Protective threshold of a potent neutralizing Zika virus monoclonal antibody in rhesus macaques

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused a global pandemic in 2016-2017 with continued ongoing transmission at low levels in several countries. In the absence of an approved ZIKV vaccine, neutralizing monoclonal antibodies (mAbs) provide an option for the prevention and treatment of ZIKV infection. Previous studies identified a potent neutralizing human mAb ZIKV-117 that reduced fetal infection and death in mice following ZIKV challenge. In this study, we report exquisite potency of ZIKV-117-LALA-YTE, which has been engineered to reduce Fc receptor binding and to extend half-life, in a titration study in rhesus macaques to protect against ZIKV challenge. We show complete protection at a dose of 0.016 mg/kg ZIKV-117-LALA-YTE, which resulted in median serum concentrations of 0.13 µg/mL. The high potency of this mAb supports its potential clinical development as a novel biotherapeutic intervention for ZIKV.IMPORTANCEIn this study, we report the potency of the Zika virus (ZIKV)-specific neutralizing antibody ZIKV-117-LALA-YTE against ZIKV challenge in a titration study rhesus macaques. This high potency supports the further development of this monoclonal antibody for ZIKV.

Keywords: Zika; antibody; biotherapeutic; efficacy; non-human primate.

FIG 1

ZIKV-117-LALA-YTE pharmacokinetics following infusion as measured by a human IgG-specific enzyme-linked immunosorbent assay (ELISA). Each line correspondences to a single animal. The horizontal dashed line represents the assay limit of detection (0.005 µg/mL).

FIG 2

ZIKV-BR viral loads following challenge as determined by reverse transcription-PCR (RT-PCR). Each black line corresponds to a single animal, and the red line depicts the median for each group.

FIG 3

(A) Comparison of peak median Zika virus (ZIKV) viral loads in each group compared with sham controls. The horizontal dashed line represents the assay limit of detection (50 copies/mL). Adjusted Kruskal–Wallis tests are shown; **P < 0.05. (B) Time-weighted average (TWA) values for the change of viral loads from day 1 to 10 after viral challenge (y-axis) compared with log serum ZIKV-117-LALA-YTE concentrations on the day of challenge (x-axis). The fitting curve was estimated using the locally weighted scatterplot smoothing (LOWESS) method and is shown in purple, and gray shading indicates the 95% CI. Horizontal black dotted lines indicate designated TWA thresholds for full (bottom line) and partial (top line) protection. Vertical dotted orange lines indicate maximal and minimal predicted cutoff for protective antibody concentration in serum.