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.

甲型流感病毒根据其表面糖蛋白、血凝素（HA）和神经氨酸酶（NA）的抗原性分为亚型;携带15种HA和9种NA亚型的流感病毒已从鸟类中分离，但只有H1N1、H2 N2和H3 N2亚型病毒在上个世纪广泛传播并在人类中引起流行性疾病。水生鸟类是甲型流感病毒新亚型进入人群的宿主。在过去10年中，曾数次发现人感染H7、H5和H9三种亚型禽流感病毒，每次都伴随着禽类疾病的同时爆发。自1997年以来，亚洲曾多次发生由高致病性禽流感H5 N1病毒引起的严重疫情。最近一次H5 N1禽流感爆发始于2003年底，至少影响到亚洲10个国家。最近的报告显示，已从亚洲、欧洲和非洲的候鸟和野鸟中分离出H5 N1病毒。自2003年12月以来，已有5个国家报告了人类感染H5 N1病例，截至2006年8月1日，共有232例病例和134例死亡。 有几种潜在的疫苗开发策略可以保护人类免受流感病毒的侵害，包括福尔马林灭活的完整或裂解病毒、HA亚单位和减毒活疫苗。减毒活疫苗通常诱导广泛的交叉反应性保护，这在大流行的情况下可能是一个有用的特征，如果从实际的大流行毒株产生的疫苗是不可用的。我们计划的目标是产生针对一系列具有大流行潜力的甲型流感亚型的候选减毒活流感病毒疫苗，并在临床前研究和临床试验中评估这些疫苗。疫苗病毒将含有具有大流行潜力的选定禽流感病毒的血凝素（HA）和神经氨酸酶（NA）基因以及来自A/安阿伯/6/60冷适应（A/AA/6/60 ca）供体病毒的减毒基因。冷适应（ca）流感病毒A/安阿伯/6/60（AA）（H2 N2）已被开发为活的减毒疫苗种子病毒，其表现出冷适应、温度敏感（ts）和减毒（att）表型，这些表型由编码非表面糖蛋白基因的基因中的突变指定，即，编码内部蛋白质基因的基因。具有AA ca病毒的六个内部基因片段的H1N1和H3 N2人类甲型流感病毒已被反复证明具有ts和att表型，并且在人类中的广泛评价已证明它们是减毒的并且作为活病毒疫苗是安全的。该方法已被许可用于甲型和B型流感病毒感染的一般用途。减毒活疫苗必须能够复制到引发保护性免疫应答而不引起宿主疾病的水平，因此必须实现减毒、感染性和免疫原性之间的平衡。在发生潜在大流行的情况下，最佳的公共卫生应对措施要求在最短的延迟时间内提供预防感染的疫苗，大流行防范的一个重要方法是在大流行病毒实际出现之前，针对被认为具有大流行潜力的甲型流感亚型，生成和评估候选疫苗。 我们产生了一个候选人H9 N2流感疫苗的基因重组，疫苗株含有血凝素和神经氨酸酶基因从禽H9 N2流感病毒和六个内部基因片段从AA CA病毒。根据小鼠和雪貂中有希望的临床前数据，产生了该疫苗的临床批次，并根据IND进行了该疫苗对健康成人的安全性和免疫原性的I期临床试验。 为了生产针对1997年、2003年和2004年在亚洲引起人类感染的H5 N1病毒的候选疫苗，LID科学家与Medimmune公司的科学家合作，根据CRADA和应用的基于质粒的反向遗传学，该技术是一种可以从用表达8种流感基因片段中的每一种的质粒共转染的细胞中回收感染性病毒的技术，以产生含有来自H5 N1流感病毒的血凝素和神经氨酸酶基因和来自AA ca病毒的6个内部基因片段的重组病毒。我们去除了高致病性H5 N1流感病毒血凝素基因中与家禽致病性相关的多个碱性氨基酸基序的毒力基序。候选H5 N1疫苗病毒具有AA ca病毒内部蛋白基因所指定的ts和att表型。更重要的是，候选疫苗在小鼠中具有免疫原性。在接受单剂量疫苗后四周，小鼠在用1997年至2005年在亚洲分离的同源和抗原性不同的异源野生型H5 N1病毒攻击后完全免于致死。在接受两剂疫苗后四周，小鼠和雪貂被完全保护免于同源和异源wt H5 N1病毒的肺部复制。根据在小鼠和雪貂中获得的有希望的临床前数据，产生了2004年H5 N1 ca疫苗的临床批次，并在IND下进行了该疫苗对健康成人的安全性和免疫原性的I期临床试验。