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

基于病毒样颗粒载体（VLPV）的三价沙粒病毒疫苗

• 批准号: 8199831
• 负责人: Peter M. Pushko
• 金额: $ 22.21万
• 依托单位: MEDIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199831
• 关键词: Advanced Development; Affect; Africa; Alphavirus; Animals; Antibody Formation; Area; Arenavirus; Attenuated; Attenuated Live Virus Vaccine; Bolivian Hemorrhagic Fever Virus; CD8B1 gene; Categories; Cavia; Cessation of life; Characteristics; Communicable Diseases; Containment; Data; Defective Viruses; Development; Disease Outbreaks; Ebola virus; Encapsulated; Equilibrium; Evaluation; Filovirus; Frankfurt-Marburg Syndrome Virus; Frequencies; Generic Drugs; Genes; Genetic; Genotype; Geographic Distribution; Glycoproteins; Goals; Human; Immunization; In Vitro; Individual; International; Junin virus; Lassa Fever; Lassa virus; Legal patent; Length; Licensing; Life; Medical; Military Personnel; Mono-S; Mus; National Institute of Allergy and Infectious Disease; Old World Arenaviruses; Phase; Polyvalent Vaccine; Population; Preparation; Preventive; Production; Proteins; Public Health; Recombinants; Research; Risk; Rodent; Safety; Small Business Innovation Research Grant; System; T-Lymphocyte; Tacaribe Complex Viruses; Technology; Testing; Travel; United States National Institutes of Health; Vaccination; Vaccines; Viral; Viral Hemorrhagic Fevers; Virulent; Virus; Virus Inactivation; Virus-like particle; base; climate change; design; environmental change; expression vector; human migration; immunogenicity; in vivo; interest; killings; neutralizing antibody; new technology; nonhuman primate; novel; particle; pathogen; preclinical safety; protective efficacy; vector; vector vaccine; vector-based vaccine

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.

描述（由申请人提供）：沙粒病毒代表了一组快速增长的新兴啮齿动物传播病毒。高致病性沙粒病毒，拉沙病毒 (LASV)、朱努病毒 (JUNV) 和马丘波病毒 (MACV) 是世界上最流行的沙粒病毒，对美国公共卫生构成了新的严重威胁。开发针对新兴病原体的安全有效的疫苗，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第一个针对 LASV、JUNV 和 MACV 的三价沙粒病毒疫苗并进行可行性测试。三价疫苗基于 Medigen 的 VLPV（病毒样颗粒载体）技术。 VLPV 包含繁殖缺陷型颗粒，其封装重组载体，用于体内递送和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爆发，以及为流行地区的医务人员、军事人员、旅行者和民众接种疫苗。如果成功，VLPV多价疫苗平台还可以用作其他传染病的通用方法。具体目标 I：表达沙粒病毒 GPC 的三价 VLPV 疫苗的设计和制备。该目标的目标是 (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 LASV、JUNV 和 MACV 的单顺反子 VLPV 疫苗； (iii) 将三顺反子或单顺反子载体封装到 VLPV 中，用于在体外和体内递送和表达沙粒病毒 GPC； (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。具体目标 II：三价沙粒病毒疫苗的临床前安全性和免疫原性评估。在 Specific Aim I（三顺反子、单独疫苗或单独疫苗的混合组合）中制备的重组三价沙粒病毒疫苗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。 公共卫生相关性：高致病性病毒拉沙病毒 (LASV)、朱努病毒 (JUNV) 和马丘波病毒 (MACV) 是世界上最常见的沙粒病毒，对美国公共卫生构成新的严重威胁。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暴发，也可用于流行地区医务人员、军事人员、旅行者和人群的疫苗接种。如果成功，Medigen 的多价疫苗平台还可以用作其他传染病的通用方法。