Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection

Abstract

The Zika virus (ZIKV) epidemic has resulted in congenital abnormalities in fetuses and neonates. Although some cross-reactive DENV antibodies can enhance ZIKV infection in mice, those recognizing the E-dimer epitope (EDE) can neutralize ZIKV infection in cell culture. We evaluated the therapeutic activity of human EDE monoclonal antibodies (mAbs) for their ability to control ZIKV infection in the brains, testes, placentas, and fetuses of mice. A single dose of EDE1-B10 antibody given three days after infection protected against lethality, reduced ZIKV levels in brains and testes, and preserved sperm counts. In pregnant mice, wild-type or engineered LALA variants of EDE1-B10, which cannot engage Fc-γ receptors, diminished ZIKV burden in maternal and fetal tissues, and protected against fetal demise. As neutralizing EDE antibodies, in addition to their established inhibitory effects against DENV, have therapeutic potential against ZIKV, it may be possible to develop therapies that control disease caused by both viruses.

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

“…In our experiments, sub-neutralizing doses of B10 did not result in enhanced ZIKV replication in mice (Supplementary Fig. S1), but nevertheless the possibility of antibody-dependent enhancement with a cross-reactive DENV/ZIKV-specific antibody requires further investigation, and if necessary Fc inactivating mutations could be incorporated 8 . Our data also raise the possibility of developing antibody therapeutics targeting both flaviviruses in endemic areas.…”

“…Our laboratory and others have shown that ZIKV-specific neutralizing antibodies correlate with vaccine protection in both mice and monkeys 3–6 as well as with rapid control of viremia following infection in monkeys 7 . Several groups have also demonstrated therapeutic efficacy of ZIKV-specific mAbs in immunosuppressed mice 8–11 , and a cocktail of three ZIKV-specific mAbs that targeted domain III was shown to prevent ZIKV infection in nonhuman primates 12 . In the present study, we assessed the therapeutic and prophylactic efficacy of a potent ZIKV-specific antibody in rhesus monkeys.…”

“…EDE-specific mAbs bind poorly to monomeric E-proteins but bind efficiently to stable E-dimers 18 and can be subdivided into two groups, EDE1 and EDE2, by their insensitivity or sensitivity, respectively, to removal of N-linked glycan at position 153, with EDE1 mAbs typically exhibiting greater potency 15,17 . Moreover, the EDE1-specific mAb B10 has been shown to prevent and treat ZIKV infection in mice 8 . We evaluated 33 EDE1-specific antibodies isolated from DENV infected patients 17 and found that B10 was the most potent at neutralizing a French Polynesian ZIKV strain (Fig.…”

“…Based on the rapid clearance of plasma virus by 24 hours after B10 infusion, we speculate that this antibody functions therapeutically by opsonization of virus followed by clearance. Previous studies have evaluated ZIKV-specific mAbs in therapeutic studies in immunosuppressed murine models 8–11 . Our data extend these prior studies by demonstrating the therapeutic and prophylactic efficacy of a ZIKV-specific antibody in nonhuman primates.…”

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

“…Vaccines for ZIKV are under development, but the path to approval may be exceedingly difficult because of antibody cross-reactivity with other flaviviruses and the possibility of disease enhancement (Bardina et al, 2017; George et al, 2017; Halstead, 2018; Harrison, 2016; Heinz and Stiasny, 2017; Katzelnick et al, 2017; Salje et al, 2018; Stettler et al, 2016). Passive administration of monoclonal antibodies represents an alternative approach to vaccines because human monoclonal antibodies can effectively neutralize the virus in vitro and protect against ZIKV infection in mice (Fernandez et al, 2017; Robbiani et al, 2017; Sapparapu et al, 2016; Stettler et al, 2016; Swanstrom et al, 2016; Yu et al, 2017). In addition, antibodies can be engineered to prevent interaction with Fcγ receptors that mediate enhancement and thus minimize the risk of disease enhancement (Beltramello et al, 2010).…”