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

开发针对肠道病毒 D68 感染的适应性 RNA 疫苗，用于预防急性弛缓性脊髓炎

• 批准号: 10325201
• 负责人: Jesse Hong-Sae Erasmus
• 金额: $ 30万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325201
• 关键词: Adult; Alpaca; Animals; Antibodies; Antibody Response; Antigenic Diversity; Antigens; Aseptic Meningitis; Biodistribution; Birth; Brain Stem; COVID-19; COVID-19 pandemic; COVID-19 vaccine; California; Cerebrospinal Fluid; Child; Clinic; Coxsackie Viruses; Cyclic GMP; Data; Development; Disease Outbreaks; Dose; Embryo; Encephalitis; Endocarditis; Enterovirus; Enterovirus 68; Enterovirus 71; Evaluation; Evolution; Family; Family Picornaviridae; Fetal Development; Fever; Formulation; Genes; Genome; Genotype; Hepatitis; Human; Human poliovirus; Immunity; Inactivated Vaccines; Incidence; Infection; Infection prevention; Intramuscular; Lead; Licensure; Lipids; Lung diseases; Maternal antibody; Meningitis; Mothers; Mus; Mutation; Myelitis; Netherlands; Neuraxis; Paralysed; Pathology; Persons; Phase; Phase I Clinical Trials; Pregnancy; Pregnant Women; Preparation; Prevalence; Production; RNA; RNA Viruses; RNA vaccine; RNA-Directed RNA Polymerase; Replicon; Respiratory System; Rhinovirus; Safety; Schedule; Serotyping; Small Business Innovation Research Grant; Symptoms; Syndrome; Target Populations; Technology; Therapeutic; Therapeutic antibodies; TimeLine; Toxicology; Translations; United States; Update; Vaccinated; Vaccination; Vaccines; Variant; Viral Antibodies; Virus; Virus-like particle; Yeasts; acute flaccid myelitis; antibody transfer; base; clinical development; combat; design; efficacy study; fetal; immunogenic; immunogenicity; in vivo; lead candidate; maternal vaccination; mouse model; nanoparticle; neonatal mice; neonate; nervous system disorder; neutralizing antibody; pathogen; pregnant; programs; pup; recombinant virus; reproductive; research clinical testing; respiratory; respiratory virus; transmission process; vaccine candidate; vaccine development; viral RNA

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.

项目摘要： 2012年在加利福尼亚首次确定的儿童急性松弛脊髓炎与肠病毒D68有关（EV-D68） 感染，发病率一直在增加，每2年检测到暴发。肠病毒是众所周知的 中枢神经系统病理的原因，从临床脑膜炎到有时致命的脑干不等 脑炎和骨髓炎，可能导致永久性衰弱的麻痹。此外，EV-D68感染了 呼吸道，导致严重的呼吸道疾病，并通过 呼吸液滴。尽管EV-D68是严重呼吸和神经系统的主要原因 疾病，没有可用于对抗和控制这种病原体传播的疫苗或治疗。 HDT Bio开发了一种自我扩增的复制RNA（retra）疫苗平台，由脂质无机提供 纳米颗粒（狮子）计划于2021年第一季度进入I期临床试验作为疫苗 新冠肺炎。这些活动将使其他候选疫苗的快速翻译，利用同一平台， 进入诊所。此外，HDT还有一个持续的程序来开发广谱抗EV-D68抗体 治疗，我们已经确定了承诺基于RNA的疫苗，这些疫苗编码必要的基因 肌肉内给药后体内产生发散的EV-D68病毒（例如颗粒（VLP））。我们的 初步数据确定1）我们可以从我们的Reprna平台启动非发育病毒的VLP，2） 我们可以快速适应EV-D68的基因型和/或抗原变异的方法，3）这些抗原是 小动物和大型动物中的免疫原性，产生一个单一的中和抗体反应 剂量。在此应用程序中，我们建议筛选六个候选疫苗，目前正在评估为 羊驼中的混合物进行抗体发现工作，以确定诱导最佳跨的单一候选者 中和抗体反应。然后，我们将表征神经系统的安全性，免疫原性和效率 EV-D68感染的呼吸疾病小鼠模型。最后，我们将评估安全性和免疫原性 在怀孕的小鼠模型和幼崽的效率中，同时表征了母子抗体的转移。