Development of an adaptable RNA vaccine against enterovirus D68 infection for the prevention of acute flaccid myelitis

项目总结： 2012年在加利福尼亚州首次发现与肠道病毒D68(EV-D68)有关的儿童急性迟缓性脊髓炎 感染，发病率一直在增加，每两年发现一次暴发。肠道病毒是众所周知的 中枢神经系统病变的原因，从无菌性脑膜炎到有时致命的脑干 脑炎和脊髓炎，这可能会导致永久性的虚弱瘫痪。此外，EV-D68还会感染 呼吸道，导致严重的呼吸道疾病，并促进人与人之间的传播 呼吸道飞沫。尽管EV-D68‘S的出现是严重呼吸系统和神经系统的主要原因 在疾病方面，没有疫苗或治疗方法可用于抗击和控制这种病原体的传播。 HDT Bio开发了一种自扩增复制子RNA(REPRNA)疫苗平台，该平台由一种脂肪无机物递送 纳米粒(LION)计划于2021年第一季度进入I期临床试验，作为抗病毒疫苗 新冠肺炎。这些活动将使其他候选疫苗能够利用相同的平台快速翻译， 送进诊所。此外，HDT正在进行一项开发广谱抗EV-D68抗体的计划 治疗学，在其中，我们已经确定了有希望的基于RNA的疫苗，这种疫苗编码必要的基因 肌肉注射后体内产生发散的EV-D68病毒样颗粒(VLP)。我们的 初步数据表明，1)我们可以从我们的epRNA平台启动非包膜病毒的VLP，2) 我们可以快速地使这种方法适用于EV-D68的基因和/或抗原变体，并且3)这些抗原是 在小型和大型动物中具有很强的免疫原性，在一次免疫后产生强大的中和抗体反应 剂量。在本申请中，我们建议筛选六种候选疫苗，目前正在进行评估 羊驼中的混合物用于抗体发现努力，以确定单个候选对象，从而诱导最佳杂交- 中和抗体反应。然后我们将在神经学方面表征安全性、免疫原性和有效性- 以及EV-D68感染的呼吸道疾病小鼠模型。最后，我们将评估安全性和免疫原性。 在怀孕的小鼠模型和出生的幼鼠中的疗效，同时表征母体抗体的转移。

Project summary: First identified in California in 2012, acute flaccid myelitis in children, associated with enterovirus D68 (EV-D68) infection, has been increasing in incidence with outbreaks detected every 2 years. Enteroviruses are well-known causes of central nervous system pathologies, ranging from aseptic meningitis to sometimes fatal brainstem encephalitis and myelitis, which can lead to permanent debilitating paralysis. Additionally, EV-D68 infects the respiratory tract, causing severe respiratory disease and facilitating person-to-person transmission via respiratory droplets. Despite EV-D68’s emergence as a major cause of severe respiratory and neurological disease, there are no vaccines or therapeutics available to combat and control the spread of this pathogen. HDT Bio has developed a self-amplifying replicon RNA (repRNA) vaccine platform delivered by a Lipid InOrganic Nanoparticle (LION) scheduled to enter phase I clinical trials in the first quarter of 2021 as a vaccine against COVID-19. These activities will enable rapid translation of other vaccine candidates, utilizing the same platform, into the clinic. Additionally, HDT has an ongoing program to develop broad-spectrum anti-EV-D68 antibody therapeutics, in which we have identified promising RNA-based vaccines that encode the necessary genes for production of divergent EV-D68 virus like particles (VLPs) in vivo upon intramuscular administration. Our preliminary data establishes that 1) we can launch VLPs of non-enveloped viruses from our repRNA platform, 2) we can rapidly adapt this approach for genotypic and/or antigenic variants of EV-D68, and 3) these antigens are very immunogenic in small and large animals, generating robust neutralizing antibody responses after a single dose. In this application, we propose to screen six vaccine candidates, which are currently being evaluated as a mixture in alpacas for antibody discovery efforts, to identify a single candidate that induces the best cross- neutralizing antibody responses. We will then characterize safety, immunogenicity and efficacy in neurological- and respiratory-disease mouse models of EV-D68 infection. Finally, we will evaluate safety and immunogenicity in pregnant mouse models and efficacy in birthed pups while characterizing maternal antibody transfer.