Improving the Translational Potential of a Prime-and-Trap Malaria Vaccine

点击翻译按钮获取中文摘要

PROJECT SUMMARY Malaria is a parasitic disease responsible for ~229 million infections and 400,000 deaths annually. An effective vaccine is urgently needed as parasites are rapidly growing resistant to drug treatments. The liver stage (LS) is a critical bottleneck in the parasite life cycle. If the LS was stopped, this would prevent blood stage infection, clinical disease, and transmission. Radiation-attenuated sporozoite (RAS) vaccines target the sporozoite (spz) and LS and can result in sterilizing protection by inducing protective antibodies and CD8+ T cells. In pre-clinical studies, RAS induced a subset of memory CD8+ T cells that reside in the liver called liver resident memory T (Trm) cells that were critical for long-term LS protection. Although RAS is highly immunogenic and presents many antigens (including the circumsporozoite protein (CSP)), RAS vaccine efficacy varies across different populations, and implementation is hindered by requirements for repeated high-dose intravenous (IV) injections. Prime-and-Trap is a two-step vaccine strategy intended to simplify and improve on RAS-only immunization by combining intradermally delivered DNA encoding the CSP antigen with a later single IV dose of RAS to direct and “trap” the activated and expanding T cells in the liver. This strategy increased protective CD8+ liver Trm cells in mice, but the reliance on the CSP priming antigen alone and the requirement for a high dose of IV- administered RAS upon trapping pose hurdles for translation to larger animal models and humans. This proposal will provide pre-clinical research to improve the efficacy and translational potential of the Prime-and-Trap malaria vaccine. We hypothesize that Prime-and-Trap can be improved by a) reducing the dose or altering the delivery route for the RAS trap, and b) by identifying additional protective LS antigens for priming. In Aim 1, we will investigate improvements of RAS trapping with co-administration of glycolipid adjuvant 7DW8- 5. We will evaluate low dose and non-IV methods to deliver RAS without reducing immunogenicity or protection. In Aim 2, we will identify protective LS antigens for priming. Recently, a ribosomal protein (RP) was identified as a potent vaccine antigen that induces protective liver Trm cells in mice. If protective, RP make attractive vaccine targets since they are highly conserved and abundant. Here, we will investigate overall RP immunogenicity and induction of CD8+ T cells in Prime-and-Trap. The research will be carried out at the University of Washington, where the applicant has assembled a multidisciplinary mentorship team with expertise in malaria biology, vaccine development, and T cell immunology. A training plan has been designed to provide supplemental coursework in global health, conference attendance, and mentorship meetings to build necessary skills for the applicant to complete her proposed research and become an independent researcher. In summary, Prime-and-Trap is a versatile malaria vaccine candidate that can induce protective LS immunity using a single RAS dose and warrants further investigation to improve its translational potential. The research on this vaccine candidate provides an optimal training opportunity for the candidate in the field of vaccine translational sciences.