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

Abstract

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.

Structure‐based design of a Plasmodium vivax Duffy‐binding protein immunogen focuses the antibody response to functional epitopes

“…Furthermore, vaccine antigens for other pathogens exhibit similar phenomena in which the key neutralizing epitopes are located in core domains integral to a larger protein. Human‐guided structure‐based design efforts have improved numerous antigen targets, but the extent of these modifications is typically minor (Ma et al, 2024 ; McLellan et al, 2013 ; Pallesen et al, 2017 ; Patel et al, 2023 ). Epitope scaffolding, another computational approach, can isolate and display individual epitopes, but these epitopes are often insufficient for achieving potent neutralization (Correia et al, 2014 ; Sesterhenn et al, 2020 ).…”