Clinical Studies of Vaccines for Pandemic Influenza

尽管研究受试者对疫苗病毒中的血凝素呈血清阴性，并且由于HA和NA基因来源于禽/动物种属的新型流感病毒亚型，因此预计受试者易感染pLAIV，但疫苗病毒的复制受到高度限制。对pLAIV的免疫应答是可变的，从对H9 N2和H7 N3的高血清转化率到对H5 N1、H6 N1和H2 N2疫苗的低血清转化率。为了寻求针对具有大流行潜力的流感病毒的减毒活流感疫苗策略，重要的是更多地了解决定pLAIV毒株在血清阴性健康成人中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应答的因素。 在2013财年，我们进行了一项研究，以确定生物标志物，预测减毒流感病毒（LAIV）活疫苗的脱落和免疫反应。本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性LAIV是否在健康成人的呼吸道中复制？(2)哪些生物标志物可预测季节性或大流行性LAIV是否会在健康成人中引起免疫应答？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I期临床试验中评估了H5 N1和H7 N7甲型流感减毒活疫苗;不幸的是，很少有疫苗通过血凝抑制或中和而脱落病毒和/或血清转化。然而，一部分接种者有其他证据（例如B细胞ELIspot）表明对疫苗产生了免疫应答。我们试图确定接种疫苗的人是否已经免疫，如果是的话，他们对灭活的H5或H7疫苗的免疫反应会有强烈的增强。本研究将解决以下问题：（1）是否有证据表明，H5 N1或H7 N7流感病毒减毒活疫苗具有高度限制复制和免疫原性差的免疫引发作用？(2)H5 N1或H7 N7减毒活流感病毒疫苗是否引发对未灭活H7 N7病毒疫苗的增强（和/或广泛）免疫应答？目前正在对这些研究的数据进行分析。

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.