Structural Characterization of the Human West Nile Virus Antibody Response 2259814

Abstract Introduction West Nile Virus (WNV) is a mosquito-borne Flavivirus capable of causing febrile and neuroinvasive disease. Rising infection rates and expanding mosquito habitats driven by climate change have increased WNV’s global burden. Current treatment strategies rely largely on vector management, as no licensed vaccines or therapeutics exist. Here, we profile the human antibody response elicited to a subdomain of the WNV Envelope glycoprotein using samples from naturally infected patients. Methods Through structural and biochemical analyses, we defined antibody epitopes, binding poses, and virion engagement patterns associated with neutralizing and cross-reactive antibody responses. Results Two antibodies, W010 and W037, potently neutralize WNV by engaging the lateral ridge epitope on ectodomain III (EDIII), a site that often elicits neutralizing antibodies. Consistent with the limited sequence conservation of this epitope within the Japanese Encephalitis Serocomplex, these mAbs did not exhibit broad neutralization. In contrast, we identified a cross-neutralizing antibody W014, that engages a combination of the lateral ridge and CC’ loop regions of EDIII, leveraging more sequentially conserved motifs. Conclusion Together, these findings delineate structural correlates governing potency and breadth in human WNV antibody responses for the first time, providing a framework for therapeutic antibody development and rational vaccine design. Funding Source HHMI Emerging Pathogen Initiative Award Topic Categories Vaccines and Immunotherapy (VAC)