Sub-neutralizing concentrations of Zika virus IgM monoclonal antibodies reduce IgG-mediated antibody-dependent enhancement of infectivity

Zika virus (ZIKV) is an arthropod-borne flavivirus endemic to Latin America and Africa for which IgG-mediated antibody-dependent enhancement of infectivity (ADE) is a phenomenon of concern. The interplay dynamics between flavivirus-specific antibodies of the IgG and IgM isotypes are mostly unknown. Here, we used DH1017.IgM, a previously described human-derived, pentameric, ultrapotent neutralizing ZIKV IgM monoclonal antibody (mAb) and a recombinantly produced IgM version of neutralizing EDE1 mAb C8 (C8.IgM) to assess if IgM antibodies can interfere with IgG-mediated ADE <i>in vitro</i>. Both mAbs consistently reduced IgG-mediated ADE across a panel of ZIKV-binding IgG mAbs in a dose-dependent manner. ADE mitigation was achieved at DH1017.IgM sub-neutralizing concentrations. C8.IgM also mitigated IgG-mediated ADE against the whole panel, demonstrating generalizability. Finally, DH1017.IgM confirmed inhibition of ADE at sub-neutralizing concentrations in sera of ZIKV-infected individuals. In conclusion, mAbs of the IgM isotype may potently counter the adverse effects of IgG-mediated ADE.