Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques

Abstract

Therapies to prevent maternal Zika virus (ZIKV) infection and its subsequent fetal developmental complications are urgently required. We isolated three potent ZIKV-neutralizing monoclonal antibodies (nmAbs) from the plasmablasts of a ZIKV-infected patient—SMZAb1, SMZAb2, and SMZAb5—directed against two different domains of the virus. We engineered these nmAbs with Fc LALA mutations that abrogate Fc-gamma receptor (FcγR) binding, thus eliminating potential therapy-mediated antibody-dependent enhancement (ADE). We administered a cocktail of these three nmAbs to nonhuman primates (NHP) one day before challenge with ZIKV and demonstrated that the nmAbs completely prevented viremia in serum following challenge. Given that numerous Abs have exceptional safety profiles in humans, the cocktail described here could be rapidly developed to protect uninfected pregnant women and their fetuses. Overline: Emerging infections

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

“…An additional possibility is that the animals in the low-dose experiments were only monitored for 7 days, which may not have been sufficient to document delayed infection seen after antibody treatment (Abbink et al, 2018). Whether other antibodies, single or in combination, will be completely protective after high-dose challenge remains to be determined but would be highly relevant for further clinical development, since the precise dose delivered by the Aedes aegypti vector is not known (Abbink et al, 2018; Magnani et al, 2017b). …”

“…A combination of three antibodies targeting epitopes on the ZIKV envelope domain II and III regions was recently shown to be effective at preventing viremia in macaques (Magnani et al, 2017b), although the same three antibodies in combination failed to prevent virus transmission to the fetus (Magnani et al, 2018). Moreover, it was reported that a single antibody to a conformational epitope prevents ZIKV viremia for 7 days after low-dose challenge (Abbink et al, 2018), but viremia was not evaluated for longer periods of time or upon high-dose viral challenge.…”

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

“…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.…”

“…2). In contrast, a cocktail of three domain III-specific mAbs was required to prevent ZIKV infection in nonhuman primates 12 .…”

“…The potency of B10 and apparent relatively high bar to escape raise the possibility of antibody monotherapy, which would be logistically far simpler than the development of antibody cocktails 12 or bi-specific antibodies 9 . The structure of B10 remains to be determined, but the related cross-reactive DENV/ZIKV EDE1-specific mAb C8 binds a conserved quaternary site at the interface between the two Env subunits in the dimer at the interaction site of prM 16 , which may explain its high bar to escape.…”