Virus-like Particle based malaria vaccines targeting vulnerable epitopes in the circumsporozoite protein

项目总结 恶性疟原虫环子孢子蛋白(CSP)是一种有吸引力的疟疾疫苗候选疫苗，因为 抗CSP抗体可以阻止肝脏入侵，并有可能提供针对寄生虫的杀菌免疫力。 然而，目前针对CSP的疫苗，包括RTS，最先进的疟疾疫苗S，引发了 随着时间的推移，保护性免疫力急剧下降。在这份提案中，我们的目标是设计新的 和更有效的针对CSP的疫苗。我们将利用最近发现的强大的 针对CSP中新的易受攻击点的表位的保护性单抗。我们会 使用高免疫原性噬菌体病毒样颗粒(VLP)疫苗特异性靶向这些表位 平台技术。在初步数据中，我们已经证明了以VLP为基础的针对短表位的免疫原 在CSP内可以诱导高滴度和持久的抗体反应，从而抑制肝脏的疟原虫感染 并能预防小鼠血液期感染。在这项提案中，我们将利用各种方法来 最大限度地提高VLP疫苗的免疫原性(目标1)，我们将谨慎使用敏感技术 监测B细胞对我们疫苗的反应(目标2)，我们将在一年内衡量疫苗的有效性 最新的小鼠感染模型(目标3)。我们的团队在疫苗工程和设计方面拥有专业知识， B细胞免疫学和疟疾挑战模型将实现这些目标，最终目标是确定 一种适合进入临床试验的红细胞前疟疾候选疫苗。

PROJECT SUMMARY The Plasmodium falciparum circumsporozoite protein (CSP) is an attractive malaria vaccine candidate because anti-CSP antibodies can block liver invasion and potentially provide sterilizing immunity against the parasite. However, current vaccines that target CSP, including RTS,S, the most advanced malaria vaccine, elicit suboptimal protective immunity that wanes dramatically over time. In this proposal, our goal is to engineer new and more effective vaccines targeting CSP. We will take advantage of the recent identification of potently protective monoclonal antibodies that target epitopes within novel sites of vulnerability in CSP. We will specifically target these epitopes using a highly immunogenic bacteriophage virus-like particle (VLP) vaccine platform technology. In preliminary data, we have shown that VLP-based immunogens targeting short epitopes within CSP can elicit high-titer and long-lasting antibody responses that inhibit Plasmodium infection of the liver and can prevent blood-stage infection in mice. In this proposal, we will utilize an arsenal of approaches to maximize the immunogenicity of VLP-based vaccines (Aim 1), we will use sensitive techniques to carefully monitor the B cell responses to our vaccines (Aim 2), and we will measure the effectiveness of vaccines in a state-of-the-art mouse infection model (Aim 3). Our team, which has expertise in vaccine engineering and design, B cell immunology, and malaria challenge models, will carry out these Aims with the ultimate goal of identifying a pre-erythrocytic malaria vaccine candidate suitable of advancing to clinical trials.