Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite devel-opment in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors natu-rally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission -reducing activity in standard membrane-feeding assays, at 10 and 2 mg/mL, respectively. Co-crystal struc-tures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission -blocking vaccine candidates.

Automated summary

Malaria transmission-blocking vaccines aim to induce antibodies that interrupt parasite development in mosquitoes, providing a tool for malaria control. We isolated and characterized 81 human monoclonal antibodies specific to the Pfs48/45 protein, a leading vaccine candidate. Potent antibodies targeting specific domains achieved high transmission-reducing activity. Co-crystal structures identified protective epitopes, providing insight for refined vaccine design.