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

基本信息

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
项目类别：
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

项目摘要

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年首次在加利福尼亚州进行促进的儿童急性松弛脊髓炎，与肠病毒D68有关（EV-D68）感染，每2年检测到武器的刺激一直在增加。中央传因神经系统病理的原因，从无菌性脑膜炎到有时致命的脑干不等脑炎和脊髓炎，这可能导致永久性瘫痪。呼吸道，导致断裂疾病并通过呼吸道液滴。疾病，没有可用于作战和控制这种病原体的疫苗或治疗剂。 HDT Bio开发了一种自我扩增的复制子RNA（ReprNA）疫苗平台，该平台由脂质无机提供纳米粒子（狮子）计划在2021年第一季度进入I期临床试验作为疫苗 COVID-19。进一步的诊所。治疗剂，我们已经确定了有希望的有希望的疫苗疫苗的疫苗在肌内给药时，在体内产生不同的EV-D68病毒（VLP）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。羊驼中的混合物进行抗体发现工作，以确定一个候选者最好的交叉中和抗体反应。 EV-D68感染的呼吸疾病小鼠鼠鼠。在孕妇的小鼠模型和出生的幼崽的功效中，同时表征了母体新的抗体转移。