Optimization of a Self-Adjuvanting Particle System for Delivering Respiratory Syncytial Virus Prefusion Protein

用于输送呼吸道合胞病毒预融合蛋白的自我辅助颗粒系统的优化

基本信息

批准号：
10666079
负责人：
Kerry McGarr Empey
金额：
$ 22.67万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-02 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666079
关键词：
5 year old Acute Adjuvant Adult Alveolar Macrophages Antibodies Antibody Formation Antibody-mediated protection Antigen-Presenting Cells Antigens Avidin Biotin Biotinylation Breast Feeding CD8-Positive T-Lymphocytes CD8B1 gene Child Childhood Chimeric Proteins Clinical Trials Collaborations Communities Coupling Data Dendritic Cells Disease Dose Drug Delivery Systems Dyes Ensure Environment Equilibrium Exhibits Family Flow Cytometry Formulation Frequencies Generations Glycolates Half-Life Hospital Charges Hospitalization Immune response Immunity Immunization Immunize Immunoglobulin A Immunoglobulin G Inbred BALB C Mice Infant Infection Inflammation Injections Interferon Type II Interleukin-12 Intramuscular Intranasal Administration Kinetics Label Lead Letters Licensing Life Lipids Lower Respiratory Tract Infection Lung Maternal antibody Methods Molecular Molecular Conformation Morbidity - disease rate Mothers Mucous Membrane Mucous body substance Mus Nature Pharmacy (field)Phase Population Predisposition Prevention Production Property Protein Conformation Protein Engineering Proteins Quality of life Research Personnel Respiratory Disease Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Risk Reduction Safety Severities Site Solvents Structure Surface System T cell response Teenagers Testing Time Vaccination Vaccines Variant Viral Viral Antigens Wheezing aluminum sulfate burden of illness clinical development clinically relevant cytokine design immune activation immune activator immunogenicity improved in vivo innovation insight manufacture maternal outcome mortality mouse model nanoparticle nanovaccine neutralizing antibody novel novel vaccines particle pathogen pre-clinical preservation prototype response tissue resident memory T cell uptake vaccine candidate vaccine delivery vaccine development vaccine formulation vaccine platform

5 year old Acute Adjuvant Adult Alveolar Macrophages Antibodies Antibody Formation Antibody-mediated protection Antigen-Presenting Cells Antigens Avidin Biotin Biotinylation Breast Feeding CD8-Positive T-Lymphocytes CD8B1 gene Child Childhood Chimeric Proteins Clinical Trials Collaborations Communities Coupling Data Dendritic Cells Disease Dose Drug Delivery Systems Dyes Ensure Environment Equilibrium Exhibits Family Flow Cytometry Formulation Frequencies Generations Glycolates Half-Life Hospital Charges Hospitalization Immune response Immunity Immunization Immunize Immunoglobulin A Immunoglobulin G Inbred BALB C Mice Infant Infection Inflammation Injections Interferon Type II Interleukin-12 Intramuscular Intranasal Administration Kinetics Label Lead Letters Licensing Life Lipids Lower Respiratory Tract Infection Lung Maternal antibody Methods Molecular Molecular Conformation Morbidity - disease rate Mothers Mucous Membrane Mucous body substance Mus Nature Pharmacy (field)Phase Population Predisposition Prevention Production Property Protein Conformation Protein Engineering Proteins Quality of life Research Personnel Respiratory Disease Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Risk Reduction Safety Severities Site Solvents Structure Surface System T cell response Teenagers Testing Time Vaccination Vaccines Variant Viral Viral Antigens Wheezing aluminum sulfate burden of illness clinical development clinically relevant cytokine design immune activation immune activator immunogenicity improved in vivo innovation insight manufacture maternal outcome mortality mouse model nanoparticle nanovaccine neutralizing antibody novel novel vaccines particle pathogen pre-clinical preservation prototype response tissue resident memory T cell uptake vaccine candidate vaccine delivery vaccine development vaccine formulation vaccine platform

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项目摘要

In the US, RSV infects nearly 100% of children, and total associated hospital charges are estimated at approximately $2.5 billion dollars. Infants are most susceptible to severe RSV-related disease in the first six months of life. During this time, infants mount poorly protective antibody-mediated immunity on their own upon RSV infection or vaccination. Rather they veer toward Th2-type responses, which can cause disease- or vaccine- enhanced severity upon re-infection, and subsequent wheezing throughout childhood and into their teens. In recent years, promising maternal RSV vaccine candidates have progressed to clinical trials, but the window of protection to the infant remains limited to the half-life of the maternally-derived antibody (~1 month) or moderately longer if the mother is breast feeding. An RSV vaccine that protects infants beyond the first month of life or ameliorates the course of their respiratory disease, will (i) reduce the frequency of infant hospitalizations, (ii) improve the quality of life for infants, families, communities, and populations, and (iii) lessen disease burden on the US economy. In this multiple PI project, we seek to optimize and characterize a nanoparticle-based intranasal RSV vaccine platform with intrinsic adjuvant properties. The biodegradable biotin-nanoparticle system (referred to as bNP) functions as an antigen carrier and immune activator. Coupling antigen delivery and adjuvant properties into a single physical entity will enhance the capacity to overcome the inherent immunosuppressive environment of mucosal tissues. The particle system has a tunable design in which the dose of the antigen can be varied without remanufacturing. To ensure a Th-1 type response, we will use a variant RSV prefusion protein (preF) engineered to lock in the native conformation as the cargo antigen. We hypothesize that preF sterically stabilized on bNP (preF-bNP) will activate antigen-presenting cells to induce important correlates of protection, including RSV-specific Th1-dominant T cell response, CD8 resident memory T cells, and neutralizing antibody. Three specific aims are proposed. In Aim 1 we will optimize display of preF on bNP and capacity of the formulation to activate antigen presenting cells. In Aim 2 we will determine preF-bNP uptake kinetics into antigen presenting cells and preF-bNP-induced immunity in vivo, including resident memory T cells. In Aim 3 we will establish the safety and efficacy of intranasal preF-bNP in an RSV mouse model. Successful completion of the studies will lead pave the way for advancing a novel RSV vaccine formulation for generating safe and protective RSV immunity in young children.

在美国，RSV感染了近100％的儿童，并且估计相关的医院总费用约25亿美元。婴儿在前六个中最容易受到与RSV相关的严重疾病的影响生命的月份。在这段时间里，婴儿在此期间安装较差的保护性抗体介导的免疫 RSV感染或疫苗接种。相反，它们转向Th2型反应，这可能引起疾病或疫苗重新感染后的严重程度加强，随后在整个童年和青少年中喘息。在近年来，有前途的母亲RSV疫苗候选者已发展为临床试验，但是对婴儿的保护仅限于母体衍生的抗体（〜1个月）或中度的半衰期如果母亲在母乳喂养的情况下更长的时间。一种RSV疫苗，可保护婴儿生命的第一个月以上或缓解其呼吸道疾病的过程，（i）降低婴儿住院的频率，（ii）改善婴儿，家庭，社区和人口的生活质量，以及（iii）减轻疾病负担美国经济。在这个多重PI项目中，我们试图优化和表征基于纳米颗粒的鼻内RSV疫苗具有内在辅助特性的平台。可生物降解的生物素 - 纳米颗粒系统（称为BNP）充当抗原载体和免疫激活剂。将抗原递送和辅助特性耦合到单个物理实体将增强克服固有的免疫抑制环境的能力粘膜组织。粒子系统具有可调的设计，其中可以改变抗原的剂量，而无需再制造。为了确保TH-1型响应，我们将使用变体的RSV预灌注蛋白（PERF）工程作为货物抗原锁定本地构型。我们假设在BNP（PERF-BNP）上稳定在空间上的Pref将激活抗原呈递细胞以诱导重要保护的重要相关性，包括RSV特异性Th1主导T细胞响应，CD8居民记忆t 细胞和中和抗体。提出了三个具体目标。在AIM 1中，我们将优化PREF的显示 BNP和制剂的能力激活抗原呈递细胞。在AIM 2中，我们将确定Pref-BNP 吸收动力学对抗原呈现细胞和Pref-BNP诱导的体内免疫力，包括常驻记忆t 细胞。在AIM 3中，我们将在RSV小鼠模型中建立鼻内前BNP的安全性和功效。成功完成研究将为推进一种新型的RSV疫苗制定的方式铺平道路在幼儿中产生安全有保护的RSV免疫。