Nature Medicine | 2 JAN 2024

Katherine L. Williams, Steve Guerrero, Yevel Flores-Garcia, Dongkyoon Kim, Kevin S. Williamson, Christine Siska, Pauline Smidt, Sofia Z. Jepson, Kan Li, S. Moses Dennison, Shamika Mathis-Torres, Xiaomu Chen, Ulrike Wille-Reece, Randall S. MacGill, Michael Walker, Erik Jongert, C. Richter King, Christian Ockenhouse, Jacob Glanville, James E. Moon, Jason A. Regules, Yann Chong Tan, Guy Cavet, Shaun M. Lippow, William H. Robinson, Sheetij Dutta, Georgia D. Tomaras, Fidel Zavala, Randal R. Ketchem & Daniel E. Emerling


Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO’s preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

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