Novel recombinant Rotavirus vaccine utilizing the probiotic microorganism Lactobacillus acidophilus

项目总结/摘要 利用益生菌嗜酸乳杆菌的新型重组轮状病毒疫苗 尽管2006年两种轮状病毒疫苗在世界范围内获得了许可证和供应，但据估计， 每年杀死大约215，000名儿童。发展中国家5岁以下的儿童是 更有可能受到严重轮状病毒病的影响，因为目前可用的疫苗 有效性（50-60%），与发达国家（>85%）相比。目前的发病率和死亡率以及 目前的减毒活疫苗所带来的风险，需要开发下一代人类疫苗。 轮状病毒疫苗我们开发了一种口服粘膜疫苗平台， 嗜酸乳杆菌我们将创新的佐剂和抗原表达策略结合在一起， 构建体，其具有经证实的诱导稳健的粘膜和全身免疫应答的潜力。这个平台 提供了几个重要的可行性优势，因为它采用了指定为GRAS（一般 被FDA认为是安全的），生产成本低，不需要冷链，并且是无针的。我们将 利用适应L.设计复杂的疫苗结构， 将使用同型小鼠轮状病毒攻击进行测试。诱导同型和异型中和 将使用新的、高灵敏度的测定来评估抗体。我们将评估疫苗株定植 以及对微生物组的潜在脱靶效应。最后，我们将直接比较我们的rLA 轮状病毒疫苗在使用动物的无菌猪模型中对抗人活减毒疫苗 移植了人类婴儿粪便微生物组。将确定抗人轮状病毒攻毒的有效性。 在完成这些拟议的研究，我们的目标是有一个rLA构建准备进行人类 临床试验

PROJECT SUMMARY / ABSTRACT Novel recombinant Rotavirus vaccine utilizing the probiotic microorganism Lactobacillus acidophilus Despite the worldwide licensure and availability of two rotavirus vaccines in 2006, it is estimated that rotavirus kills approximately 215,000 children each year. Children under the age of 5 in developing countries are significantly more likely to be affected by severe rotavirus disease as the currently available vaccines have lower efficacy (50-60%) as compared to developed nations (>85%). The ongoing morbidity and mortality as well as the risk posed by current live-attenuated vaccines, necessitate the development of a next generation human rotavirus vaccine. We have developed an orally-delivered, mucosal vaccine platform that employs Lactobacillus acidophilus. We have brought together innovative adjuvant and antigen-expression strategies in unique constructs with demonstrated potential to induce robust mucosal and systemic immune responses. This platform offers several important feasibility advantages as it employs a commensal designated as GRAS (generally regarded as safe) by the FDA, is inexpensive to produce, does not require cold-chain, and is needleless. We will utilize a novel CRISPR-Cas9 system adapted to L. acidophilus to engineer sophisticated vaccine constructs that will be tested using a homotypic mouse rotavirus challenge. Induction of homotypic and heterotypic neutralizing antibodies will be assessed using a novel, highly sensitive assay. We will assess vaccine strain colonization and potential off-target effects on the microbiome. Finally, we will perform a direct comparison of our rLA rotavirus vaccine against a human live attenuated vaccine in the gnotobiotic pig model using animals transplanted with human infant fecal microbiome. Efficacy against human rotavirus challenge will be determined. At the completion of these proposed studies, we aim to have a rLA construct ready to proceed toward human clinical trials.