In-life Chemical Inactivation of Plasmodium Parasites by Cabamiquine Induces Long-Lasting Immune Protection

BACKGROUND: Malaria remains a major global health challenge, and current vaccine strategies provide limited protection. Cabamiquine (CBQ), a Plasmodium translation elongation factor 2 inhibitor, arrests parasite growth during both the liver and blood stages of infection and may promote protective immune responses during controlled parasite infection. METHODS: We evaluated whether CBQ-based infection-and-treatment strategies could induce protective immunity in mouse models of liver- and blood-stage Plasmodium infection. Mice received a single oral dose of CBQ during liver-stage infection or CBQ in combination with pyronaridine during blood-stage infection and were subsequently challenged with homologous or heterologous Plasmodium parasites. RESULTS: CBQ treatment during liver-stage infection induced durable protective immunity against homologous and heterologous sporozoite challenge, reduced disease severity, and was associated with liver-resident memory CD8+ T cells. CBQ administered with pyronaridine during blood-stage infection elicited stage-specific immunity that limited parasitemia and protected against severe malaria following homologous or heterologous challenge. Together, these findings demonstrate that CBQ-based infection-and-treatment can combine effective parasite clearance with induction of protective immune responses following both liver- and blood-stage infections. CONCLUSIONS: CBQ enables in-life chemical inactivation of Plasmodium parasites while promoting long-lasting protective immunity in experimental malaria. These findings provide proof of concept for a simple oral infection-and-treatment strategy that could complement existing malaria vaccination and control approaches.