9N8I

Pfs230 domain 1 bound by RUPA-39 Fab

Summary for 9N8I

• Entry DOI: 10.2210/pdb9n8i/pdb
• Descriptor: RUPA-39 Heavy chain, RUPA-39 Kappa chain, Gametocyte surface protein P230, ... (7 entities in total)
• Functional Keywords: antibody, malaria, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 81954.59

Authors

Ivanochko, D.,Semesi, A.,Julien, J.P. (deposition date: 2025-02-08, release date: 2026-02-04, Last modification date: 2026-06-10)

Primary citation

Ivanochko, D.,Miura, K.,Hailemariam, S.,Ravichandran, R.,Song, Y.,Huang, W.C.,Stoter, R.,Teelen, K.,van Gemert, G.J.,Leaf, E.M.,Chan, S.,Men, C.,Semesi, A.,Shiu, C.,MacGill, R.S.,Long, C.A.,Jore, M.M.,King, N.P.,Lovell, J.F.,Julien, J.P.
A stabilized tandem antigen chimera that elicits potent malaria transmission-reducing activity.
Nat Commun, 17:-, 2026

PubMed Abstract: 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.

PubMed: 41580424
DOI: 10.1038/s41467-026-68761-1

Experimental method

X-RAY DIFFRACTION (1.85 Å)