Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality

Abstract

The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.

Seroprevalence of Zika virus in pregnant women from central Thailand

“…The clinical outcome of a fetus of ZKV infected women is also related to gestational age at the time of infection and the stage of brain development [ 35 ]. Absent or insufficient nAb against ZKV may increase susceptibility to infection [ 36 ], while pre-existing nAb is able to prevent viral infection or reduce disease severity [ 37 ]. Thus, most of the participants in our study were at risk of ZKV infection.…”

Zika virus-specific IgM elicited during pregnancy exhibits ultrapotent neutralization

“…Structural analysis of DH1017.Fab in complex with whole ZIKV virion identified a quaternary epitope footprint encompassing primarily DII that differs from that of known potently ZIKVneutralizing mAbs. Antibody responses targeting quaternary epitopes on multimeric E protein epitopes or mature virions are associated with protection from ZIKV infection in mice (Maciejewski et al, 2020;Metz et al, 2019). Recognition of a quaternary epitope on ZIKV is the defining feature of a class of potently neutralizing mAbs (Collins et al, 2019;Hasan et al, 2017b;Long et al, 2019;Rogers et al, 2017;Sapparapu et al, 2016;Stettler et al, 2016).…”

Distinct cellular immune signatures in acute Zika virus infection are associated with high or low persisting neutralizing antibody titers

“…Finally, we sought to correlate cellular immune features from acute infection with the formation of ZIKV neutralizing antibody titers. While it is likely that neutralizing antibodies play a key role in immunologic protection from ZIKV and other acute viral infections ( 73 ), a titer that correlates with protection in humans has not been identified ( 16 ) and other antibody functions ( 74 ) and/or other types of immune responses may be critical to providing robust protection.…”