Abstract
Malaria resurgence in 2022 saw 249 million clinical cases and 608,000 deaths, mostly in children under five. The WHO-approved circumsporozoite protein (CSP)-targeting vaccines, RTS,S and R21, remain limited in availability. Strong humoral responses are crucial for sporozoite neutralization before hepatocyte infection, yet first-generation vaccines provide suboptimal protection, necessitating improved strategies. With the success of mRNA-LNP vaccines against COVID-19, there is interest in leveraging this approach to malaria. Here, we developed a novel chemokine fusion mRNA vaccine targeting immature dendritic cells (iDC) to enhance immunity against P. falciparum CSP (PfCSP). Mice immunized with MIP3α-CSP mRNA-LNP exhibited stronger CD4 + T cell responses and higher anti-NANP6 antibody titers than conventional CSP mRNA-LNP. Importantly, upon P. berghei PfCSP transgenic sporozoite challenge, MIP3α-CSP mRNA provided significantly greater protection from liver infection, strongly associated with multifunctional CD4 + T cells and anti-NANP6 titers. This study underscores iDC targeting as a promising strategy to enhance malaria vaccine efficacy.