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McLeod, Brandon; Mabrouk, Moustafa T; Miura, Kazutoyo; Ravichandran, Rashmi; Kephart, Sally; Hailemariam, Sophia; Pham, Thao P; Semesi, Anthony; Kucharska, Iga; Kundu, Prasun; Huang, Wei-Chiao; Johnson, Max; Blackstone, Alyssa; Pettie, Deleah; Murphy, Michael; Kraft, John C; Leaf, Elizabeth M; Jiao, Yang; van de Vegte-Bolmer, Marga; van Gemert, Geert-Jan; Ramjith, Jordache; King, C Richter; MacGill, Randall S; Wu, Yimin; Lee, Kelly K; Jore, Matthijs M; King, Neil P; Lovell, Jonathan F; Julien, Jean-Philippe
Immunity, 09/2022, Volume: 55, Issue: 9Journal Article
Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. Pfs48/45 is a leading clinical TBV candidate antigen and is recognized by the most potent transmission-blocking monoclonal antibody (mAb) yet described; still, clinical development of Pfs48/45 antigens has been hindered, largely by its poor biochemical characteristics. Here, we used structure-based computational approaches to design Pfs48/45 antigens stabilized in the conformation recognized by the most potently inhibitory mAb, achieving >25°C higher thermostability compared with the wild-type protein. Antibodies elicited in mice immunized with these engineered antigens displayed on liposome-based or protein nanoparticle-based vaccine platforms exhibited 1-2 orders of magnitude superior transmission-reducing activity, compared with immunogens bearing the wild-type antigen, driven by improved antibody quality. Our data provide the founding principles for using molecular stabilization solely from antibody structure-function information to drive improved immune responses against a parasitic vaccine target.
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