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

在美国，RSV感染了近100%的儿童，相关的医院总费用估计为 大约25亿美元。前六个阶段的婴儿最容易感染严重的呼吸道合胞病毒相关疾病 几个月的生命。在此期间，婴儿自行安装保护性很差的抗体介导的免疫系统。 RSV感染或接种疫苗。相反，他们倾向于Th2型反应，这可能会导致疾病--或疫苗-- 再次感染时病情加重，随后在整个童年和青少年时期都会出现喘息。在……里面 近年来，有希望的母体RSV候选疫苗已经进入临床试验，但 对婴儿的保护仍然限于母源抗体的半衰期(~1个月)或中等程度 如果母亲正在哺乳，则持续时间更长。一种RSV疫苗，用于保护出生后第一个月或 改善他们的呼吸道疾病的病程，将(I)减少婴儿住院的频率，(Ii) 改善婴儿、家庭、社区和人口的生活质量，以及(三)减轻疾病负担 美国经济。 在这个多PI项目中，我们试图优化和表征一种基于纳米颗粒的鼻内RSV疫苗 具有内在佐剂特性的平台。生物可降解生物素纳米粒体系(简称BNP) 起抗原载体和免疫激活剂的作用。将抗原递送和佐剂特性耦合到一个 单一的物理实体将增强克服固有免疫抑制环境的能力 粘膜组织。微粒系统有一个可调节的设计，其中抗原的剂量可以不同地 再制造。为了确保Th-1型反应，我们将使用一种变异的RSV预融合蛋白(PREF) 将天然构象锁定为货物抗原。 我们假设在BNP上立体稳定的pref(pref-BNP)会激活抗原提呈细胞来诱导 重要的保护相关因素，包括RSV特异性Th1主导的T细胞反应，CD8驻留记忆T 细胞和中和抗体。提出了三个具体目标。在目标1中，我们将优化首选项的显示 BNP和该制剂激活抗原提呈细胞的能力。在目标2中，我们将确定首选BNP 体内抗原提呈细胞摄取动力学和Pref-BNP诱导的免疫，包括驻留记忆T 细胞。在目标3中，我们将在RSV小鼠模型中建立鼻腔注射pref-BNP的安全性和有效性。 这些研究的成功完成将为推进新的RSV疫苗配方铺平道路 在幼儿中产生安全和保护性的RSV免疫。

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.