Novel recombinant Rotavirus vaccine utilizing the probiotic microorganism Lactobacillus acidophilus

利用益生微生物嗜酸乳杆菌的新型重组轮状病毒疫苗

基本信息

批准号：
10411604
负责人：
Zaid Abdo
金额：
$ 1.14万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-13 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411604
关键词：
5 year old Address Adjuvant Affect Age Agonist Animals Antibiotic Resistance Antibody Response Antigens Attenuated Attenuated Vaccines Biological Assay CRISPR/Cas technology Capsid Capsid Proteins Cause of Death Cells Cessation of life Child Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cold Chains Country Data Developed Countries Developing Countries Development Disease Engineering Epitopes Family suidae Flagellin Genome Gnotobiotic Hospitalization Human Immune response Immunization Immunize Immunoglobulin A Inbred BALB C Mice Individual Infant Injections Intussusception Knowledge Lactobacillus acidophilus Length Licensure M cell Modeling Morbidity - disease rate Mucosal Immune Responses Mucous Membrane Mus Oral Organism Pathogenicity Peptides Populations at Risk Probiotics Proteins Recombinants Risk Rotavirus Rotavirus Infections Rotavirus Vaccines Rotavirus disease Safety Subunit Vaccines System Technology Testing Transplantation Vaccines Viral Virulence Virus Virus Replication World Health Organization base comparative efficacy diarrheal disease enteric pathogen fecal microbiome gastrointestinal immune activation immunogenic immunogenicity innovation interest microbiome microorganism mortality mouse model mucosal vaccine neutralizing antibody next generation novel novel vaccines oral vaccine porcine model programs resistance gene vaccination protocol vaccine access vaccine candidate vaccine delivery vaccine platform vaccine strategy

项目摘要

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.

项目摘要 /摘要利用益生菌微生物乳杆菌嗜酸菌的新型重组轮状病毒疫苗尽管在2006年获得了两种轮状病毒疫苗的全球许可和可用性，但据估计轮状病毒每年杀死约215,000名儿童。发展中国家5岁以下的儿童是由于目前可用的疫苗较低，因此可能受到严重轮状病毒疾病的影响更大的可能性与发达国家（> 85％）相比，功效（50-60％）。持续的发病率和死亡率以及当前的活疫苗带来的风险，需要开发下一代人轮状病毒疫苗。我们已经开发了一种口服粘膜疫苗平台，该平台采用了乳酸杆菌嗜酸菌。我们将创新的辅助和抗原表达策略汇集在一起具有诱导强大粘膜和全身免疫反应的潜力的结构。这个平台提供几个重要的可行性优势，因为它采用了指定为GRA的共生（通常 FDA被认为是安全的，价格便宜，不需要冷链，而且是无用的。我们将利用一种新型的CRISPR-CAS9系统，该系统适用于嗜酸乳杆菌，以工程师的复杂疫苗构建体将使用同型小鼠轮状病毒挑战进行测试。同型和异型中和的诱导抗体将使用一种新颖的高敏感测定法进行评估。我们将评估疫苗菌株定植以及对微生物组的潜在脱靶影响。最后，我们将直接比较我们的RLA 轮状病毒疫苗针对gnotobiotic猪模型中的人类活疫苗使用动物用人类婴儿粪便微生物组移植。将确定针对人轮状病毒挑战的功效。这些拟议的研究完成后，我们旨在让RLA构造准备向人类发展临床试验。