A/H5N1 VACCINE PHASE I/II STUDY IN HEALTHY ADULTS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 流感是一种每年以流行方式发生的严重疾病。在1918年大流行期间，全世界发生了多达4000万人的死亡。在1957年和1968年的大流行期间，也注意到了大量的死亡、疾病和社会混乱。最近在人类群体中出现了新的流感病毒株(所谓的“禽流感”甲型H5N1和H9N2型流感病毒)，这加强了正在进行的制定大流行预防计划的全球努力。根据世界卫生组织的数据，去年泰国和越南至少发现了52例人感染H5禽流感病例，其中39例(75%)死亡。这种疾病的全球传播将是灾难性的。开发和测试针对潜在H5N1大流行毒株的流感疫苗是一项国际公共卫生优先事项--请参阅所附DMID/NIAID/NIH副主任的信函。 这项研究的主要目标是在健康的成年人中确定1)能够产生可接受的抗体反应的A/H5N1流感疫苗的最低剂量水平；以及2)这种H5疫苗的安全性。 这项建议描述了一项随机、双盲、安慰剂对照、剂量范围的甲型H5N1流感疫苗I/II期研究，研究对象为大约450-470名健康成年人，年龄从18岁到，包括在内。参与者将被随机分配到上臂肌肉注射2剂生理盐水安慰剂(N=50)，或7.5、15、45或90克甲型H5N1流感病毒疫苗(N=100/剂组)。 研究将分两个阶段进行。第一阶段(第一阶段)包括每个疫苗剂量组25名受试者和安慰剂组13名受试者的初始疫苗接种(总共113名受试者)，随后是7天的安全性评估期。第一阶段受试者接种疫苗后7天的安全数据将由数据和安全监测委员会(DSMB)审查。在进行这项检讨后，卫生福利局会建议应否进行第二阶段科目的登记和接种疫苗工作。如果第一阶段的参与者没有安全问题，那么第二阶段的研究将开始。在第二剂疫苗接种后，将对第一阶段参与者的安全性数据进行另一次DMSB审查。如果在第二次接种后，第一阶段的受试者没有安全问题，那么第二阶段的受试者将接受第二次接种。第一阶段的参与者还将在每次疫苗接种前后抽取额外的血液进行血细胞计数和化学分析；这些实验室测试将有助于监测疫苗对肝脏、肾脏或血细胞的任何影响。 所有参与者都将接种两剂疫苗。第一次疫苗接种将在第0天进行。接种后将在诊所评估症状和体征30分钟，受试者将在每次接种后7天内保持记忆辅助器，记录口腔温度和全身和局部不良事件(AE)。所有受试者将在每次接种疫苗后2至3天收到安全跟踪电话，以了解任何AE信息。受试者将在每次接种疫苗后7天返回诊所进行记忆辅助检查，评估不良反应和伴随药物，并进行有针对性的体检(如果有指示)。在第一次接种后大约第28天，受试者将返回诊所进行血液样本采集和安全跟踪，随后进行第二次接种。安全随访将与第一次接种疫苗后进行的相同。在第二次接种疫苗后大约28天，受试者将返回诊所进行血样采集、AE和伴随的药物评估，并在有指示的情况下进行有针对性的体检。在第一次接种疫苗后大约7个月，受试者将返回诊所进行最后的血液样本和随访。所有血液样本都将在一个中心实验室进行抗体水平测试。 主要的结果衡量标准将是每个剂量组中AEs的频率和严重程度，以及达到预定水平的A/H5N1流感保护性抗体的受试者的比例。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza is a serious illness which occurs in epidemic fashion every year. During the 1918 pandemic, up to 40 million deaths occurred worldwide. Significant numbers of deaths, illness and social disruption were also noted during the 1957 and 1968 pandemics. The recent emergence of novel influenza virus strains in human populations (so-called "bird flu" influenza A/H5N1 and H9N2 viruses) has bolstered ongoing global efforts to develop pandemic preparedness plans. According to the World Health Organization, at least 52 human cases of H5 bird flu have been identified in the last year in Thailand and Vietnam and 39 (75%) have died. Global spread of this disease would be catastrophic. Development and testing of an influenza vaccine against potential H5N1 pandemic strains is an international public health priority - please see the attached letter from the Deputy Director of DMID/NIAID/NIH. The primary goals of this study are to determine, among healthy adults, 1) the lowest dose level of A/H5N1 influenza vaccine that will result in an acceptable antibody response; and 2) the safety profile of this H5 vaccine. This proposal describes a randomized, double-blinded, placebo-controlled, dose-ranging, Phase I/II study of A/H5N1 influenza vaccine in approximately 450-470 healthy adults, 18 to 64 years old, inclusive. Participants will be randomly assigned to receive 2 doses of saline placebo (N=50), or 7.5, 15, 45, or 90 g of the influenza A/H5N1 virus vaccine (N=100/dose group) by intramuscular injection in the upper arm. The study will proceed in 2 stages. The first stage (Stage I) consists of an initial vaccination of 25 subjects in each vaccine dose group and 13 subjects in the placebo group (113 subjects total), followed by a 7-day safety assessment period. The 7 day safety data following the vaccination of Stage I subjects will be reviewed by a Data and Safety Monitoring Board (DSMB). Following this review, the DSMB will make a recommendation as to whether enrollment and vaccination of the Stage II subjects should proceed. If there are no safety issues among Stage I participants, then Stage II of the study will be initiated. There will be another DMSB review of Stage I participants' safety data after the second dose of vaccine is given. If there are no safety issues in the Stage I subjects following the second vaccination, then the Stage II subjects will receive their second vaccination. Stage I participants will also have extra blood taken for a blood count and chemistry panel prior to and after each vaccine dose; these lab tests will help to monitor any effect of the vaccine on the liver, kidneys or blood cells. All participants will receive two doses of vaccine. The first vaccination will occur on Day 0. Symptoms and signs will be assessed in the clinic for 30 minutes after inoculation, and the subjects will maintain a memory aid to record oral temperature and systemic and local adverse events (AE) for 7 days after each immunization. All subjects will receive a safety follow-up telephone call at 2 to 3 days after each vaccination to elicit any AE information. Subjects will return to the clinic 7 days after each vaccination for review of the memory aid, assessment of AEs and concomitant medications, and a targeted physical examination (if indicated). At approximately Day 28 after the first vaccination, subjects will return to the clinic for blood sample collection and safety follow-up, followed by a second vaccination. Safety follow-up will be identical to that performed after the first vaccination. Approximately 28 days after the second vaccination, subjects will return to the clinic for blood sample collection, AE and concomitant medication assessment, and a targeted physical examination if indicated. Approximately 7 months after the first vaccination, subjects will return to the clinic for a final blood sample and follow-up. All blood samples will be tested in a central laboratory for antibody levels. The primary outcome measures will be the frequency and severity of AEs in each dose group and the proportions of subjects who achieve a predefined level of protective antibody against A/H5N1 flu.