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

性状（由申请方提供）：沙粒病毒是一组快速增长的新型啮齿动物传播病毒。高致病性沙粒病毒，拉沙（LASV），Junun（JUNV）和Machupo（MACV），是世界上最流行的沙粒病毒，代表了对美国公共卫生的严重威胁。针对新出现的病原体开发安全有效的疫苗，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开发和可行性测试的第一个三价沙粒病毒疫苗，针对LASV，JUNV和MACV。三价疫苗是基于Medigen的VLPV（病毒样颗粒载体）技术。VLPV包含包封重组载体的繁殖缺陷型颗粒，所述重组载体用于递送和体内表达源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沙粒病毒的威胁，包括遏制非流行地区的疫情，以及为医务工作者、军事人员、旅行者和流行地区的人口接种疫苗。如果成功，VLPV多价疫苗平台也可作为其他传染病的通用方法。具体目的I：设计和制备表达沙粒病毒GPCs的三价VLPV疫苗。该目的的目标是（i）制备用于表达源自LASV、JUNV和MACV的全长GPC基因的三顺反子载体;（ii）制备用于LASV、JUNV和MACV的单独的单顺反子VLPV疫苗;（iii）将三顺反子或单顺反子载体包封到VLPV中，用于在体外和体内递送和表达沙粒病毒GPC;和（iv）优化和表征三顺反子和单顺反子VLPV疫苗的表达水平、稳定性和产量。特定目的II：三价沙粒病毒疫苗的临床前安全性和免疫原性评价。将使用在特定目的I中制备的重组三价沙粒病毒疫苗（三顺反子、单个疫苗或单个疫苗的混合组合）评价其在小鼠和豚鼠中的安全性和免疫原性，包括诱导稳健的CD 8 + T细胞和中和抗体（nAB）应答的能力。 公共卫生相关性：高致病性病毒拉沙病毒（LASV）、Junun病毒（JUNV）和Machupo病毒（MACV）是世界上最常见的沙粒病毒，对美国公共卫生构成严重威胁。该项目的主要目标是针对这些沙粒病毒的个体和三价疫苗的开发和可行性测试。成功的三价疫苗可用于控制非流行地区的疾病爆发，以及用于流行地区的医务工作者、军事人员、旅行者和人群的疫苗接种。如果成功，Medigen的多价疫苗平台也可以作为其他传染病的通用方法。

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.