-Gates Foundation (INV-008866 and OPP1156262) -National Institutes of Health grant (1R01AI148557-01A1) -Canadian Institutes for Health Research grant (428410)
United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
1R01AI148557-01A1
United States
Canadian Institutes of Health Research (CIHR)
428410
Canada
Citation
Journal: Nat Commun / Year: 2026 Title: A stabilized tandem antigen chimera that elicits potent malaria transmission-reducing activity. Authors: Danton Ivanochko / Kazutoyo Miura / Sophia Hailemariam / Rashmi Ravichandran / Yiting Song / Wei-Chiao Huang / Rianne Stoter / Karina Teelen / Geert-Jan van Gemert / Elizabeth M Leaf / ...Authors: 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 / Abstract: Malaria parasite transmission remains a barrier to elimination since asymptomatic individuals sustain the infectious reservoir. Transmission-blocking vaccine (TBV) candidates targeting Plasmodium ...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.
Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: LEICA EM GP Details: A Leica Automatic Plunge Freezer EM GP2 was used for sample freezing..
Details
Stabilized tandem antigen chimera of Pfs230 and Pfs48/45, complexed with Fabs RUPA-44, TB31F, LMIV1, and RUPA-97.
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Electron microscopy
Microscope
TFS KRIOS
Specialist optics
Energy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recording
Film or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 52.0 e/Å2 Details: Images were collected at average electron doses per image of 50 and 53.7 electrons per square Angstrom during two data collections.
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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