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

项目概要： 2012年首次在加州发现，儿童急性弛缓性肌炎与肠道病毒D 68（EV-D 68）相关 感染，发病率一直在增加，每两年发现一次疫情。肠道病毒是众所周知的 中枢神经系统病理的原因，从无菌性脑膜炎到有时致命的脑干 脑炎和肌萎缩，这可能导致永久性衰弱性瘫痪。此外，EV-D 68感染 呼吸道感染，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-D 68作为严重呼吸和神经系统疾病的主要原因出现， 由于这种疾病，没有疫苗或治疗方法可用于对抗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，由Lipid InOrganic 纳米颗粒（LION）计划于2021年第一季度进入I期临床试验，作为对抗 2019冠状病毒病。这些活动将使其他候选疫苗能够利用同一平台快速翻译， 进了诊所此外，HDT正在开发广谱抗EV-D 68抗体 治疗，其中我们已经确定了有前途的RNA疫苗，编码必要的基因， 肌内给药后体内产生不同的EV-D 68病毒样颗粒（VLP）。我们 初步数据确定：1）我们可以从repRNA平台上推出无包膜病毒的VLP，2） 我们可以快速地将这种方法用于EV-D 68的基因型和/或抗原变体，和3）这些抗原是 在小型和大型动物中非常具有免疫原性，在单次免疫后产生强大的中和抗体应答。 次给药结束在本申请中，我们建议筛选六种候选疫苗，目前正在评估这些疫苗是否为 在羊驼的抗体发现工作的混合物，以确定一个单一的候选人，诱导最好的交叉- 中和抗体反应。然后，我们将描述安全性、免疫原性和神经系统- 和EV-D 68感染的腹泻病小鼠模型。最后，我们将评估安全性和免疫原性 在妊娠小鼠模型和出生幼仔中的有效性，同时表征母体抗体转移。

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.