Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy.
Bibliographical noteFunding Information:
We thank Victor A. Kostyuchenko and P. Robert Beatty for scientific discussion and Kuiama Lewandowski at PHE for the technical support in viral sequencing and Rocco D’Antuono for microscope assistance. We thank Fabio Benigni at Humabs for critical reading of the manuscript and Antonio Piralla from San Matteo Hospital in Pavia for helping in the sequencing of MARMs. We thank the European Virus Archive for consenting to the use of the ZIKV H/PF/2013 strain. The work was supported by Singapore Ministry of Education Tier 3 grant ( MOE2012-T3-1-008 ), National Research Foundation Investigatorship award ( NRF-NRFI2016-01 ), National Research Foundation Competitive Research Project grant ( NRF2016NRF-CRP001-063 ) and the Duke-NUS Signature Research Programme funded by the Ministry of Health, Singapore , awarded to S-M.L, and grant 5U19AI109761 from the US National Institutes of Health to Ian Lipkin and E.H. L.V. is grateful for support by G. Noseda, SNF grant 310030_166445 , 157699 , KFS-3728-08-2015 and Lions Club Monteceneri . A.L. is the scientific founder of Humabs BioMed SA. A.L. holds shares in Humabs BioMed. K.S., F.Z., S.J., E.C., M.B. and D.C. are employees of Humabs Biomed.
- neutralizing antibody