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；已从鸟类中分离出具有15个HA和9个NA亚型的流感病毒，但上个世纪只有H1N1、H2N2和H3N2亚型病毒在人类中广泛传播并引起流行性疾病。水禽是甲型流感病毒新亚型进入人类的储存库。过去10年中，多次发现人类感染H7、H5和H9三种亚型禽流感病毒（AIV），每次都伴随着家禽疾病的同时爆发。自1997年以来，亚洲曾多次爆发高致病性H5N1禽流感疫情。最近一次在家禽中爆发的 H5N1 疫情始于 2003 年底，影响了亚洲至少 10 个国家。最近的报告表明，H5N1 病毒已从亚洲、欧洲和非洲的候鸟和野生鸟类中分离出来。自2003年12月以来，已有5个国家报告了人类H5N1感染病例，截至2006年8月1日，共有232例病例和134例死亡。 开发保护人类免受流感病毒侵害的疫苗有多种潜在策略，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。减毒活疫苗通常会引起广泛的交叉反应保护，如果无法获得由实际大流行毒株产生的疫苗，这在大流行事件中可能是一个有用的功能。我们计划的目标是针对一系列具有大流行潜力的甲型流感亚型产生候选减毒重配流感病毒活疫苗，并在临床前研究和临床试验中评估这些疫苗。疫苗病毒将含有选定的具有大流行潜力的禽流感病毒的血凝素（HA）和神经氨酸酶（NA）基因，以及来自A/Ann Arbor/6/60冷适应病毒（A/AA/6/60 ca）的减毒基因。 ）供体病毒。冷适应 (ca) 流感病毒 A/Ann Arbor/6/60 (AA) (H2N2) 已被开发为活减毒疫苗种子病毒，具有冷适应、温度敏感 (ts) 和减毒 (att )表型，其由编码非表面糖蛋白基因的基因（即编码内部蛋白质基因的基因）中的突变指定。具有 AA ca 病毒六个内部基因片段的重配 H1N1 和 H3N2 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估已证明它们作为活病毒疫苗是减毒且安全的。该方法已获准普遍用于大流行期间的甲型和乙型流感病毒感染。减毒活疫苗必须能够复制到引发保护性免疫反应而不引起宿主疾病的水平，因此必须实现减毒、传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能够在最短的时间内提供疫苗来预防感染，而大流行防范的一个重要方法是，在发生大流行之前，针对被认为具有大流行潜力的甲型流感亚型生成并评估候选疫苗。到大流行病毒的实际出现。 我们通过基因重组产生了候选H9N2流感疫苗；该疫苗株含有来自禽 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 6 个内部基因片段。基于小鼠和雪貂的有希望的临床前数据，生产了该疫苗的临床批次，并根据 IND 开展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。临床试验的实验室结果分析正在进行中。 为了研制针对 1997 年、2003 年和 2004 年在亚洲引起人类感染的 H5N1 病毒的候选疫苗，LID 科学家与 Medimmune, Inc. 的科学家在 CRADA 下合作，并应用基于质粒的反向遗传学，这是一种将传染性病毒转化为病毒的技术。可以从表达 8 个流感基因片段的质粒共转染的细胞中回收，以产生含有血凝素和神经氨酸酶的重配病毒H5N1 流感病毒的基因和 AA ca 病毒的六个内部基因片段。我们去除了高致病性 H5N1 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 H5N1 疫苗病毒具有 AA ca 病毒内部蛋白基因指定的 ts 和 att 表型。更重要的是，候选疫苗在小鼠中具有免疫原性。接受单剂疫苗 4 周后，小鼠在受到 1997 年至 2005 年间在亚洲分离的同源和抗原不同的异源野生型 H5N1 病毒攻击后得到充分保护，免于死亡。接受两剂疫苗后 4 周，小鼠和雪貂完全免受同源和异源 wt H5N1 病毒的肺部复制。基于小鼠和雪貂中令人鼓舞的临床前数据，生产了 2004 年 H5N1 ca 疫苗的临床批次，并根据 IND 开展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。临床试验正在进行中。