Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine

Placental accumulation of Plasmodium falciparum infected erythrocytes results in maternal anemia, low birth weight, and pregnancy loss. The parasite protein VAR2CSA facilitates the accumulation of infected erythrocytes in the placenta through interaction with the host receptor chondroitin sulfate A (CSA). Antibodies that prevent the VAR2CSA-CSA interaction correlate with protection from placental malaria, and VAR2CSA is a high-priority placental malaria vaccine antigen. Here, structure-guided design leveraging the full-length structures of VAR2CSA produced a stable immunogen that retains the critical conserved functional elements of VAR2CSA. The design expressed with a six-fold greater yield than the full-length protein and elicited antibodies that prevent adhesion of infected erythrocytes to CSA. The reduced size and adaptability of the designed immunogen enable efficient production of multiple variants of VAR2CSA for use in a cocktail vaccination strategy to increase the breadth of protection. These designs form strong foundations for the development of potent broadly protective placental malaria vaccines. Malaria remains a major cause of death globally despite considerable dedication to eradication. Plasmodium falciparum is the most lethal malaria parasite that infects human. One reason for the parasite's deadly impact lies in the expression of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) protein family. These proteins adhere to host receptors leading to parasite accumulation in various tissues and organs. VAR2CSA is a PfEMP1 protein that binds to a host receptor in the placenta causing severe outcomes for pregnant women and their unborn children including maternal anemia, low birth weight, still birth, and loss of pregnancy. The development of a vaccine to combat these devastating outcomes has long been anticipated, but the intricate and diverse nature of VAR2CSA has posed significant hurdles. Here, we adopted structure-guided principles to design a next-generation VAR2CSA vaccine candidate, HPISVpmv1, that is stable, has high production yields, and consists of the entire functional domains of VAR2CSA. Preclinical studies showed that HPISVpmv1 is immunogenic and effective, and the adoption of a cocktail immunization strategy produced antibodies that worked against multiple strains. This work provides new insights into vaccine development for malaria and other highly variable human pathogens.