Abstract
There are no licensed therapeutics or vaccines available against Zika virus (ZIKV) to counteract its potential for congenital disease. Antibody-based countermeasures targeting the ZIKV envelope protein have been hampered by concerns for cross-reactive responses that induce antibody-dependent enhancement (ADE) of heterologous flavivirus infection. Nonstructural protein 1 (NS1) is a membrane-associated and secreted glycoprotein that functions in flavivirus replication and immune evasion but is absent from the virion. Although some studies suggest that antibodies against ZIKV NS1 are protective, their activity during congenital infection is unknown. Here we develop mouse and human anti-NS1 monoclonal antibodies that protect against ZIKV in both non-pregnant and pregnant mice. Avidity of antibody binding to cell-surface NS1 along with Fc effector functions engagement correlate with protection in vivo. Protective mAbs map to exposed epitopes in the wing domain and loop face of the β-platform. Anti-NS1 antibodies provide an alternative strategy for protection against congenital ZIKV infection without causing ADE.
Highlights
There are no licensed therapeutics or vaccines available against Zika virus (ZIKV) to counteract its potential for congenital disease
We examined binding to these mutants as an alternative approach for mapping the anti-ZIKV Nonstructural protein 1 (NS1) Monoclonal antibodies (mAbs) in competition groups B (Z11, Z15, Z18, and ZIKV-292) and D (Z14)
We examined the protective efficacy of newly generated mAbs targeting ZIKV NS1 in vivo
Summary
There are no licensed therapeutics or vaccines available against Zika virus (ZIKV) to counteract its potential for congenital disease. Soluble NS1 can bind back to the surface of uninfected or infected cells, and this activity may impact endothelial integrity and permeability at blood-tissue barriers[25,26,27,28]. The significance of these findings to pathogenesis, remains uncertain[13]. The dimer creates a surface for membrane interaction via conserved hydrophobic residues within the β-roll domain and flexible loop (residues 108–129) and “greasy finger” (residues 159–163) regions of the wing domain[29,31,32]. Other regions of the wing and β-platform domains contribute to forming the electrostatic exterior surface of the hexamer and the membranedistal surface of the dimer
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