Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice
Katherine L. Mallory, Justin A. Taylor, Xiaoyan Zou, Ishita N. Waghela, Cosette G. Schneider, Michael Q. Sibilo, Neeraja M. Punde, Leah Perazzo, Tatyana Savransky, Martha Sedegah, Sheetij Dutta, Chris J. Janse, Norbert Pardi, Paulo J.C. Lin, Ying K. Tam, Drew Weissman, Evelina Angov
Abstract
Human malaria affects the vast majority of the world's population with the Plasmodium falciparum species causing the highest rates of morbidity and mortality. With no licensed vaccine and leading candidates achieving suboptimal protection in the field, the need for an effective immunoprophylactic option continues to motivate the malaria research community to explore alternative technologies. Recent advances in the mRNA discipline have elevated the long-neglected platform to the forefront of infectious disease research. As the immunodominant coat protein of the invasive stage of the malaria parasite, circumsporozoite protein (PfCSP) was selected as the antigen of choice to assess the immunogenic and protective potential of an mRNA malaria vaccine. In mammalian cell transfection experiments, PfCSP mRNA was well expressed and cell associated. In the transition to an in vivo murine model, lipid nanoparticle (LNP) encapsulation was applied to protect and deliver the mRNA to the cell translation machinery and supply adjuvant activity. The immunogenic effect of an array of factors was explored, such as formulation, dose, number, and interval of immunizations. PfCSP mRNA-LNP achieved sterile protection against infection with two P. berghei PfCSP transgenic parasite strains, with mRNA dose and vaccination interval having a greater effect on outcome. This investigation serves as the assessment of pre-erythrocytic malaria, PfCSP mRNA vaccine candidate resulting in sterile protection, with numerous factors affecting protective efficacy, making it a compelling candidate for further investigation.