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.