A cytotoxic-skewed immune set point predicts low neutralizing antibody levels after Zika virus infection

Although generating high neutralizing antibody levels is a key component of protective immunity after acute viral infection or vaccination, little is known about why some individuals generate high versus low neutralizing antibody titers. Here, we leverage the high-dimensional single-cell profiling capacity of mass cytometry to characterize the longitudinal cellular immune response to Zika virus (ZIKV) infection in viremic blood donors in Puerto Rico. During acute ZIKV infection, we identify widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated cell types during acute infection are associated with high titers of ZIKV neutralizing antibodies 6 months post-infection, while stable immune features suggesting a cytotoxic-skewed immune set point are associated with low titers. Our study offers insight into the coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials aimed at inducing high levels of antiviral neutralizing antibodies. [Display omitted] •We investigate coordinated immune activation during acute ZIKV infection•Individuals have distinct cellular immune signatures during acute ZIKV infection•High immune activation in acute ZIKV predicts high neutralizing antibody levels•A stable cytotoxic-skewed set point predicts low neutralizing antibody levels McCarthy et al. use mass cytometry to longitudinally characterize peripheral cellular immune features during Zika virus (ZIKV) infection in non-pregnant adults. They identify distinct cellular immune signatures during acute infection that reliably predict the persistence of high versus low ZIKV-specific neutralizing antibody levels 6 months after infection.