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<p>Malaria parasite transmission remains a barrier to elimination since asymptomatic individuals sustain the infectious reservoir. Transmission-blocking vaccine (TBV) candidates targeting <i>Plasmodium falciparum</i> (Pf) gametocyte surface proteins Pfs230 and Pfs48/45 have shown promise in clinical trials. Several vaccine candidates have been developed for these antigens, yet it is unclear which elicit the most robust and durable transmission-blocking responses. From structure-function relationships of monoclonal antibodies in complex with both antigens, we report the development of a stabilized tandem antigen chimera (STAC), which presents the most potent epitopes from Pfs230 domain 1&#xa0;(Pfs230-D1) and Pfs48/45 domain 3&#xa0;(Pfs48/45-D3) in a single construct, while masking non-functional epitopes using an engineered pseudo-native domain disposition. Iterative structure-guided optimization improved antigen yields and stability, while nanoparticle-based multimerization enhanced the functional transmission-reducing activity elicited by the immunogen in female mice. Immunizations with STAC genetically conjugated to self-assembling protein nanoparticles elicited antibodies with potent transmission-reducing activity comparable or superior to the multimerized Pfs230-D1 and Pfs48/45-D3. These findings establish STAC as a promising next-generation TBV candidate to disrupt malaria transmission and accelerate elimination efforts. More broadly, our results support the engineering of highly ordered and stable multi-domain antigens in a single protein as a strategy for the cost-efficient development of multi-component vaccines.</p>

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A stabilized tandem antigen chimera that elicits potent malaria transmission-reducing activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月24日

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  • Danton Ivanochko,
  • Kazutoyo Miura,
  • Sophia Hailemariam,
  • Rashmi Ravichandran,
  • Yiting Song,
  • Wei-Chiao Huang,
  • Rianne Stoter,
  • Karina Teelen,
  • Geert-Jan van Gemert,
  • Elizabeth M. Leaf,
  • Sidney Chan,
  • Christine Men,
  • Anthony Semesi,
  • Carol Shiu,
  • Randall S. MacGill,
  • Carole A. Long,
  • Matthijs M. Jore,
  • Neil P. King,
  • Jonathan F. Lovell,
  • Jean-Philippe Julien

摘要

Malaria parasite transmission remains a barrier to elimination since asymptomatic individuals sustain the infectious reservoir. Transmission-blocking vaccine (TBV) candidates targeting Plasmodium falciparum (Pf) gametocyte surface proteins Pfs230 and Pfs48/45 have shown promise in clinical trials. Several vaccine candidates have been developed for these antigens, yet it is unclear which elicit the most robust and durable transmission-blocking responses. From structure-function relationships of monoclonal antibodies in complex with both antigens, we report the development of a stabilized tandem antigen chimera (STAC), which presents the most potent epitopes from Pfs230 domain 1 (Pfs230-D1) and Pfs48/45 domain 3 (Pfs48/45-D3) in a single construct, while masking non-functional epitopes using an engineered pseudo-native domain disposition. Iterative structure-guided optimization improved antigen yields and stability, while nanoparticle-based multimerization enhanced the functional transmission-reducing activity elicited by the immunogen in female mice. Immunizations with STAC genetically conjugated to self-assembling protein nanoparticles elicited antibodies with potent transmission-reducing activity comparable or superior to the multimerized Pfs230-D1 and Pfs48/45-D3. These findings establish STAC as a promising next-generation TBV candidate to disrupt malaria transmission and accelerate elimination efforts. More broadly, our results support the engineering of highly ordered and stable multi-domain antigens in a single protein as a strategy for the cost-efficient development of multi-component vaccines.