Pandemic Influenza Translational Research; Novel Vaccine and Drug Therapy

大流行性流感转化研究；

• 批准号: 10014206
• 负责人: Matthew Memoli
• 金额: $ 251.44万
• 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/10014206
• 关键词: Antibodies; Cessation of life; Clinical; Clinical Protocols; Clinical Research; Collaborations; Cooperative Research and Development Agreement; Data Analyses; Development; Enrollment; Epidemic; FDA approved; Family suidae; Future; Goals; Human; Human Volunteers; Immunity; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza B Virus; Investments; Lead; Longitudinal Studies; Measures; Modeling; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; National Institute of Allergy and Infectious Disease; Natural History; Neuraminidase; Patients; Pharmacotherapy; Phase; Public Health; Questionnaires; Severities; T-Lymphocyte; Therapeutic Monoclonal Antibodies; Translational Research; United States National Institutes of Health; Universities; Vaccination; Vaccine Therapy; Virus; Virus Diseases; follow-up; healthy volunteer; human pathogen; influenza epidemic; influenza virus vaccine; influenzavirus; mortality; novel; novel therapeutics; novel vaccines; pandemic disease; pandemic influenza; patient population; phase 2 study; screening; seasonal influenza; universal influenza vaccine; universal vaccine; vaccine candidate; volunteer

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. This past year has lead to significant breakthroughs in terms of understanding influenza immunity and issues to consider in development of universal vaccine. The challenge studies have demonstrated the importance of anti-neuraminidase antibodies over anti-HA and anti-HA stalk antibodies, the benefit of T-cell immunity, and the potential of mucosal immunity. This has lead to the co-development of multiple vaccine candidates between the LID CSU and LID VPES. It has also lead to the initiation of new challenge studies to further evaluate these forms of immunity. 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. In addition, we have performed further analysis of data collected from the previously completed challenge studies. We recently started the first human challenge study to assess the mucosal immune response after vaccination and challenge.

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。 在过去的一年里，在理解流感免疫和开发通用疫苗时需要考虑的问题方面取得了重大突破。 攻毒研究已经证明了抗神经氨酸酶抗体相对于抗HA和抗HA茎抗体的重要性、T细胞免疫的益处和粘膜免疫的潜力。 这导致LID CSU和LID VPES之间共同开发多种候选疫苗。 它还导致启动新的挑战研究，以进一步评估这些形式的免疫力。 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。 此外，我们还对从先前完成的挑战研究中收集的数据进行了进一步分析。 我们最近开始了第一项人体攻毒研究，以评估疫苗接种和攻毒后的粘膜免疫应答。