Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults

Abstract

Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, in vitro T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches—NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.

Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort

“…Participants with anti-hepatitis B surface antigen (HBs) antibody levels under 3.1IU/L were considered seronegative and a total of 15 eligible individuals enrolled to participate in the study. For detailed inclusion/exclusion criteria, see the HBV vaccine Methods manuscript: Systems biology methods applied to blood and tissue for a comprehensive analysis of immune response to Hepatitis B vaccine in adults (8). Enrolled individuals attended the first study visit involving the collection of clinical history, a physical examination as well as pre-vaccination biospecimen collection (blood and fecal microbiome samples).…”

“…HBV serology of study participants at baseline were performed at the BC Centre for Disease Control. In total, participants were monitored during 12 visits spanning the course of seven months (8). HBV titres were measured once during the screening phase, and at three additional time points, corresponding to 28, 180, and 208 days after the first dose of HBV vaccine.…”

Machine learning-based single cell and integrative analysis reveals that baseline mDC predisposition predicts protective Hepatitis B vaccine response

“…Descriptions of all methods not detailed below have recently been published in [Ben-Othman 2020, Shannon 2020].…”

“…Various omics studies were performed as described [Ben-Othman 2020, Shannon 2020]. Briefly, peripheral whole blood cells were profiled by flow cytometry, genome-wide DNA methylation (Illumina Infinium MethylationEPIC BeadChip), transcript abundance (bulk RNA-Seq), and proteome-wide protein abundance (mass spectrometry) at various time points.…”

“…Third, around 10% of subjects respond with protective antibody titres following a single dose [Schillie 2013]. We recently applied a series of validated multi-omics assays to measure the full range of cellular and molecular components of the immune system, including immune cell composition, DNA methylation, gene expression, protein abundance, and fecal 16S microbiome, to provide an exhaustive picture of the immune response to the HBV vaccine [Ben-Othman 2020]. Multi-omics integrative analysis on these data sets identified a number of candidate baseline predictors of vaccine response using serum antibody titers to the HBV surface antigen following three vaccine doses as the quantitatively-defined endpoint in a relatively small cohort of 15 vaccine recipients [Shannon 2020].…”