Toward a Universal Influenza Virus Vaccine

总体项目摘要 流感病毒继续对全球公共卫生构成重大威胁。因此，有一个至关重要的 因此，迫切需要研制新的流感病毒疫苗和创新的疫苗接种战略。的 开发一种长寿命的广泛保护性流感病毒疫苗将对 全世界努力控制流感病毒。这次更新的目的是继续努力， 满足这一需求。自该计划最初获得资金以来，我们在以下方面取得了重大进展： 人类对流感病毒的免疫反应，以及我们对一类独特的广泛的 中和抗体我们发现了抗体体内中和病毒的新机制， 识别血凝素糖蛋白的保守区域，在B细胞 诱导和持久的体液免疫在人类，关键是，产生新的疫苗免疫原 和免疫方案。通过这项工作，我们阐明了流感疫苗接种的新范式 我们计划通过继续我们长期建立的研究合作来进一步推进。因此我们 将提高我们的血凝素免疫原诱导具有最佳效应子功能的抗体的能力。 我们将研究长寿命浆细胞的诱导和维持，并利用这些信息来识别 有效的B细胞佐剂，促进持久的免疫反应。此外，我们将探索病毒 神经氨酸酶作为广泛中和抗体的靶点;这种表面糖蛋白有可能 提高通用疫苗的总体广度和免疫原性。这种方法将与 同时努力生产针对2型甲型流感HA和B型流感的通用茎基疫苗 病毒。这些发现将转化为流感的动物模型，并得到我们的试剂的支持。 高度复杂的mAb核心。鉴于我们在上一个供资期取得的成就和 通过合作调查人员的专业知识，我们坚信，我们的持续努力将推动 - 产生广泛保护性疫苗，其在提供针对第1组的保护方面是真正通用的， 组2和流感B病毒。

OVERALL PROJECT SUMMARY Influenza viruses continue to pose a significant threat to global public health. Consequently, there is a vitally important need to generate new influenza virus vaccines and innovative vaccination strategies. The development of a long-lived broadly-protective influenza virus vaccine would have a tremendous impact on worldwide efforts to control influenza viruses. The purpose of this renewal is to continue on our efforts to address this need. Since the initial funding of this Program we have made major advances in our knowledge of the human immune response to influenza viruses and in our understanding of a unique class of broadly- neutralizing antibodies. We discovered new mechanisms for virus neutralization in vivo by antibodies that recognize conserved regions of the hemagglutinin glycoprotein, made new discoveries regarding B-cell induction and persistence of humoral immunity in humans, and crucially, generated novel vaccine immunogens and immunization regimens. Through this work, we have elucidated new paradigms in influenza vaccination that we plan to advance further by continuing our long established research collaboration. To achieve this, we will improve the ability of our hemagglutinin immunogens to induce antibodies with optimal effector functions. We will examine the induction and maintenance of long-lived plasma cells and use this information to identify potent B-cell adjuvants that promote long-lasting immune responses. Moreover, we will look to explore the viral neuraminidase as a target of broadly neutralizing antibodies; this surface glycoprotein has the potential to improve the overall breadth and immunogenicity of a universal vaccine. This approach will be combined with parallel efforts to generate universal stalk-based vaccines for group 2 influenza A HAs and also influenza B viruses. These findings will be translated into animal models of influenza and supported by reagents from our highly sophisticated mAb Core. Given our accomplishments in the previous funding period and the combined expertise of the collaborating investigators, we strongly believe that our continued efforts will advance the generation of broadly-protective vaccines which are truly universal in providing protection against group 1, group 2 and influenza B viruses.