Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype.
Barrett JR., Pipini D., Wright ND., Cooper AJR., Gorini G., Quinkert D., Lias AM., Davies H., Rigby CA., Aleshnick M., Williams BG., Bradshaw WJ., Paterson NG., Martinson T., Kirtley P., Picard L., Wiggins CD., Donnellan FR., King LDW., Wang LT., Popplewell JF., Silk SE., de Ruiter Swain J., Skinner K., Kotraiah V., Noe AR., MacGill RS., King CR., Birkett AJ., Soisson LA., Minassian AM., Lauffenburger DA., Miura K., Long CA., Wilder BK., Koekemoer L., Tan J., Nielsen CM., McHugh K., Draper SJ.
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.