Recombinant life attenuated vaccine against Argentine hemorrhagic fever

阿根廷出血热重组减毒疫苗

• 批准号: 8637909
• 负责人: Slobodan Paessler
• 金额: $ 96.41万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-04 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637909
• 关键词: Acute; Adverse effects; Aerosols; Agricultural Workers; Animal Model; Animals; Antiviral Agents; Area; Arenavirus; Arenavirus Infections; Attenuated; Attenuated Live Virus Vaccine; Biological; Biological Models; Body Temperature; Body Weight; Callithrix; Callithrix jacchus jacchus; Categories; Cavia; Cell Line; Cells; Clinical; Clinical Pathology; Communicable Diseases; Complementary DNA; Cultured Cells; Data; Development; Disease; Dose; Experimental Models; FDA approved; Future; Genetic; Genomics; Growth; Health; Human; Immunization; Infection; Junin virus; Lethal Dose 50; Licensing; Life; Macaca mulatta; Medical; Morbidity - disease rate; Mus; Mutation; Neurologic Manifestations; Population; Production; Property; Public Health; Readiness; Recombinant Vaccines; Recombinants; Recording of previous events; Records; Renal function; Ribavirin; Risk; Safety; Sampling; Seeds; Serial Passage; Series; System; Tacaribe Complex Viruses; Testing; Toxic effect; Vaccine Production; Vaccines; Variant; Vero Cells; Viral; Viral Hemorrhagic Fevers; Virulence; Virus; Virus Diseases; base; biodefense; combat; design; genome sequencing; hemorrhagic fever virus; immunogenic; immunogenicity; interest; liver function; meetings; mortality; novel; nucleoside analog; pathogen; positional cloning; prevent; protective efficacy; public health emergency; public health relevance; weapons

DESCRIPTION (provided by applicant): Several arenaviruses cause hemorrhagic fever (HF) disease in humans and pose a serious threat to public health within their endemic regions. Thus, the New World arenavirus Junin (JUNV) is the etiological agent of Argentine HF (AHF), a severe illness with hemorrhagic and neurological manifestations and a case fatality of 15-30%. In addition, JUNV is very stable, highly infectious by aerosol and causes high morbidity and mortality at low dose, features that make it highly suitable as potential biological weapon. Concerns about arenavirus infections are aggravated by the lack of licensed vaccines in the US and current anti-arenavirus therapies being limited to the use of the nucleoside analogue ribavirin, which is only partially effective and can cause significant toxicity. Accordingly, the development of antiviral drugs against JUNV has been considered as one of the top priorities within the Implementation Plan of the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE). Therefore, medical countermeasures against JUNV infections are eligible for acquisition by BARDA for the Strategic National Stockpile. We have developed a reverse genetic system for JUNV and rescued infectious viruses, both Candid1 and the pathogenic Romero strain, entirely from cloned cDNAs. This advance has provided us with the unique opportunity to generate a genetically well-defined seeds of Candid1 (rJUNV/Candid1cSD) and Romero (rJUNV/Romero) strains of JUNV to be utilized in immunogenicity and efficacy studies. This proposal is designed to provide a comprehensive characterization of the stability, immunogenic and protective properties of rJUNV/Candid1cSD as a first and necessary step for the development of a Candid 1-based vaccine able to meet the safety and efficacy criteria required for future FDA licensing. For this we propose the following specific aims: 1. Determine the genetic and phenotypic stability of rJUNV/Candid1cSD. We propose to generate and characterize a Master Virus Seed (MVS) of rCandid1cSD. We will use the MVS from rCandid1cSD to conduct independent serial passages in different cell substrates, including FDA approved cell lines for vaccine production. Infectious progenies from selected passages from each series will be characterized genetically (genome sequencing) and phenotypically (growth properties and virulence). Genetic and phenotypic information derived from these studies will be used to generate novel rCandid1 strains optimized for genetic and phenotypic stability. 2. To determine the safety, immunogenicity and efficacy of rJUNV/Candid1cSD in guinea pigs. We propose to conduct a comprehensive assessment of the virulence of our genetically well-defined MVS rCandid1cSD in guinea pigs. For this, we will determine clinical parameters associated with immunization of rCandid1cSD including: body temperature and weight, overall activity, assessment of hematological and clinical pathology data covering kidney and liver function, and protection against lethal challenge with JUNV. These studies will also include relevant viral variants identified during studies aimed at assessing the genetic and phenotypic stability of the MVS. 3. Determine the efficacy of rJUNV/Candid1cSD against JUNV in common marmoset (Callithrix jacchus). We propose to evaluate the protective efficacy of rJUNV/Candid1cSD against HF disease caused by the pathogenic rJUNV/Romero strain in the common marmoset (Callithrix jacchus) animal model of JUNV infection. Results from these studies will be correlated with immunogenicity data obtained from studies described in aim 2.

描述（由申请人提供）：几种体育症病毒会导致人类出血热（HF）疾病，并对其流行地区内的公共卫生构成严重威胁。因此，新世界竞技病毒Junin（JUNV）是阿根廷HF（AHF）的病因，是一种严重的疾病，患有出血和神经​​系统表现，病例死亡为15-30％。此外，JUNV非常稳定，被气溶胶高度感染力，并在低剂量下引起高发病率和死亡率，其特征使其非常适合作为潜在的生物武器。在美国缺乏许可的疫苗和当前的抗动脉粥样硬病毒疗法的担忧加剧了，仅限于使用核苷类模拟利巴韦林，这仅是部分有效的，并且可能引起明显的毒性。因此，针对JUNV的抗病毒药物的开发被认为是HHS公共卫生紧急医疗对策企业（PHEMCE）实施计划中的首要任务之一。因此，针对JUNV感染的医学对策有资格被Barda以战略性国家库存收购。我们已经开发了一种用于JUNV的反向遗传系统，并拯救了完全来自克隆的CDNA的念珠菌病和致病性Romero菌株的感染性病毒。这一进步为我们提供了独特的机会，可以在免疫原性和有效性研究中生成candid1（Rjunv/candid1csd）和Romero（Rjunv/Romero）菌株的遗传定义明确的种子。该建议旨在为Rjunv/Candid1CSD的稳定性，免疫原性和保护性质提供全面的特征，以此作为开发基于1的1个基于1的候选疫苗，能够满足能够满足未来FDA许可所需的安全性和功效标准。为此，我们提出以下具体目标： 1。确定RJUNV/candid1CSD的遗传和表型稳定性。我们建议生成和表征RCANDID1CSD的主要病毒种子（MVS）。我们将使用RCANDID1CSD的MV在不同的细胞底物中进行独立的串行通道，包括FDA认可的细胞系用于疫苗的生产。来自每个系列的选定段落的传染性后代将以遗传（基因组测序）和表型（生长特性和毒力）为特征。这些研究得出的遗传和表型信息将用于生成针对遗传和表型稳定性优化的新型RCANDID1菌株。 2。确定Rjunv/candid1csd在豚鼠中的安全性，免疫原性和功效。我们建议对豚鼠中遗传定义明确的MVS RCANDID1CSD的毒力进行全面评估。为此，我们将确定与RCANDID1CSD免疫相关的临床参数，包括：体温和体重，整体活性，涵盖肾脏和肝功能的血液学和临床病理数据评估以及对JUNV致命挑战的保护。这些研究还将包括旨在评估MVS遗传和表型稳定性的研究中鉴定出的相关病毒变异。 3。确定RJUNV/candid1CSD对公共果棒中JUNV的功效（Callithrix jacchus）。我们建议评估RJUNV/CANDID1CSD对HF疾病的保护性疗效，该疾病是由常见的Marmoset（Callithrix Jacchus）JunV感染模型中的致病性Rjunv/Romero菌株引起的。这些研究的结果将与AIM 2中描述的研究获得的免疫原性数据相关。