Pandemic Influenza Translational Research and Novel Drug Therapy

尽管进行了长期投资，但流感仍然是一个重大的世界性问题。甲型流感病毒（Influenza A virus，IAV）是人类重要的病原体，每年都会引起流行病，偶尔也会引起大流行。过去的大流行导致了严重的发病率和死亡率。1918年的流感大流行被认为导致美国至少67.5万人死亡，全球4000万人死亡。1957年和1968年的大流行虽然不那么严重，但也具有重大的公共卫生意义。2009年，一种新型猪源甲型流感病毒大流行，导致41年来首次大流行。此外，每年流行性流感病例也非常显著，导致美国每年多达49，000人死亡。 根据FDA批准的IND，NIH临床中心正在继续使用2009年甲型流感/H1N1病毒和2012年甲型流感/H3 N2病毒进行人类志愿者流感病毒攻毒研究。 在临床中心继续进行一项健康志愿者筛选研究，以确定符合资格并可用于当前和未来挑战研究的患者。 此外，一项长期研究（包括对参与既往攻毒研究的患者进行2年随访）也继续入组，首批患者完成了2年随访。 过去一年的这些临床研究还包括II期挑战研究，以评估新的治疗方法和疫苗。 Crucell/约翰逊和约翰逊的CRADA下的一项研究正在评估一种新型单克隆治疗性抗体，而另一项CRADA下的II期研究与SEEK今年完成了招募，以评估一种新型通用流感疫苗。 我们还继续通过开发其他季节性甲型和B型流感攻毒病毒进一步开发攻毒模型，并继续与DCR合作开发FLUPRO，这是一种经验证的用于测量流感感染严重程度的问卷。 除了这些临床研究，我们继续与洛克菲勒大学、斯坦福大学、FDA和NIAID合作，进一步研究人类流感感染及其与其他病毒感染的关系。 其中一些合作导致了埃博拉和登革热病毒领域的出版物，这两个领域都具有全球公共卫生意义。 此外，我们还对先前完成的攻毒研究中收集的数据进行了进一步分析。 我们最近完成了对天然存在的HA茎抗体作为保护相关物的首次评估，以及与血凝抑制（HAI）滴度和神经氨酸酶滴度相比，它作为疾病预测因子的作用。 流感病毒血凝素（HA）表面糖蛋白目前是所有许可的流感疫苗的主要靶标，并且被认为是个体对其产生体液免疫应答的主要抗原。 直到最近，HA的抗原性和遗传可变头部区域的抗体一直是流感血清学研究和疫苗开发的主要焦点，特别是空间抑制血凝素受体结合的抗体，利用血凝抑制（HAI）测定来评估抗体滴度。 在过去的十年中，人们更多地关注于发现靶向HA的更保守的茎（或茎）区的抗体。 这些抗体可以广泛中和18种已知甲型流感病毒（IAV）HA亚型中的两组之一，第1组包括季节性人类H1和高致病性禽类H5，第2组包括禽类H7N9 IAV流行病形式的2016-2017年季节性H3。这些广泛中和的抗HA茎抗体被假设在2009年H1N1 pdm病毒出现后，在先前流行的大流行前季节性H1N1谱系的灭绝中发挥了重要作用。 这些与组1或组2 HA茎的保守表位结合的广泛中和的抗茎抗体可以引发广泛的保护性应答的可能性已经导致许多小组研究基于抗茎抗体技术的新型疫苗和治疗剂。 已经显示了基于抗茎抗体的疫苗/构建体在动物模型中的广泛保护作用，并且这些研究产品中的一些正在为未来的临床试验评价做准备。 在我们的挑战研究参与者的二次分析中，我们观察到天然存在的抗HA茎抗体滴度比以前认为的更常见，并且天然存在的抗HA茎抗体滴度不是疾病结果的独立预测因子，它们与HAI滴度类似地预测疾病，并证实NAI滴度似乎是这些研究中疾病减轻的最佳鉴定的预测因子和保护的相关性。

Despite long-term investment, influenza continues to be a significant worldwide problem. Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S. and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza cases are also very significant resulting in up to 49,000 deaths in the U.S. annually. Human volunteer influenza virus challenge studies are continuing at the NIH Clinical Center using both a 2009 influenza A/H1N1 virus and a 2012 influenza A/H3N2 virus under FDA-approved INDs. A healthy volunteer screening study continued at the Clinical Center to identify patients who will qualify and be available for current and future challenge studies. In addition, a long-term study consisting of a 2 year follow up of patients who participated in previous challenge studies also continued to enroll with the first patients completing their 2 years follow up. These clinical studies over the past year have also included Phase II challenge studies to evaluate novel therapeutic and vaccines. One study under a CRADA with Crucell/Johnson and Johnson is evaluating a novel monoclonal therapeutic antibody, while another Phase II study under a CRADA with SEEK completed enrollment this year to evaluate a novel universal influenza vaccine. We also continue to further develop the challenge model through the development of other seasonal influenza A and B challenge viruses and continued collaboration with DCR on the development of FLUPRO, a validated questionnaire for measuring the severity of influenza infections. In addition to these clinical studies we continued our collaborations with Rockefeller University, Stanford, FDA, and within NIAID to further study human influenza infection and how it relates to other viral infections. Some of these collaborations have led to publications in the Ebola and Dengue virus fields, both of worldwide public health significance. In addition, we have performed further analysis of data collected from the previously completed challenge studies has continued. We recently completed the first evaluation of naturally occurring HA stalk antibody as a correlate of protection and what role it plays as a disease predictor in comparison to hemagglutination inhibition (HAI) titer and neuraminidase titer. The influenza virus hemagglutinin (HA) surface glycoprotein is currently the primary target of all licensed vaccines for influenza and considered the dominant antigen to which individuals develop a humoral immune response. Until recently, antibodies to the antigenically and genetically variable head region of the HA have been the major focus of influenza serological studies and vaccine development, specifically antibodies that sterically inhibit hemagglutinin receptor binding, utilizing the hemagglutination inhibition (HAI) assay to assess antibody titers. Over the course of the past decade there has been more focus on discovery of antibodies that target the more conserved stalk (or stem) region of the HA. These antibodies can be broadly neutralizing across one of two groups of the 18 known influenza A virus (IAV) HA subtypes, Group 1, which includes seasonal human H1 and highly pathogenic avian H5, and Group 2, which includes seasonal H3 2016-2017 in the form of an avian H7N9 IAV epizootic. These broadly neutralizing anti-HA stalk antibodies have been hypothesized to have played a major role in the extinction of the previously circulating pre-pandemic seasonal H1N1 lineage after the 2009 H1N1pdm virus emerged. The possibility that these broadly neutralizing anti-stalk antibodies that bind to conserved epitopes of group 1 or group 2 HA stalk could elicit broadly protective responses have led a number of groups to investigate novel vaccines and therapeutics based on anti-stalk antibody technology. Broad protection in animal models with anti-stalk antibody based vaccines/constructs has been shown and some of these investigational products are in preparation for future clinical trial evaluation. In a secondary analysis of our challenge study participants we observed that naturally occurring anti-HA stalk antibody titers were more common than previously thought, and that naturally occurring anti-HA stalk antibody titers are not independent predictors of disease outcome, that they predict disease similarly to HAI titer, and confirmed that NAI titer seems to be the best identified predictor of disease reduction and correlate of protection in these studies.