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：
9886606
负责人：
Zaid Abdo
金额：
$ 69.15万
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/9886606
关键词：
5 year old Address Adjuvant Affect Age Agonist Animals Antibiotic Resistance Antibody Response Antigens Attenuated Attenuated Live Virus Vaccine 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 Protocols documentation Recombinants Risk Rotavirus Rotavirus Infections Rotavirus Vaccines Rotavirus disease Safety Subunit Vaccines System Technology Testing Transplantation Vaccination 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 programs resistance gene vaccine candidate

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.

项目概要/摘要利用益生微生物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许可并可供使用，但据估计，轮状病毒每年约有 215,000 名儿童死亡。发展中国家 5 岁以下儿童由于目前可用的疫苗具有较低的感染率，因此更容易受到严重轮状病毒病的影响与发达国家 (>85%) 相比，疗效 (50-60%)。持续的发病率和死亡率以及当前减毒活疫苗带来的风险，需要开发下一代人类疫苗轮状病毒疫苗。我们开发了一种采用乳酸菌的口服粘膜疫苗平台嗜酸菌。我们以独特的方式汇集了创新的佐剂和抗原表达策略具有诱导强烈粘膜和全身免疫反应潜力的构建体。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 的共生体（通常被 FDA 认为是安全的），生产成本低廉，不需要冷链，并且是无针头。我们将利用适合嗜酸乳杆菌的新型 CRISPR-Cas9 系统来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。同型和异型中和的诱导将使用一种新颖的、高灵敏度的测定法来评估抗体。我们将评估疫苗株定植情况以及对微生物组的潜在脱靶影响。最后，我们将对 rLA 进行直接比较在动物限生猪模型中针对人类减毒活疫苗的轮状病毒疫苗移植了人类婴儿粪便微生物组。将确定针对人类轮状病毒攻击的功效。在完成这些拟议的研究后，我们的目标是让 rLA 构建体准备好用于人类临床试验。