Global Analyses of Human Immune Variation Reveal Baseline Predictors of Postvaccination Responses

Abstract

A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of post-vaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time-points. Most of the parameters contributing to prediction delineated temporally-stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.

Vaccinology in the era of high-throughput biology

“…At an earlier time point, even with no virus replication, TIV elicits signatures associated with innate immunity, such as interferon and inflammatory responses [7]. Others also found similar results in adults [11,12] and even in children [15].…”

“…Although systems vaccinology has been extensively applied to study immune responses to TIV influenza vaccination in young adults [7,[9][10][11], very little has been done to investigate such responses in extreme age groups such as young children and the elderly [58], which have suboptimal responses to TIV vaccination [59,60]. In our work, in collaboration with Advanced Immunization Technologies, we are identifying early signatures of TIV immunogenicity in children of less than 2 years of age [61].…”

“…Among these, influenza vaccines are the most studied [7,[9][10][11][12]15]. Our group compared the [7].…”

“…Fluarix ) or a cold-adapted live attenuated vaccine, administered as a nasal spray (e.g. FluMist w ); which time points to analyse (clonal expansion of plasmablasts in the blood of young adults peaks at day 7 post-trivalent influenza vaccine (TIV) vaccination [6], whereas monocyte-and interferonrelated signatures peak at earlier time points [7]); the use of adjuvants such as MF-59 w [8]; which influenza strains to immunize subjects with, the seasonal ones [7,[9][10][11][12], or specific strains such as the 2009 H1N1 pandemics strain [11] and the avian-origin strains [13,14]; and, finally, the population target, which may include those with suboptimal responses or from different age groups, such as children [15], elderly or immunocompromised patients.…”

“…The tool kit accessible to modern immunologists includes a broad range of 'omics' technologies, such as high-throughput sequencing of DNA (DNA-seq), RNA (RNA-seq) or transcription factor binding sites (chromatin immunoprecipitation, ChIP-seq) [18], microarrays [7,[9][10][11]16,17,19], high-resolution mass-spectrometry proteomics/metabolomics [20], CyTOF mass cytometer [21] and genome-wide RNAi screening [22]. It is essential that the data obtained from these techniques are integrated or associated with data obtained from 'conventional' immunological assays, such as ELISA, ELISpot, FACS, and neutralization assays.…”