Multistage protective anti-CelTOS monoclonal antibodies with cross-species sterile protection against malaria

Wai Kwan Tang, Nichole D. Salinas, Surendra Kumar Kolli, Shulin Xu, Darya V. Urusova, Hirdesh Kumar, John R. Jimah, Pradeep Annamalai Subramani, Madison M. Ogbondah, Samantha J. Barnes, John H. Adams and Niraj H. Tolia ()
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Wai Kwan Tang: National Institutes of Health
Nichole D. Salinas: National Institutes of Health
Surendra Kumar Kolli: University of South Florida
Shulin Xu: University of South Florida
Darya V. Urusova: Washington University School of Medicine
Hirdesh Kumar: National Institutes of Health
John R. Jimah: Washington University School of Medicine
Pradeep Annamalai Subramani: University of South Florida
Madison M. Ogbondah: University of South Florida
Samantha J. Barnes: University of South Florida
John H. Adams: University of South Florida
Niraj H. Tolia: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract CelTOS is a malaria vaccine antigen that is conserved in Plasmodium and other apicomplexan parasites and plays a role in cell-traversal. The structural basis and mechanisms of CelTOS-induced protective immunity to parasites are unknown. Here, CelTOS-specific monoclonal antibodies (mAbs) 7g7 and 4h12 demonstrated multistage activity, protecting against liver infection and preventing parasite transmission to mosquitoes. Both mAbs demonstrated cross-species activity with sterile protection against in vivo challenge with transgenic parasites containing either P. falciparum or P. vivax CelTOS, and with transmission reducing activity against P. falciparum. The mAbs prevented CelTOS-mediated pore formation providing insight into the protective mechanisms. X-ray crystallography and mutant-library epitope mapping revealed two distinct broadly conserved neutralizing epitopes. 7g7 bound to a parallel dimer of CelTOS, while 4h12 bound to a novel antiparallel dimer architecture. These findings inform the design of antibody therapies and vaccines and raise the prospect of a single intervention to simultaneously combat P. falciparum and P. vivax malaria.

Date: 2024
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DOI: 10.1038/s41467-024-51701-2

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