Scientific Core: Animal Models

项目摘要 尽管近年来在治疗方面取得了进展，但艾滋病毒仍造成50多万人死亡 此外，新感染病例继续超过公共卫生机构设定的里程碑。 最近，许多基于生殖系靶向或表位聚焦的候选免疫原已经被发现。 进入第一阶段临床试验。艾滋病毒疫苗学的这些发展得到了以下方面的极大帮助： 用于产生人源化小鼠模型的改进技术，其可用于迭代 免疫原设计、早期向下选择和疫苗开发的其他重要组成部分。 这些改进包括多重CRISPR/Cas9双重免疫球蛋白重链和轻链。 knockins（KI）是巴蒂斯塔实验室开发的。通过这种方法，携带真正人类BCR的B细胞的小鼠， 它可以在几周内生产出来。在这里，巴蒂斯塔实验室建议使用这种方法及其 动物实验方面的专业知识，作为多组学疫苗评估的动物模型核心（AMC） （MOVE）Consortium. AMC将根据MOVE对天真的询问开发多达六个新的KI系列 人B细胞库。此外，AMC还将为免疫接种提供其现有的艾滋病毒模型。 由MOVE Project 1发起的实验。从鼠淋巴、脾和其他组织产生的样品将 然后提供给MOVE Project 2进行免疫表征。AMC将作为Prime和 加强阶段免疫原、制剂和方案开发和评估。

PROJECT SUMMARY Despite advances in treatment in recent years, HIV is still responsible for more than half a million deaths annually; new infections have, furthermore, continued to exceed the milestones set by public health institutions. Recently, a number of candidate immunogens based on either germline targeting or epitope focusing have moved to Phase 1 clinical trials. These developments in HIV vaccinology have been immensely aided by improved technology for the generation of humanized mouse models, which can be used in iterative immunogen design, early stage down-selection, and other important components of vaccine development. Among those improvements include the multiplexed CRISPR/Cas9 dual immunoglobulin heavy and light chain knockins (KI) developed by the Batista lab. With this approach, mice with B cells bearing genuine human BCRs, which can be produced in a matter of weeks. Here, the Batista lab proposes to use this approach and its expertise in animal experiments to act as the Animal Model Core (AMC) for the Multi-Omics Vaccine Evaluation (MOVE) Consortium. The AMC will develop up to six new KI lines based on MOVE's interrogation of the naïve human B cell repertoire. The AMC will furthermore contribute its existing HIV models to immunization experiments initiated by MOVE Project 1. Samples generated from murine lymph, spleen, and other tissues will then be provided to MOVE Project 2 for immunocharacterization. The AMC will act as the fulcrum of prime and boost stage immunogen, formulation, and regiment development and assessment.