Directed in vivo assembly of a robust biopolymer particle-based multistage malaria vaccine

PROJECT SUMMARY The long-term goal of this proposal is to utilize a biopolymer particle-based vaccine platform technology to develop a safe, effective multistage malaria vaccine that is ambient-temperature stable and can be cost- effectively mass produced to protect the world against malaria caused by the parasite Plasmodium falciparum. The objective of this proposal is to apply our innovative vaccine technology that is based on antigen-coated biopolymer particles (~300 nm) assembled inside bacterial cell factories for design of multistage malaria vaccine candidates preventing malaria in a rodent model. Safe and effective biopolymer particle vaccine candidates inducing long-lasting immunity had been developed against eight different infectious diseases. The central hypothesis is that biopolymer particles can be designed to simultaneously display epitopes or antigen subdomains of various stage-specific malaria antigens selected to induce broad immune responses to target the pre-erythrocytic-, blood- and sexual-stage of the parasite. The rationale underlying this proposal is that antigen- specific antibody and CD8+ T cell responses were shown to inhibit the individual stages of the parasite, and hence a combination of antigens/epitopes biologically assembled into a biopolymer particle could simultaneously induce immune responses to block all life cycle stages. Multiple antigens/epitopes had been displayed on biopolymer particles inducing specific antibody and T cell responses that mediated protective immunity. The central hypothesis will be tested by pursuing two specific aims: 1) Design and manufacture biopolymer particle- based malaria vaccine candidates and 2) Evaluate biopolymer particle-based multistage malaria vaccine candidates. We will pursue these aims by designing and manufacturing biopolymer particles that are densely coated with selected epitopes and antigen subdomains from vaccine candidate antigens representing the pre- erythrocytic-, blood- and sexual-stage. Safety and induction of functional inhibitory antibodies against the various life cycle stages of the parasite will be tested in rats. The ability to induce protective immunity will be evaluated in the mouse model of malaria infection using transgenic Plasmodium berghei. The proposed research is significant, because it will determine which biopolymer particle design features are required to induce desirable immune responses. It will generate foundational resources to advance rational design of vaccines that can be used by other researchers in the quest of providing solutions for unmet needs in vaccine development. The proximate expected outcome of this work is an understanding on how biopolymer particle vaccine designs correlate with cell-mediated and humoral immune responses that mediate protective immunity. The results will have an important positive impact on providing insight into immune mechanisms correlated with protective immunity, hence enabling development of an innovative multistage particulate malaria vaccine.