RSV Nanocapsule Vaccine Engineered with a G Protein Peptide Payload

采用 G 蛋白肽有效负载设计的 RSV 纳米胶囊疫苗

• 批准号: 8450155
• 负责人: RALPH A TRIPP
• 金额: $ 52.82万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450155
• 关键词: Affect; Amino Acids; Antibodies; Antibody Formation; Antigen-Presenting Cells; Attenuated Vaccines; B-Lymphocytes; Base Sequence; Binding; Biological Assay; Blocking Antibodies; CX3C Chemokines; CX3CL1 gene; Cells; Child; Custom; Cysteine; Disease; Elderly; Embryo; Engineering; Epitopes; Evaluation; Frequencies; Functional disorder; GTP-Binding Proteins; Goals; Human; Humoral Immunities; Immune; Immune response; Immunity; Infant; Infection; Inflammatory Response; Leukocytes; Lower respiratory tract structure; Lung; Mediating; Memory; Modification; Mucous body substance; Mus; Pathogenesis; Peptides; Play; Positioning Attribute; Principal Investigator; Protein Region; Recombinant Delta Chemokine; Research; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Respiratory syncytial virus; Role; Safety; Subunit Vaccines; T cell response; T-Lymphocyte; Technology; Time; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Virus Diseases; base; chemokine receptor; comparative; cytokine; design; immunogenicity; immunoregulation; improved; innovation; kidney cell; migration; mimicry; mouse model; nanocapsule; neutralizing antibody; novel; peptide G; polypeptide; prevent; programs; response; vaccine candidate; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract illness in infants and the elderly. Currently, no safe and efficacious RSV vaccine exists. Advances in our understanding of immunity and disease pathogenesis associated with infection have shown that RSV G protein contains a CX3C chemokine motif that interacts with the CX3CR1 chemokine receptor, modifies the activities of CX3CL1, and affects aspects of immunity and disease pathogenesis. Antibodies directed to the CX3C motif inhibit G protein CX3C-CX3CR1 interaction and reduce disease pathogenesis. The long- term goal of our research is to develop a novel nanocapsule vaccine engineered to carry a RSV G protein polypeptide that we have previously shown to induce neutralizing and disease protective antibody. The nanocapsule technology is attractive for vaccine development as it targets professional antigen- presenting cells which we have shown to improve the immunogenicity of both T cell and antibody target epitopes. The proposal will take advantage of well-defined assays and a mouse model to: (1) Identify the optimal CX3C motif vaccine antigen sequence based on G polypeptide vaccination of mice and evaluation of G protein CX3C-CX3CR1 blocking antibody responses, (2) Construct nanocapsule vaccine candidates with the appropriate G polypeptide and demonstrate immunogenicity and protection in a mouse model, (3) Use optimized, efficacious nanocapsule vaccines to further understand the disease modifying effect of antibodies that block G protein CX3C-CX3CR1 interaction and disease pathogenesis, 4) Evaluate parameters of safety and duration of vaccine efficacy in the memory response to (G peptide nanocapsule vaccination and RSV challenge, and (5) Evaluate the safety and efficacy of G peptide nanocapsule vaccine in the context of pre-existing RSV immunity. The proposed research is innovative because it will identify regions in the RSV G protein that induce antibodies which neutralize infection and block RSV disease, incorporate the optimal polypeptide in an novel nanocapsule-based vaccine candidate that targets antigen-presenting cells, and will provide long-term protection against RSV strains. Respiratory syncytial virus is the most important cause of sever lower respiratory tract illness in infants and the elderly. Currently, no safe and efficacious RSV vaccine exists. The long-term goal of our research is to develop a novel nanocapsule vaccine engineered to carry a RSV G protein polypeptide that we have previously shown to induce neutralizing and disease protective antibody.

描述（由申请人提供）： 呼吸道合胞病毒（RSV）是婴儿和老年人严重下呼吸道疾病的最重要原因。目前，还没有安全有效的RSV疫苗。我们对与感染相关的免疫和疾病发病机制的理解的进展表明，RSV G蛋白含有CX 3C趋化因子基序，其与CX 3CR 1趋化因子受体相互作用，修饰CX 3CL 1的活性，并影响免疫和疾病发病机制的各个方面。针对CX 3C基序的抗体抑制G蛋白CX 3C-CX 3CR 1相互作用并减少疾病发病机制。我们研究的长期目标是开发一种新的纳米疫苗，该疫苗被工程化以携带RSV G蛋白多肽，我们先前已经证明该多肽可以诱导中和和疾病保护性抗体。纳米胶囊技术对于疫苗开发是有吸引力的，因为它靶向专职抗原呈递细胞，我们已经显示其改善T细胞和抗体靶表位两者的免疫原性。该提案将利用明确定义的测定和小鼠模型来：（1）基于小鼠的G多肽疫苗接种和G蛋白CX 3C-CX 3CR 1阻断抗体应答的评价，鉴定最佳CX 3C基序疫苗抗原序列，（2）用适当的G多肽构建纳米帽疫苗候选物，并在小鼠模型中证明免疫原性和保护，（3）使用优化的，有效的纳米胶囊疫苗，以进一步了解阻断G蛋白CX 3C-CX 3CR 1相互作用和疾病发病机制的抗体的疾病修饰作用，4）评价记忆应答中疫苗功效的安全性和持续时间的参数，（G肽纳米帽疫苗接种和RSV攻击，和（5）在预先存在的RSV免疫的情况下评价G肽纳米帽疫苗的安全性和有效性。拟议的研究是创新的，因为它将确定RSV G蛋白中诱导中和感染和阻断RSV疾病的抗体的区域，将最佳多肽纳入靶向抗原呈递细胞的新型基于纳米胶囊的疫苗候选物中，并将提供长期保护针对RSV毒株。呼吸道合胞病毒是婴幼儿和老年人严重下呼吸道疾病的最重要原因。目前，还没有安全有效的RSV疫苗。我们研究的长期目标是开发一种新的纳米疫苗，该疫苗被工程化以携带RSV G蛋白多肽，我们先前已经证明该多肽可以诱导中和和疾病保护性抗体。