Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes
Amanda Fabra-García, Sophia Hailemariam, Roos M. de Jong, Kirsten Janssen, Karina Teelen, Marga van de Vegte‐Bolmer, Geert‐Jan van Gemert, Danton Ivanochko, Anthony Semesi, Brandon McLeod, Martijn Vos, Marloes H.C. de Bruijni, Judith M. Bolscher, Marta Szabat, Stefanie Vogt, Lucas Kraft, Sherie Duncan, Moses R. Kamya, Margaret E. Feeney, Prasanna Jagannathan, Bryan Greenhouse, Koen J. Dechering, Robert W. Sauerwein, C. Richter King, Randall S. MacGill, Teun Bousema, Jean‐Philippe Julien, Matthijs M. Jore
Abstract
Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development 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 naturally 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 μg/mL, respectively. Co-crystal structures 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.