Scientific Core: Animal Models

项目总结 尽管近年来在治疗方面取得了进展，但艾滋病毒仍导致50多万人死亡 每年；此外，新感染人数继续超过公共卫生机构设定的里程碑。 最近，一些基于种系靶向或表位聚焦的候选免疫原已经 转移到第一阶段临床试验。艾滋病毒疫苗学的这些发展在很大程度上得到了 改进了生成人性化老鼠模型的技术，可以在迭代中使用 免疫基因设计、早期向下选择以及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 敲门人(KI)由巴蒂斯塔实验室开发。通过这种方法，带有B细胞的小鼠携带真正的人BCR， 它可以在几周内生产出来。在这里，巴蒂斯塔实验室提议使用这种方法和它的 动物实验专业知识作为多组学疫苗评价的动物模型核心(AMC) (移动)财团。AMC将根据Move对天真的审问开发最多六条新的KI系列 人类B细胞谱系。AMC将进一步将其现有的艾滋病毒模型用于免疫接种 由Move Project 1发起的实验。从小鼠淋巴、脾和其他组织中产生的样本将 然后被提供来移动项目2以进行免疫鉴定。AMC将作为素数和 促进阶段免疫原、配方和团的发展和评估。

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.