Vaccines for Pandemic Influenza

大流行性流感疫苗

• 批准号: 7312957
• 负责人: Kanta Subbarao
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312957
• 关键词: Vaccines; Pandemic; Influenza

Influenza A viruses are divided into subtypes on the basis of the antigenicity of their surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA); influenza viruses bearing 15 HA and 9 NA subtypes have been isolated from birds, but only H1N1, H2N2, and H3N2 subtype viruses have circulated widely and caused epidemic disease in humans in the last century. Aquatic birds serve as a reservoir from which new subtypes of influenza A viruses enter the human population. In the last 10 years, human infections with avian influenza viruses (AIV) of three subtypes, H7, H5 and H9, have been detected on several occasions, accompanied in each case by contemporaneous outbreaks of disease in poultry. On several occasions since 1997, there have been serious outbreaks caused by a highly pathogenic avian influenza H5N1 viruses in Asia. The most recent H5N1 outbreak in poultry began in late 2003 and affected at least 10 countries in Asia. Recent reports indicate that H5N1 viruses have been isolated from migratory and wild birds in Asia, Europe and Africa. Human cases of H5N1 infection have been reported since December 2003 in 5 countries with a total of 232 cases and 134 deaths as of August 1, 2006. There are several potential strategies for the development of vaccines to protect humans against influenza viruses, including formalin inactivated whole or split virus, HA subunit, and live attenuated vaccines. Live attenuated vaccines generally induce broadly cross-reactive protection, which may be a useful feature in the event of a pandemic if a vaccine generated from the actual pandemic strain is not available. The goal of our program is to generate candidate live attenuated reassortant influenza virus vaccines against a range of influenza A subtypes that have pandemic potential and to evaluate these vaccines in preclinical studies and clinical trials. The vaccine viruses will contain the hemagglutinin (HA) and neuraminidase (NA) genes of a selected avian influenza virus with pandemic potential and the attenuating genes from the A/Ann Arbor/6/60 cold adapted (A/AA/6/60 ca) donor virus. The cold-adapted (ca) influenza virus A/Ann Arbor/6/60 (AA) (H2N2) has been developed as a live attenuated vaccine seed virus that exhibits cold-adaptation, temperature-sensitive (ts), and attenuation (att) phenotypes which are specified by mutations in the genes encoding the non-surface glycoprotein genes, i.e., the genes encoding the internal protein genes. Reassortant H1N1 and H3N2 human influenza A viruses with the six internal gene segments of the AA ca virus have been repeatedly demonstrated to bear the ts and att phenotypes and extensive evaluation in humans has proven them to be attenuated and safe as live virus vaccines. This approach has been licensed for general use for interpandemic influenza A and B virus infections. Live attenuated vaccines must be able to replicate to levels that elicit a protective immune response without causing disease in the host so a balance between attenuation, infectivity and immunogenicity must be achieved. An optimal public health response in the event of a potential pandemic requires that vaccines be available to prevent infection with minimum delay and an important approach to pandemic preparedness is to generate and evaluate candidate vaccines against influenza A subtypes that are recognized to have pandemic potential, prior to their actual emergence of a pandemic virus. We generated a candidate H9N2 influenza vaccine by genetic reassortment; the vaccine strain contains the hemagglutinin and neuraminidase genes from an avian H9N2 influenza virus and six internal gene segments from the AA ca virus. Based on promising preclinical data in mice and ferrets, a clinical lot of this vaccine was generated and a Phase I clinical trial of the safety and immunogenicity of the vaccine for healthy adults was undertaken under an IND. Analysis of laboratory results from the clinical trial is under way. In order to generate candidate vaccines against H5N1 viruses that have caused human infections in Asia in 1997, 2003 and 2004, LID scientists collaborated with scientists from Medimmune, Inc., under a CRADA and applied plasmid based reverse genetics, a technique in which infectious virus can be recovered from cells co-transfected with plasmids expressing each of the 8 influenza gene segments, to generate reassortant viruses that contain the hemagglutinin and neuraminidase genes from H5N1 influenza viruses and six internal gene segments from the AA ca virus. We removed the virulence motif of multiple basic amino acid motifs in the hemagglutinin gene of the highly pathogenic H5N1 influenza virus that are associated with pathogenicity in poultry. The candidate H5N1 vaccine viruses possessed the ts and att phenotypes specified by the internal protein genes of the AA ca virus. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of vaccine, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wild-type H5N1 viruses isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses. Based on promising preclinical data in mice and ferrets, a clinical lot of the 2004 H5N1 ca vaccine was generated and a Phase I clinical trial of the safety and immunogenicity of the vaccine for healthy adults was undertaken under an IND. The clinical trial is in progress.

流感A病毒根据其表面糖蛋白，黑凝集素（HA）和神经氨酸酶（NA）的抗原性分为亚型；从鸟类中分离出具有15公顷和9个Na亚型的流感病毒，但仅H1N1，H2N2和H3N2亚型病毒已经广泛散发，并在上个世纪引起了人类流行病。水生鸟是一种储层，从中，流感病毒的新亚型进入了人口。在过去的十年中，已经多次检测到了三种亚型H7，H5和H9的鸟类流感病毒（AIV）的人类感染，每种情况下都伴随着家禽中疾病的同时爆发。自1997年以来，有几个场合发生了严重的爆发，这是由于亚洲高度致病的禽流感H5N1病毒引起的。最近在家禽中发生的H5N1爆发始于2003年底，并影响了亚洲至少10个国家。最近的报道表明，H5N1病毒已从亚洲，欧洲和非洲的迁徙和野生鸟类中分离出来。自2003年12月以来，人类H5N1感染的病例已报告为5个国家，截至2006年8月1日，总计232例和134例死亡。 有几种潜在的策略来开发疫苗来保护人类免受流感病毒的侵害，包括福尔马林灭活或分裂病毒，HA亚基和活疫苗。活的减毒疫苗通常会引起广泛的交叉反应保护，如果没有实际的大流行菌株产生的疫苗，这可能是有用的特征。我们计划的目的是针对具有流行潜力的一系列流感A亚型产生候选活性流感病毒疫苗，并在临床前研究和临床试验中评估这些疫苗。该疫苗病毒将包含具有大流行潜力的选定禽流感病毒的血凝集素（HA）和神经氨酸酶（Na）基因，并且来自A/ANN ARBOR/6/60冷适应率（A/AA/6/60 CA）的供体病毒的衰减基因。冷适应的（CA）流感病毒A/Ann Arbor/6/60（AA）（H2N2）已开发为一种活的减毒疫苗病毒，表现出冷适应，温度敏感性（TS）和衰减（ATT），并通过基因中的突变中指定的基因genes genes genes genes genes genes genore genore gene nimcopl genore face gene n.蛋白质基因。重新分类的H1N1和H3N2人流感A具有AA CA病毒的六个内部基因段的病毒，已反复证明可以承受TS和ATT表型，并且在人类中进行了广泛的评估，已证明它们可以使它们减弱，并作为活病毒疫苗安全且安全。该方法已获得许可用于一般使用，用于室内流感和B病毒感染。活疫苗的活疫苗必须能够复制到引起保护性免疫反应而不会引起宿主疾病的水平，因此必须达到衰减，感染性和免疫原性之间的平衡。在潜在的大流行时，最佳的公共卫生反应要求可以使用疫苗以防止以最小的延迟和大流行准备的重要方法来防止感染，以便在实际出现Pandemic Virus之前，生成和评估对流感的候选疫苗，对流感的亚型产生候选疫苗。 我们通过遗传改良生成了候选H9N2流感疫苗。疫苗菌株包含来自禽H9N2流感病毒的血凝素和神经氨酸酶基因，以及来自AA CA病毒的六个内基因片段。基于小鼠和雪貂的有前途的临床前数据，产生了这种疫苗的临床批次，并根据IND进行了对健康成年人的安全性和免疫原性的I期临床试验。正在进行临床试验实验室结果的分析。 In order to generate candidate vaccines against H5N1 viruses that have caused human infections in Asia in 1997, 2003 and 2004, LID scientists collaborated with scientists from Medimmune, Inc., under a CRADA and applied plasmid based reverse genetics, a technique in which infectious virus can be recovered from cells co-transfected with plasmids expressing each of the 8 influenza gene segments, to从H5N1流感病毒和来自AA CA病毒的六个内部基因片段中产生重新成分的病毒，这些病毒含有血凝素和神经氨酸酶基因。我们去除了与家禽致病性有关的高度致病性H5N1流感病毒中多个碱性氨基酸基序的毒力基序。候选H5N1疫苗病毒具有由AA CA病毒的内部蛋白质基因指定的TS和ATT表型。更重要的是，候选疫苗在小鼠中具有免疫原性。接收一剂疫苗后的四个星期，在1997年至2005年之间在亚洲分离的同源和抗原上不同的异源野生型H5N1病毒在挑战之后得到了完全保护。在1997年至2005年之间，在亚洲分离出来。在接受两剂疫苗，小鼠和腌鱼的疫苗，小鼠和腌鱼后，完全保护了肺部和HEROLOLIOL fALOLICE和HEROLOLIC WTTOLOLICENOLICEROTIC HEROMITION fROMATIC HEROLICT herololic wtt。基于小鼠和雪貂的有前途的临床前数据，产生了2004 H5N1 CA疫苗的临床批次，并根据IND进行了对健康成年人的安全性和免疫原性的I期临床试验。临床试验正在进行中。