摘要Antibodies targeting non-structural protein 1(NS1)confer protection against Zika virus(ZIKV).Although monoclonal an-tibodies(MAbs)3G2 and 4B8 are more potent than MAb 4F10 in suppressing ZIKV infection in neonatal mice models,the epitopes are unclear.Herein,we determined the Cryo-electron microscopy(Cryo-EM)structures of ZIKV NS1 in com-plex with five human antibodies at 2.6-2.9 ? resolution.Group I antibodies(3G2 and 4B8)recognize the previously un-reported epitopes on the outer surface of the NS1 dimer.The unique binding mode of Group I antibodies led to a stronger recognition of the cell surface form of NS1 and completely inhibited secreted form non-structural protein 1(sNS1)-induced endothelial permeability via their immunoglobulin G(IgG)and Fab.Group Ⅱ antibodies(4F10,2E11,and 14G5)recognize common epitopes in the distal end of the β-ladder domain,with a blockade efficiency that may be related to their affinity for the sNS1 protein and the presence of full-length IgG.These findings elucidate the correlation between epitope recognition and protective efficacy of anti-NS1 antibodies and highlight the diagnostic and therapeutic potential of 3G2 and 4B8.