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<p>Biomedical interventions that block the transmission of <i>Plasmodium falciparum</i> (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a target of clinical-stage transmission-blocking vaccines and monoclonal antibodies (mAbs) that disrupt Pf transmission to mosquitoes. Antibodies directed to domain 3 of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent human mAbs targeting all three domains. Our data indicate that although Pfs48/45 domains 1 and 2 are rigidly coupled, there is substantial conformational flexibility between domains 2 and 3. Characterization of mAbs against domain 1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by potent antibodies. Our study provides insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria interventions.</p>

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Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月22日

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  • Iga Kucharska,
  • Danton Ivanochko,
  • Sophia Hailemariam,
  • Maartje R. Inklaar,
  • Hee Ryung Kim,
  • Karina Teelen,
  • Rianne Stoter,
  • Marga van de Vegte-Bolmer,
  • Geert-Jan van Gemert,
  • Anthony Semesi,
  • Brandon McLeod,
  • Ahyoung Ki,
  • Won-Kyu Lee,
  • John L. Rubinstein,
  • Matthijs M. Jore,
  • Jean-Philippe Julien

摘要

Biomedical interventions that block the transmission of Plasmodium falciparum (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a target of clinical-stage transmission-blocking vaccines and monoclonal antibodies (mAbs) that disrupt Pf transmission to mosquitoes. Antibodies directed to domain 3 of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent human mAbs targeting all three domains. Our data indicate that although Pfs48/45 domains 1 and 2 are rigidly coupled, there is substantial conformational flexibility between domains 2 and 3. Characterization of mAbs against domain 1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by potent antibodies. Our study provides insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria interventions.