Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Pathog. 2024 Mar 4;20(3):e1011879. doi: 10.1371/journal.ppat.1011879. eCollection 2024 Mar.
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.
疟原虫感染的红细胞在胎盘内的积累会导致母亲贫血、低出生体重和妊娠丢失。寄生虫蛋白 VAR2CSA 通过与宿主受体硫酸软骨素 A（CSA）相互作用，促进感染红细胞在胎盘内的积累。预防 VAR2CSA-CSA 相互作用的抗体与预防胎盘疟疾相关，VAR2CSA 是一种高优先级的胎盘疟疾疫苗抗原。在这里，基于结构的设计利用全长 VAR2CSA 结构产生了一种稳定的免疫原，保留了 VAR2CSA 的关键保守功能元件。该设计的表达产量比全长蛋白高出六倍，并诱发出可阻止感染红细胞与 CSA 黏附的抗体。设计的免疫原体积更小、适应性更强，能够高效生产多种 VAR2CSA 变体，用于鸡尾酒疫苗接种策略，以增加保护范围。这些设计为开发强效、广谱的胎盘疟疾疫苗奠定了坚实的基础。
