Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys

Abstract

Strategies to treat Zika virus (ZIKV) infection in dengue virus (DENV)-endemic areas are urgently needed. Here we show that a DENV-specific antibody against the E-dimer epitope (EDE) potently cross-neutralizes ZIKV and provides robust therapeutic efficacy as well as prophylactic efficacy against ZIKV in rhesus monkeys. Viral escape was not detected, suggesting a relatively high bar to escape. These data demonstrate the potential for antibody-based therapy and prevention of ZIKV.

Figure 1. Characterization and pharmacokinetics of B10

(a) Neutralization of ZIKV-PF13/251013-18 (PF13), an Asian strain of Zika virus isolated from French Polynesia in 2013, using a panel of 33 EDE1-specific mAbs originally isolated from DENV-infected patients. B10 was the most potent mAb in this panel. Data are representative of n=3 biologically independent experiments. (b) Neutralization curves of B10 against DENV-1, DENV-2, DENV-3, DENV-4, and ZIKV-PF13. Data are representative of n=3 biologically independent experiments, and mean ± SEM are shown. (c) Levels of B10 (μg/ml) were determined in monkey sera at multiple timepoints in singlet following B10 infusion by ELISA.

Figure 1. Characterization and pharmacokinetics of B10

(a) Neutralization of ZIKV-PF13/251013-18 (PF13), an Asian strain of Zika virus isolated from French Polynesia in 2013, using a panel of 33 EDE1-specific mAbs originally isolated from DENV-infected patients. B10 was the most potent mAb in this panel. Data are representative of n=3 biologically independent experiments. (b) Neutralization curves of B10 against DENV-1, DENV-2, DENV-3, DENV-4, and ZIKV-PF13. Data are representative of n=3 biologically independent experiments, and mean ± SEM are shown. (c) Levels of B10 (μg/ml) were determined in monkey sera at multiple timepoints in singlet following B10 infusion by ELISA.

Figure 2. Therapeutic and prophylactic efficacy of B10 in rhesus monkeys

Rhesus monkeys (N=4/group) received 10 mg/kg B10 or the isotype matched sham control antibody PGT121 by the i.v. route on day −1 or day +2. All animals were challenged on day 0 by the s.c route with 10⁶ VP (10³ PFU) ZIKV-BR. Viral loads are shown in (a) plasma, (b) cerebrospinal fluid (CSF), and (c) lymph nodes (LN). Viral loads were determined on days 0, 1, 2, 3, 4, 5, and 7 for the plasma samples and on days 0, 3, 7, 14, and 35 for the other samples. Assay sensitivity 100 copies/ml or 1×10⁶ cells. Arrows designate the day +2 infusions.

Figure 2. Therapeutic and prophylactic efficacy of B10 in rhesus monkeys

Rhesus monkeys (N=4/group) received 10 mg/kg B10 or the isotype matched sham control antibody PGT121 by the i.v. route on day −1 or day +2. All animals were challenged on day 0 by the s.c route with 10⁶ VP (10³ PFU) ZIKV-BR. Viral loads are shown in (a) plasma, (b) cerebrospinal fluid (CSF), and (c) lymph nodes (LN). Viral loads were determined on days 0, 1, 2, 3, 4, 5, and 7 for the plasma samples and on days 0, 3, 7, 14, and 35 for the other samples. Assay sensitivity 100 copies/ml or 1×10⁶ cells. Arrows designate the day +2 infusions.

Figure 2. Therapeutic and prophylactic efficacy of B10 in rhesus monkeys

Rhesus monkeys (N=4/group) received 10 mg/kg B10 or the isotype matched sham control antibody PGT121 by the i.v. route on day −1 or day +2. All animals were challenged on day 0 by the s.c route with 10⁶ VP (10³ PFU) ZIKV-BR. Viral loads are shown in (a) plasma, (b) cerebrospinal fluid (CSF), and (c) lymph nodes (LN). Viral loads were determined on days 0, 1, 2, 3, 4, 5, and 7 for the plasma samples and on days 0, 3, 7, 14, and 35 for the other samples. Assay sensitivity 100 copies/ml or 1×10⁶ cells. Arrows designate the day +2 infusions.