Our results identify s.l. vaccination as a user-friendly method to prime for influenza-specific immune responses toward homologous and drifted variants.KEY WORDS: bird flu, H5N1, mucosal vaccine, sublingual vaccine tablet, whole inactivated virus