Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1

Zika virus (ZIKV) Non-structural protein 1 (NS1) plays an essential role in viral replication and immune evasion. Our understanding of the differential protective mechanism of NS1-targeting antibodies is limited. Here, we determined the cryoEM structures of ZIKV NS1 in complex with two group antibodies at 2.6-2.9Å. Group I antibodies (3G2 and 4B8) potently recognize cell surface form of NS1 and multiple oligomeric forms of NS1 by occupy the epitopes on outer surface of dimeric NS1. IgG and Fab from group I antibodies completely abrogate sNS1-mediated endothelial dysfunction in vitro. Group II antibodies (4F10, 2E11, and 14G5) recognize the previously reported epitopes in distal end of the β -ladder domain of monomeric NS1, and their blockade efficiency depends on the affinity with NS1 protein. These findings elucidate the correlation between the epitope recognition and the protective efficacy of anti-NS1 antibodies and highlight the distinct mechanisms of therapeutic potential of 3G2 and 4B8.