Development of Recombinant SARS VLP Vaccines

描述(申请人提供)：这项资助计划的目标是开发和制造大量使用Novasome佐剂配制的新型重组SARS亚单位蛋白疫苗，用于在小动物和灵长类挑战模型中评估预防SARS冠状病毒感染和疾病的能力。该计划将开发由重组SARS冠状病毒S、M和E蛋白组成的三种SARS候选疫苗，它们已被密码子优化、克隆并在Novavax公司感染杆状病毒的昆虫细胞中表达。候选疫苗包括：(1)展示在新体上的重组多蛋白免疫原；(2)在体内自组装的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法和层析法进行纯化。疫苗免疫原将与佐剂一起配制，并将首先评估小鼠的粘膜和系统免疫原性。在小鼠免疫原性模型中诱发SARS中和抗体的候选疫苗将在一种新的SARS小鼠挑战模型中与最近开发该模型的坎塔·苏巴拉奥博士合作进行进一步评估。许多在小鼠挑战模型中产生中和抗体并降低病毒滴度的临床前候选疫苗将在SARS灵长类挑战模型中与食蟹猴博士在他们的BSL3灵长类设施中进行进一步测试。最后，将生产临床批量的SARS疫苗候选，证明在灵长类攻击模型中具有最高的SARS中和抗体效价和最大的病毒减少率，并进行批量释放测试。SARS候选疫苗的毒理学研究将在兔子身上进行。将准备一项I期临床研究的临床方案，并向CBER/FDA提交IND申请。

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.