Clinical Studies of Vaccines for Pandemic Influenza

大流行性流感疫苗的临床研究

• 批准号: 8745450
• 负责人: Kanta Subbarao
• 金额: $ 298.36万
• 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/8745450
• 关键词: Address; Adult; Animals; Attenuated; Attenuated Live Virus Vaccine; B-Lymphocytes; Biological Markers; Birds; Clinical Research; Clinical Trials; Data; Data Analyses; Disease; Equilibrium; Ferrets; Genes; Goals; H7N7; Hemagglutination; Hemagglutinin; Immune response; Immunologics; Inactivated Vaccines; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Learning; Licensing; Life; Mus; Neuraminidase; Phase I Clinical Trials; Reporting; Respiratory System; Respiratory tract structure; Safety; Study Subject; Universities; Vaccines; Virus; Virus Diseases; Virus Shedding; attenuation; base; clinical lot; immunogenic; immunogenicity; influenza virus vaccine; influenzavirus; novel; pandemic disease; pandemic influenza; pandemic preparedness; pre-clinical; preclinical study; programs; vaccine candidate

Although the study subjects were seronegative to the hemagglutinins in the vaccine viruses and were predicted to be susceptible to infection with the pLAIVs because the HA and NA genes were derived from novel influenza virus subtypes from avian/animal species, the vaccine viruses were highly restricted in replication. The immune responses to the pLAIVs were variable, ranging from high seroconversion rates to H9N2 and H7N3 to low seroconversion rates for H5N1, H6N1 and H2N2 vaccines. In order to pursue a live attenuated influenza vaccine strategy for influenza viruses with pandemic potential, it is important to learn more about factors that determine the level of replication of the pLAIV strains in seronegative healthy adults and factors that determine whether a vaccine recipient will develop an immune response to the vaccine. In FY13, we undertook a study to identify biomarkers that would that predict shedding and immune response to live attenuated influenza virus (LAIV) vaccines. This study would address the following questions: (1) Which biomarkers predict whether seasonal or pandemic LAIV replicate in the respiratory tract of healthy adults? (2) Which biomarkers predict whether seasonal or pandemic LAIV will elicit an immune response in healthy adults? These studies are in progress. We had previously evaluated H5N1 and H7N7 live attenuated influenza A virus vaccines in Phase I clinical trials at Johns Hopkins University and the University of Rochester; unfortunately, few vaccinees shed virus and/or seroconverted by hemagglutination inhibition or neutralization. However, a proportion of the vaccinees had other evidence (e.g. B cell ELIspot) of an immune response to the vaccine. We sought to determine whether the vaccinees were immunologically primed, and if so, would have a strong boost in their immune response to an inactivated H5 or H7 vaccine. This study would address the following questions: (1) Is there evidence of immunologic priming with a live attenuated H5N1 or H7N7 influenza virus vaccine that was highly restricted in replication and poorly immunogenic? (2) Does the H5N1 or H7N7 live attenuated influenza virus vaccine prime for an enhanced (and/or broad) immune response to the unadjuvated H7N7 inactivated virus vaccine? The analysis of the data from these studies is in progress.

尽管研究对象对疫苗病毒中的血凝素呈血清阴性反应，并预测容易感染pLAIV，因为HA和NA基因来自禽类/动物物种的新流感病毒亚型，但疫苗病毒的复制受到高度限制。对pLAIV的免疫反应是多种多样的，从对H9N2和H7N3的高血清转换率到H5N1、H6N1和H2N1疫苗的低血清转换率。为了对具有大流行潜力的流感病毒实施减毒活疫苗策略，重要的是要更多地了解决定血清阴性健康成年人中pLAIV毒株复制水平的因素，以及决定疫苗接受者是否会对疫苗产生免疫反应的因素。 在2013财年，我们进行了一项研究，以确定预测减毒流感病毒(LAIV)活疫苗的脱落和免疫反应的生物标志物。这项研究将解决以下问题：(1)哪些生物标志物预测季节性或大流行LAIV是否会在健康成年人的呼吸道中复制？(2)哪些生物标记物预测季节性或大流行LAIV是否会在健康成年人中引发免疫反应？这些研究正在进行中。 我们之前在约翰·霍普金斯大学和罗切斯特大学的第一阶段临床试验中评估了H5N1和H7N7减毒活甲型流感病毒疫苗；不幸的是，很少有疫苗受试者通过血凝抑制或中和来摆脱病毒和/或血清转换。然而，一定比例的接种者有其他证据(例如B细胞ELISPOT)表明对疫苗有免疫反应。我们试图确定接种疫苗的人是否已经做好了免疫准备，如果是的话，他们对灭活H5或H7疫苗的免疫反应将会有很大的增强。这项研究将解决以下问题：(1)是否有证据表明，H5N1或H7N7流感病毒减毒活疫苗的复制受到高度限制，且免疫原性较差？(2)H5N1或H7N7减毒活流感病毒疫苗是否为增强(和/或广泛)对未经调整的H7N7灭活病毒疫苗的免疫反应做好准备？对这些研究的数据的分析正在进行中。