Mucosal live vector vaccine against recurrent Clostridium difficile infections

针对复发性艰难梭菌感染的粘膜活载体疫苗

• 批准号: 8435947
• 负责人: James E Galen
• 金额: $ 36.07万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435947
• 关键词: Adherence; Antibiotic Therapy; Antibiotics; Antibody Formation; Antigens; Attenuated; Bacterial Vaccines; Binding; Cause of Death; Cells; Clinical Trials; Clostridium difficile; Development; Dose; Engineering; Enterotoxins; Epidemic; Escherichia coli; Flagella; Future; Genes; Genetic Engineering; Human; Immune response; Immune system; Immunity; Infection; Lethal Dose 50; Life; Lipopolysaccharides; Modeling; Mus; Oral; Patients; Plasmids; Proteins; Recurrence; Recurrent disease; Relapse; Reproduction spores; Research; Safety; Salmonella typhi; Serum; Site; Synthetic Genes; System; Techniques; Technology; Testing; Toxin; Vaccines; Viral; Work; attenuation; base; flexibility; holotoxins; immunogenic; immunogenicity; improved; innovation; nonhuman primate; novel; oral vaccine; pathogen; public health relevance; research study; response; success; vaccination strategy; vaccine development; vaccine safety; vector; vector vaccine; vector-based vaccine

DESCRIPTION (provided by applicant): Bacterial live vector vaccines represent a vaccine development strategy that offers exceptional flexibility. In this approach, genes that encode foreign antigens of unrelated bacterial, viral or parasitic pathogens are expressed in an attenuated bacterial vaccine strain that delivers these foreign antigens to the immune system, thereby eliciting relevant immune responses. Significant progress has been made in the development of attenuated Salmonella enterica serovar Typhi live vector vaccines. Advances have been made in genetically stabilized expression plasmids, antigen export systems to improve foreign antigen-specific immunity, and the establishment of intranasal models in both mice and non-human primates for characterizing mucosal, humoral, and cellular immune responses to these live vectors. Of critical importance to future clinical trials, non-antibiotic plasmid selection systems have recently been engineered to improve the safety of these vaccines. The broad hypothesis of this research plan is that by appropriate manipulation of the Salmonella enterica serovar Typhi live vector platform technologies, we can construct a mucosally administered multivalent vaccine to immunize against recurrent Clostridium difficile infections (RCDI). To accomplish this, we will engineer within a single strain both non-antibiotic plasmid-based and novel chromosomal expression systems to express in concert the non-toxic cell-binding domains of three C. difficile toxins; enterotoxins A and B and binary toxin. The immunogenicity of this live vector strain will be determined using a murine intranasal model of immunogenicity, and a vaccination strategy based on a heterologous prime/boost approach in which the host is immunized sequentially with C. difficile antigens delivered both using live vectors and as purified proteins. Promising candidates eliciting antibody responses against all three C. difficile antigens will be further tested for protection in mice similarly immunized with he multivalent strain and challenged orogastrically with spores from an epidemic strain of C. difficile.

描述（由申请人提供）：细菌活载体疫苗代表了一种具有非凡灵活性的疫苗开发策略。在这种方法中，编码无关细菌、病毒或寄生病原体的外来抗原的基因在减毒细菌疫苗株中表达，该疫苗株将这些外来抗原递送至免疫系统，从而引发相关的免疫反应。减毒肠沙门氏菌伤寒活载体疫苗的开发取得了重大进展。在遗传稳定表达质粒、改善外来抗原特异性免疫的抗原输出系统以及在小鼠和非人灵长类动物中建立鼻内模型以表征对这些活载体的粘膜、体液和细胞免疫反应方面已经取得了进展。对于未来的临床试验至关重要，最近设计了非抗生素质粒选择系统以提高这些疫苗的安全性。该研究计划的广泛假设是，通过适当操作伤寒沙门氏菌血清型活载体平台技术，我们可以构建一种粘膜给药的多价疫苗，以针对复发性艰难梭菌感染（RCDI）进行免疫。为了实现这一目标，我们将在单一菌株中设计基于非抗生素质粒的新型染色体表达系统，以一致表达三种艰难梭菌毒素的无毒细胞结合域；肠毒素A和B以及二元毒素。该活载体菌株的免疫原性将使用免疫原性的鼠鼻内模型和基于异源初免/加强方法的疫苗接种策略来确定，其中使用活载体和纯化蛋白递送的艰难梭菌抗原依次对宿主进行免疫。引发针对所有三种艰难梭菌抗原的抗体反应的有前途的候选物将在用多价菌株进行类似免疫并用来自艰难梭菌流行菌株的孢子进行口胃攻击的小鼠中进一步测试其保护作用。