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

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Science Translational Medicine  10 Jun 2020:
Vol. 12, Issue 547, eaaw9066
DOI: 10.1126/scitranslmed.aaw9066

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Quantity and quality

The Zika virus epidemic prompted rapid development of several vaccines. Maciejewski et al. tested two similar DNA vaccines in nonhuman primates and found that although both induced neutralizing antibodies, only one was protective against a viral challenge. Further testing with samples from animals or from clinical trials with these vaccines revealed an important aspect regarding neutralizing antibody quality. The protective vaccine generated relatively more antibodies that could bind the mature form of Zika virions, whereas antibodies induced by the other vaccine were more sensitive to virion maturation state. Passive transfer experiments with sera normalized for mature virion neutralization showed equivalent protection between the two vaccines. These results highlight how antibody quality plays a major role in vaccine efficacy. Furthermore, thinking beyond conventional assays for antibody responses may lead to identification of correlates of protection.


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.

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