Trivalent Arenaviral Vaccine Based on Virus-Like Particle Vectors (VLPVs)

描述（由申请人提供）：沙粒病毒是一种快速增长的新型啮齿动物传播病毒。高致病性沙病毒，拉沙（LASV）， Junun （JUNV）和Machupo (MACV)，是世界上最流行的沙病毒，代表了对美国公共卫生的新严重威胁。开发安全有效的新发病原体疫苗，特别强调多价策略和先进的平台技术，是NIH/NIAID的首要任务之一。该项目的主要目标是研制第一种针对LASV、JUNV和MACV的三价沙粒病毒疫苗并进行可行性测试。这种三价疫苗基于美迪根的VLPV（病毒样颗粒载体）技术。vlpv包含有繁殖缺陷的颗粒，它们包裹着重组载体，用于在体内传递和表达来自三种沙粒病毒的全长糖蛋白（GPC）基因。拟议的三价疫苗将保护人们免受世界上主要的沙粒病毒威胁，包括控制非流行地区的疫情，以及为医疗工作者、军事人员、旅行者和流行地区的人口接种疫苗。如果成功，VLPV多价疫苗平台也可以作为其他传染病的通用方法。特异性目的一：设计和制备表达沙粒病毒GPCs的三价VLPV疫苗。本研究的目的是：(1)制备三顺反子载体，用于表达LASV、JUNV和MACV衍生的全长GPC基因；（ii）制备LASV、JUNV和MACV单顺反子VLPV单株疫苗；（iii）将三或单顺反电子载体包封到vlpv中，在体外和体内递送和表达沙粒病毒性GPCs；（iv）优化和表征三反式和单反式VLPV疫苗的表达水平、稳定性和产量。特异性目的II：三价沙粒病毒疫苗的临床前安全性和免疫原性评价。在Specific Aim I中制备的重组三价沙粒病毒疫苗（三顺反子、单个或单个疫苗的混合组合）将用于评估其在小鼠和豚鼠中的安全性和免疫原性，包括诱导强大的CD8+ T细胞和中和抗体（nAB）反应的能力。

DESCRIPTION (provided by applicant): Arenaviruses represent a rapidly growing group of emerging rodent-borne viruses. Highly pathogenic arenaviruses, Lassa (LASV), Junun (JUNV), and Machupo (MACV), are the most prevalent arenaviruses in the world that represent the emerging severe threat to the U.S. public health. The development of safe and efficacious vaccines against emerging pathogens with particular emphasis on multivalent strategy and advanced platform technology is one of the top priorities of NIH/NIAID. The main goal of this project is the development and feasibility testing of the first trivalent arenaviral vaccine against LASV, JUNV, and MACV. The trivalent vaccine is based on Medigen's VLPV (virus-like-particle-vector) technology. VLPVs comprise propagation-defective particles that encapsulate recombinant vector for delivery and expression in vivo of the full-length glycoprotein (GPC) genes derived from three arenaviruses. The proposed trivalent vaccine would protect populations from the world's major arenavirus threats, including containment of the outbreaks in non-endemic areas, as well as vaccination of medical workers, military personnel, travelers, and population in endemic areas. If successful, VLPV polyvalent vaccine platform can also be used as a generic approach for other infectious diseases. SPECIFIC AIM I: Design and Preparation of Trivalent VLPV Vaccine Expressing Arenaviral GPCs. The goal of this aim is (i) to prepare a tri-cistronic vector for expression of the full-length GPC genes derived from LASV, JUNV, and MACV; (ii) to prepare individual monocistronic VLPV vaccines for LASV, JUNV, and MACV; (iii) encapsulate tri- or monocistronic vectors into VLPVs for delivery and expression of arenaviral GPCs in vitro and in vivo; and (iv) to optimize and characterize expression levels, stability, and production yields of tri- and monocistronic VLPV vaccines. SPECIFIC AIM II: Preclinical Safety and Immunogenicity Evaluation of Trivalent Arenavirus Vaccines. Recombinant trivalent arenavirus vaccine prepared in Specific Aim I (tri-cistronic, individual, or blended combination of individual vaccines) will be used to evaluate their safety and immunogenicity in mice and guinea pigs including the ability to induce robust CD8+ T cell and neutralizing antibody (nAB) responses. PUBLIC HEALTH RELEVANCE: Highly pathogenic viruses, Lassa (LASV), Junun (JUNV), and Machupo (MACV) represent the world's most common arenaviruses and an emerging severe threat for the U.S. public health. The main goal of this project is the development and feasibility testing of the individual and trivalent vaccines against these arenaviruses. The successful trivalent vaccine can be used for the containment of disease outbreaks in non-endemic areas, as well as for vaccination of medical workers, military personnel, travelers, and population in endemic areas. If successful, Medigen's polyvalent vaccine platform can also be used as a generic approach for other infectious diseases.