The proposed study is relevant to the Department of Defense because it focuses on developing a malaria vaccine for administration to Department of Defense personnel prior to deployment in malaria endemic settings. "Malaria" is a Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area. Malaria infects approximately 220 million people annually with close to 550,000 deaths annually. Malaria infection remains a major obstacle for troops sent to endemic regions of the world. To date, investigators have struggled to develop a highly efficacious subunit malaria vaccine. The two malaria vaccines in clinical trials require three and five vaccinations, respectively. One goal of this proposed research is to reduce this to two vaccinations. One problem for developing an effective malaria vaccine is the "limited" vaccine delivery options available. The need for new approaches to improve vaccines for infectious diseases such as malaria and biodefense organisms has reached a critical level. Towards the goal of improving vaccine efficacy, we developed VacSIM, (Vaccine Self-Assembling Immune Matrix) to deliver vaccines. VacSIM is based on the properties of a synthetic peptide developed for wound healing, tissue repair, and implant applications. The synthetic oligopeptide in VacSIM is in clinical trials as a hemostat (PuraStat) and for wound healing, tissue repair, and implant applications as PuraMatrix. The remarkable and critical property of this synthetic peptide solution is that it is comes as a liquid, allowing one to add vaccine antigens with or without adjuvants. Once VacSIM combined with the vaccine is injected, VacSIM self-assembles into a hydrated gel, concentrating the vaccine components, slowly releasing them to the immune system. In preliminary studies in mice, vaccination via VacSIM significantly improved vaccine-specific immune responses to the Hepatitis B vaccine compared to conventional delivery. VacSIM delivery also increased immune responses to Burkholderia candidate vaccines as well as influenza vaccines. Lastly, VacSIM delivery of flu vaccine induced 100% protection against a highly lethal dose of influenza challenge in mice and reduced levels of the influenza virus in lungs on days 1-3 post lethal challenge by 100-fold compared to lung viral loads in conventional flu vaccinated mice. As promising as our preliminary data look, we have not yet optimized the VacSIM delivery platform. We propose to optimize VacSIM delivery of two malaria vaccine antigens CelTOS (cell-traversal protein for ookinetes and sporozoites) and CSP (circumsporozoite) to enhance their immunogenicity and efficacy. Our specific aims are: (1) Optimize VacSIM delivery parameters for malaria vaccines. (2) Compare immunogenicity and protective efficacy of PfCelTOS and PfCSP at Walter Reed Army Institute of Research. Therefore, our first goal will determine the optimal VacSIM concentration, route of injection, time between boosts and adjuvant for delivery of malaria subunit vaccines. We will measure immune responses in malaria vaccinated mice to determine which VacSIM delivery regimen works best. Our second goal is to compare optimal VacSIM delivery of CelTOS or CSP to conventional vaccine delivery using a live malaria challenge infection to measure vaccine efficacy. If successful, the proposed studies will lead to an enhanced VacSIM delivery platform, which can be utilized to improve immunogenicity and efficacy of any vaccine. Using the remarkable properties of the synthetic oligopeptide to develop the VacSIM delivery method is innovative and a use that was not foreseen by the inventors of the synthetic oligopeptide technology.