Influenza Vaccine Development

改进流感疫苗，提高效力、保护范围和保护时间，将提高全世界应对流感病毒季节性变化（漂移）和新的大流行毒株出现（转变）的能力。这项研究旨在开发新的平台和流感疫苗接种策略。已经开发了针对多种季节性和大流行性流感毒株的基于纳米颗粒和核酸的疫苗，包括H7N9和H5 N1禽流感病毒。此外，正在进行研究以鉴定和优化疫苗抗原以呈递流感病毒血凝素（HA）的保守区域，从而开发提供更广泛的普遍保护的疫苗。这些包括1型和2型流感HA稳定的茎三聚体的纳米颗粒展示，以及较不保守的HA头部结构域的集合。已经进行了测试，以评估候选人，以及佐剂，以加强免疫反应，并确定最佳的免疫策略。几种候选物显示出有希望的结果，这些结果导致进一步的评价，使用DNA和DNA初免与灭活疫苗加强或显示全长、茎和/或受体结合结构域HA抗原的纳米颗粒。基于结构的迭代设计的多个循环产生了来自H1N1 A/New Caledonia/20/1999的HA茎的结构稳定的三聚体，其属于组1。产生了这些免疫原的几个版本，并在动物模型中测试了其免疫原性，以及与茎结合单克隆抗体共结晶。用这些纳米颗粒免疫诱导小鼠和雪貂中具有低水平中和抗体的同源和异源结合抗体。尽管这种中和活性相对较弱，但免疫在小鼠中赋予完全保护，在雪貂中赋予几乎完全保护，使其免受异亚型H5 N1致命流感攻击。免疫小鼠免疫球蛋白的被动转移在受体小鼠中提供了针对致死性H5攻击的保护，表明保护是抗体介导的。进一步的研究，以确定保护的免疫学基础正在进行中，以及努力改善组1免疫原，以增加中和反应。第2组设计也通过体外表征、动物研究和产品开发得到了推进，目前主要候选产品正在GMP生产中。此外，正在合作开发基于基因的疫苗平台，如mRNA平台。第一次人类流感HA纳米颗粒疫苗临床试验已接近完成，目前正在招募测试H1干细胞铁蛋白免疫原的1期临床试验。利用第2组干细胞免疫原的第1期试验预计将于2020年春季开放。已经建立了设计新型多组分纳米颗粒的合作，第一个候选物在动物模型中显示出有希望的免疫原性结果，并正在转移到先进的产品开发中。去年启动的利用病毒神经氨酸酶（NA）的设计计划仍在继续，在试剂、测定和用于动物模型测试的候选免疫原方面取得了进展。正在进行合作，以在1期临床试验中将候选疫苗与先进的佐剂配对。

Improvements in vaccines against influenza that increase potency, breadth and duration of protection would improve worldwide ability to combat seasonal changes in influenza viruses (drift) and emergence of new pandemic strains (shift). This study aims to develop new platforms and vaccination strategies against influenza. Nanoparticle-, and nucleic acid-based vaccines have been developed against multiple seasonal and pandemic strains of influenza, including H7N9, and H5N1 avian influenza viruses. In addition, studies are ongoing to identify and optimize vaccine antigens to present conserved regions of the influenza virus hemagglutinin (HA) in order to develop a vaccine that provides broader universal protection. These include nanoparticle display of both group 1 and group 2 influenza HA stabilized stem trimers, as well as a collection of less-conserved HA head domains. Testing has been conducted to evaluate candidates, as well as adjuvants to boost immune response, and determine the optimal strategies for immunization. Several candidates showed promising results that lead to further evaluations, using DNA and DNA prime with inactivated vaccine boost or nanoparticles displaying full length, stem, and/or receptor-binding domain HA antigens. Multiple cycles of iterative structure-based design yielded a structurally stabilized trimer of the HA stem derived from H1N1 A/New Caledonia/20/1999, which belongs to group 1. Several versions of these immunogens were generated and tested its immunogenicity in animal models, as well as to co-crystallize with stem-binding monoclonal antibodies. Immunization with these nanoparticles induces homologous and heterologous binding antibodies in mice and ferrets with low levels of neutralizing antibodies. Despite this relatively weak neutralizing activity, immunization confers complete protection in mice and near-complete protection in ferrets from heterosubtypic H5N1 lethal influenza challenge. Passive transfer of immunoglobulins from immunized mice provides protection against lethal H5 challenge in recipient mice, indicating the protection is antibody-mediated. Further studies to determine the immunological basis of protection are underway, as well as efforts to improve the group 1 immunogen to increase neutralizing responses. Group 2 designs have also been advanced through in vitro characterizations, animal studies and product development, and a lead candidate is now in GMP manufacturing. In addition, collaborations to develop gene-based vaccine platforms such as mRNA platform are underway. The first-in-human influenza HA nanoparticle vaccine clinical trial is nearly complete, and the Phase 1 clinical trial testing the H1 stem ferritin immunogen is currently enrolling. The Phase 1 trial utilizing the group 2 stem immunogen is expected to open in spring 2020. Collaborations have been established to design novel multi-component nanoparticles, and the first candidate shows promising immunogenicity results in animal models and is being transferred into advanced product development. The design program utilizing viral neuraminidase (NA) initiated last year continues, with progress made on reagents, assays, and candidate immunogens for testing in animal models. Collaborations are in progress to pair vaccine candidates with advanced adjuvants in Phase 1 clinical trials.