Beyond VAR2CSA: redefining the antigenic landscape of placental malaria vaccines

Placental malaria (PM) remains a leading driver of maternal and neonatal mortality, largely attributed to the sequestration of Plasmodium falciparum-infected red blood cells in the placenta. For decades, PM vaccine development has singularly focused on VAR2CSA, the immunodominant variant surface antigen. However, extreme polymorphism, limited cross-strain protection, and the structural complexity of VAR2CSA have hindered the development of a highly efficacious PM vaccine, necessitating a paradigm shift.

This review examines existing literature to map potential vaccine antigens implicated in placental malaria ,and outlines a comprehensive vaccine development pipeline. It synthesizes emerging data on antigen expression profiles, immunogenicity, and mechanistic roles in placental pathogenesis. In addition, it highlights both key placental and blood-stage antigens expressed during pregnancy and reviews identification and testing strategies to guide rational PM vaccine design.

This Review maps the expanding antigenic landscape of PM beyond VAR2CSA, identifying non-canonical surface and exported proteins, including SURFINs, PHISTs, PfRON3, and PfCSA-L, as critical targets that may circumvent current bottlenecks. The findings highlight the relevance of these antigens in placental malaria pathogenesis and their potential as alternative or complementary vaccine candidates.

Furthermore, we propose an integrated framework for rational vaccine design that couples high-throughput antigen discovery and structural immunogen engineering with multivalent formulation strategies. By bridging the gap between molecular parasitology and translational immunology, this roadmap offers a strategic path toward a broadly protective placental malaria (PM) vaccine.