A SINGLE-CENTER, DOUBLE-BLIND, RANDOMIZED, ESCALATING DOSE-RANGING STUDY TO

一项单中心、双盲、随机、逐步升级的剂量范围研究

• 批准号: 7719199
• 负责人: Christine B. Turley
• 金额: $ 10.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7719199
• 关键词: Accounting; Acute; Adult; Affect; Age; Age-Years; Amino Acid Sequence; Antibodies; Antigens; Categories; Cessation of life; Communicable Diseases; Computer Retrieval of Information on Scientific Projects Database; Confidence Intervals; Consent; Data; Development; Disease; Dose; Double-Blind Method; Emergency Situation; End Point; Enrollment; Epidemic; Escherichia coli; Exhibits; Experimental Designs; Fatigue; Fermentation; Frequencies; Funding; Genetic Structures; Grant; Health; Hospitalization; Human; Immune response; Immunity; Individual; Infection; Influenza; Influenza A virus; Injection of therapeutic agent; Institution; Laboratory Study; Life; Lung diseases; Methods; Monitor; Muscle; Mutation; Numbers; Pain; Phase I Clinical Trials; Placebo Control; Placebos; Population; Procedures; Process; Production; Purpose; Randomized; Range; Reaction; Recombinant Proteins; Redness; Reporting; Research; Research Personnel; Resources; Safety; Seasons; Severities; Side; Source; Standards of Weights and Measures; Swelling; Symptoms; Techniques; Testing; United States National Institutes of Health; Vaccine Production; Vaccines; Viral Antigens; Viral Proteins; base; day; design; diaries; egg; follow-up; immunogenicity; influenza virus vaccine; influenzavirus; member; novel strategies; pandemic influenza; statistics; volunteer

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. Background: Influenza, a highly communicable acute respiratory disease, is one of the major infectious disease threats to the human population. Influenza virus affects individuals of all ages, causes repeated infections throughout life, and is responsible for annual worldwide epidemics of varying severity. In average years there are an estimated 3 to 5 million cases of severe illness and 0.5 million deaths per year worldwide. There are an estimated 36,000 deaths and more than 200,000 hospitalization caused by influenza every year in the US. Pandemic influenza viruses spread rapidly and cause high levels of disease and death globally. Some of the challenges in developing an effective vaccine for influenza occur because influenza viruses exhibit change in genetic structure each season. None of the current vaccines offer protection in a way that accounts for this genetic change. Other challenges to the development of influenza vaccine occur because of the current technique available for manufacturing this vaccine. Currently the vaccines that are available are made in eggs, which limit the number of doses and also cause lengthy delays in vaccine production. VaxInnate has developed a cross-protective influenza A vaccine, VAX102, which is based on a recombinant protein expressed in E. coli. Unlike the HA and NA viral proteins, the 24 amino acid sequence of M2e has remained remarkably stable in all human influenza A virus isolates since the influenza pandemic of 1918. Thus an influenza vaccine based on the M2e antigen could elicit broad, cross-protective immunity against most human influenza A virus strains. Because the VAX102 vaccine relies on a single cross-reactive influenza A virus antigen manufactured by a recombinant protein fermentation-production process that does not involve eggs, stock-piling of this vaccine is possible to alleviate concerns of vaccine shortages or a need to quickly respond to an emergency. Hypothesis: The hypothesis is that the VAX102 vaccine will be generally well-tolerated and will cause the development of antibodies to influenza virus in at least one dose level tested. Specific Aims and Procedures (summary): The main purpose of the study is to assess the safety, reactogenicity and tolerability of the VAX102 vaccine given as an injection into the muscle at 3 doses, 10 ¿¿g, 33 ¿¿g and 100 ¿¿g. The vaccine will be given at Day 0 and a booster at Day 28 to healthy adults, 18-49 years of age. Additional purposes of the study are to assess the immune response to the VAX102 vaccine. Volunteers will be consented, screened, and enrolled in a double-blind, randomized, placebo-controlled vaccine study, with a prime-boost design. There are 3 dose groups, with 20 members to each group, to be enrolled starting with the lowest dose and increasing to the highest. The first 8 members of each group will be evaluated with 7 day follow up data after receiving the first dose of vaccine. Lab results and the type of reactions reported by individuals will be reviewed prior to enrolling the remaining 12 members of a group. Before increasing to the next highest dose, each group of 20 will have their 7 day follow up data reviewed. Lab results and the type of reactions reported by individuals for the entire group will be included in the review. This information will be reviewed by a Safety Monitoring Committee. Within each group of 20, the randomization will occur 3:1 for vaccine:placebo. Following the booster dose of vaccine to each group, the safety data for the next 7 day period will be reviewed, before recommending that the next group receive booster dosing. Laboratory studies will be performed to evaluate safety and immune response. Subjects will be asked to keep a diary of local reactions (i.e., redness or swelling) and systemic symptoms such as pain and fatigue. Subjects will be followed frequently during the one month post each dose of study agent, and at other intervals during the 6 months following the first vaccine dose. Experimental Design (summary): All data collected will be reported using descriptive statistics, such as frequencies and percentages in each category. Continuous variables will be summarized by dose group as numbers of subjects, means, standard deviations, medians, and minimum/maximum values. Two-sided, 95% confidence intervals will be calculated for immunogenicity endpoints and differences between each dose and placebo, and among dose groups. Placebo subjects from all dose groups will be grouped together and used for summaries and analyses. Since this is a Phase I study to assess safety and preliminary immunogenicity, no adjustments for multiple statistical testing will be required. Significance (summary): Development of an alternative influenza vaccine that will be protective across multiple influenza seasons and will be produced in a method that will allow for rapid production is critical to global health. New approaches to influenza protection are a national priority.

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。 背景：流感是一种高度传染性的急性呼吸道疾病，是威胁人类人口的主要传染病之一。流感病毒影响所有年龄段的人，在一生中造成反复感染，并导致每年不同严重程度的全球流行病。平均每年，全世界估计有300万至500万例严重疾病病例和50万例死亡。据估计，美国每年有3.6万人死于流感，20多万人住院。大流行性流感病毒迅速传播，在全球范围内造成高水平的疾病和死亡。 开发有效的流感疫苗的一些挑战是因为流感病毒在每个季节都表现出基因结构的变化。目前的疫苗都没有一种能够解释这种基因变化的保护方式。流感疫苗发展面临的其他挑战是由于目前可用于生产这种疫苗的技术。目前可用的疫苗是用鸡蛋制成的，这限制了剂量，也造成了疫苗生产的长时间延误。 VaxInnate已经开发出一种交叉保护性甲型流感疫苗，VAX102，它是基于在大肠杆菌中表达的重组蛋白。与HA和NA病毒蛋白不同，自1918年流感大流行以来，M2e的24个氨基酸序列在所有人类甲型流感病毒分离株中保持显著稳定。因此，基于M2e抗原的流感疫苗可以对大多数人类甲型流感病毒株产生广泛的交叉保护性免疫。由于VAX102疫苗依赖于通过不涉及鸡蛋的重组蛋白发酵生产过程制造的单一交叉反应甲型流感病毒抗原，因此堆积这种疫苗可能会缓解人们对疫苗短缺或快速应对紧急情况的担忧。 假设：假设VAX102疫苗总体上耐受性良好，并将在至少一个测试剂量水平上导致流感病毒抗体的产生。 具体目标和程序(摘要)：本研究的主要目的是评估VAX102疫苗肌肉注射的安全性、反应性和耐受性。该疫苗将在第0天接种，第28天接种给18-49岁的健康成年人。这项研究的其他目的是评估VAX102疫苗的免疫反应。志愿者将被同意、筛选并登记参加一项双盲、随机、安慰剂对照的疫苗研究，采用Prime-Boost设计。有3个剂量组，每组20人，从最低剂量开始，增加到最高剂量。每组前8名成员在接种第一剂疫苗后7天内进行随访。在招募小组的其余12名成员之前，将审查实验室结果和个人报告的反应类型。在增加到下一个最高剂量之前，每组20人将对他们的7天随访数据进行审查。整个小组的实验室结果和个人报告的反应类型将包括在审查中。这些信息将由安全监测委员会审查。在每组20人中，疫苗和安慰剂的随机化比例为3：1。在给每一组增加疫苗剂量后，在建议下一组接受加强剂量之前，将审查下一个7天期间的安全数据。 将进行实验室研究，以评估安全性和免疫反应。受试者将被要求记录局部反应(即发红或肿胀)以及疼痛和疲劳等全身症状。受试者将在每次注射研究试剂后的一个月内以及在第一次接种疫苗后的6个月内进行频繁的跟踪调查。 实验设计(总结)：收集的所有数据将使用描述性统计方法报告，例如每个类别中的频率和百分比。连续变量将按剂量组汇总为受试者数量、平均值、标准差、中位数和最小/最大值。将计算免疫原性终点和每个剂量与安慰剂之间以及剂量组之间的差异的双侧95%可信区间。来自所有剂量组的安慰剂受试者将被分组在一起，用于总结和分析。由于这是一项评估安全性和初步免疫原性的第一阶段研究，因此不需要对多重统计测试进行调整。 意义(摘要)：开发一种跨多个流感季节具有保护性的替代流感疫苗，并将以一种允许快速生产的方法生产，对全球健康至关重要。预防流感的新方法是国家优先事项。