Development of Recombinant SARS VLP Vaccines

重组SARS VLP疫苗的研制

• 批准号: 6835240
• 负责人: Gale Smith
• 金额: $ 26.07万
• 依托单位: NOVAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6835240
• 关键词: Baculoviridae; SARS virus; chromatography; cooperative study; drug design /synthesis /production; enzyme linked immunosorbent assay; glycoproteins; laboratory mouse; neutralizing antibody; recombinant virus; severe acute respiratory syndrome; tissue /cell culture; toxicology; ultracentrifugation; vaccine development; vaccine evaluation; virus protein; viruslike particle; western blottings

DESCRIPTION (provided by applicant): The objective of this grant proposal is to develop and manufacture preclinical and clinical lots of novel recombinant SARS subunit protein vaccines formulated with Novasome adjuvants for evaluation in small animal and primate challenge models to prevent SARS coronavirus infection and disease. This plan will develop three types of SARS vaccine candidates comprised of recombinant SARS coronavirus S, M, and E proteins, which have been codon-optimized, cloned, and expressed in baculovirus-infected insect cells at Novavax, Inc. Vaccine candidates include the following: (1) recombinant multiprotein immunogens displayed on Novasomes, (2) VLPs self-assembled in vivo, and (3) chimeric VLPs comprised of SARS viral proteins and human influenza virus hemagglutinin proteins. Vaccine immunogens, expressed in baculovirus-infected insect cells and/or CHO cells, will be purified by ultracentrifugation and chromatographic methods. Vaccine immunogens will be formulated with adjuvants and will be evaluated initially for mucosal and systemic immunogenicity in mice. Vaccine candidates that elicit SARS neutralizing antibodies in the murine immunogenicity model, as determined by microneutralization assays, will be evaluated further in a novel SARS mouse challenge model in collaboration with Dr. Kanta Subbarao (NIH), who recently developed the model. Preclinical lots of vaccine candidates that elicit neutralizing antibodies and reduce virus titers in the murine challenge model will be tested further in a SARS primate challenge model using cynomolgus monkeys in collaboration with Dr. James Estep (Battelle Institute) in their BSL3 primate facility. Finally, clinical lots of a SARS vaccine candidate that demonstrates the highest SARS neutralizing antibody titer and the greatest virus reduction in the primate challenge model will be manufactured and lot release tested. Toxicology studies of the SARS vaccine candidate will be conducted in rabbits. A clinical protocol for a Phase I clinical study will be prepared, and an IND application will be submitted to CBER/FDA.

描述（由申请人提供）：本拨款提案的目的是开发和生产临床前和临床批次的新型重组 SARS 亚基蛋白疫苗，采用 Novasome 佐剂配制，用于在小动物和灵长类动物攻击模型中进行评估，以预防 SARS 冠状病毒感染和疾病。该计划将开发三种类型的 SARS 候选疫苗，由重组 SARS 冠状病毒 S、M 和 E 蛋白组成，这些疫苗已在 Novavax, Inc. 的杆状病毒感染的昆虫细胞中进行密码子优化、克隆和表达。候选疫苗包括以下内容：(1) Novasomes 上展示的重组多蛋白免疫原，(2) VLP (3)由SARS病毒蛋白和人流感病毒血凝素蛋白组成的嵌合VLP。在杆状病毒感染的昆虫细胞和/或CHO细胞中表达的疫苗免疫原将通过超速离心和层析方法进行纯化。疫苗免疫原将与佐剂一起配制，并首先评估小鼠的粘膜和全身免疫原性。通过微量中和试验确定，在小鼠免疫原性模型中引发 SARS 中和抗体的候选疫苗将与最近开发出该模型的 Kanta Subbarao 博士 (NIH) 合作，在新型 SARS 小鼠攻击模型中进行进一步评估。在鼠类攻击模型中引发中和抗体并降低病毒滴度的大量临床前候选疫苗将与 James Estep 博士（巴特尔研究所）在其 BSL3 灵长类动物设施中合作，使用食蟹猴在 SARS 灵长类动物攻击模型中进行进一步测试。最后，将生产临床批次的 SARS 候选疫苗，并在灵长类动物攻击模型中表现出最高的 SARS 中和抗体滴度和最大的病毒减少量，并进行批次发布测试。 SARS候选疫苗的毒理学研究将在兔子身上进行。将制定 I 期临床研究的临床方案，并向 CBER/FDA 提交 IND 申请。