Recombinant life attenuated vaccine against Argentine hemorrhagic fever

阿根廷出血热重组减毒疫苗

• 批准号: 8076684
• 负责人: Slobodan Paessler
• 金额: $ 90.18万
• 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/8076684
• 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; 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）：几种沙粒病毒会引起人类出血热（HF）疾病，并对其流行地区的公共卫生构成严重威胁。因此，新世界沙粒病毒胡宁 (JUNV) 是阿根廷 HF (AHF) 的病原体，这是一种具有出血和神经​​系统表现的严重疾病，病死率为 15-30%。此外，JUNV非常稳定，通过气溶胶具有高度传染性，低剂量时会导致高发病率和死亡率，这些特点使其非常适合作为潜在的生物武器。由于美国缺乏获得许可的疫苗，并且目前的抗沙粒病毒疗法仅限于使用核苷类似物利巴韦林，这加剧了人们对沙粒病毒感染的担忧，而利巴韦林仅部分有效，并可能引起显着的毒性。因此，开发针对 JUNV 的抗病毒药物已被视为 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 感染的医疗对策有资格被 BARDA 采购用于国家战略储备。我们为 JUNV 开发了反向遗传系统，并完全从克隆的 cDNA 中拯救了感染性病毒，包括 Candid1 和致病性 Romero 毒株。这一进展为我们提供了独特的机会来生成遗传明确的 Candid1 (rJUNV/Candid1cSD) 和 Romero (rJUNV/Romero) JUNV 菌株种子，用于免疫原性和功效研究。该提案旨在提供 rJUNV/Candid1cSD 的稳定性、免疫原性和保护特性的全面表征，作为开发基于 Candid 1 的疫苗的第一步也是必要的一步，该疫苗能够满足未来 FDA 许可所需的安全性和有效性标准。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。我们建议生成并表征 rCandid1cSD 的主病毒种子 (MVS)。我们将使用 rCandid1cSD 的 MVS 在不同的细胞基质中进行独立的连续传代，包括 FDA 批准的用于疫苗生产的细胞系。来自每个系列的选定传代的感染性后代将在遗传学（基因组测序）和表型（生长特性和毒力）上进行表征。从这些研究中获得的遗传和表型信息将用于生成针对遗传和表型稳定性进行优化的新型 rCandid1 菌株。 2. 确定rJUNV/Candid1cSD在豚鼠中的安全性、免疫原性和有效性。我们建议对我们基因明确的 MVS rCandid1cSD 在豚鼠中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、总体活性、涵盖肾和肝功能的血液学和临床病理学数据评估，以及针对 JUNV 致命攻击的保护。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发现的相关病毒变体。 3. 确定 rJUNV/Candid1cSD 对普通狨猴 (Callithrix jacchus) 中 JUNV 的功效。我们建议在 JUNV 感染的普通狨猴 (Callithrix jacchus) 动物模型中评估 rJUNV/Candid1cSD 对致病性 rJUNV/Romero 菌株引起的 HF 疾病的保护功效。这些研究的结果将与目标 2 中描述的研究获得的免疫原性数据相关联。