While antibody titers and neutralization are considered the gold-standards for the selection of a successful vaccine, these parameters are often inadequate predictors of protective immunity. Instead, antibodies mediate an array of additional extra-neutralizing Fc-mediated activities. Thus, when neutralization fails to predict protection, additional features of the humoral immune response, including Fc-mediated antibody activity, may participate in protective immunity, necessitating the use of more complex antibody profiling tools for the identification of unanticipated immunological correlates and/or for the downselection of protective vaccine antibody profiles. Thus a comprehensive, multivariate computational approach was developed that profiles relationships between humoral markers, termed Systems Serology, to profile individual vaccine trials. Each vaccine regimen induced a unique humoral “fingerprint,” clustering based on immunogen type/regimen, but also by protective/non-protective outcomes. Deeper interactome analyses, additionally, highlighted mechanistically critical antibody Fc-profiles and relationships that may mark “protective” humoral immune signatures. Moreover, application of this multivariate approach to case-control sample data from the RV144 HIV vaccine trial identified unexpected relationships between correlates of risk, and raises potential mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Collectively, multi-dimensional relational comparisons of humoral fingerprints offers a unique method for the evaluation and design of novel vaccines against pathogens for which the correlates of protection remain elusive.
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