Bioinformatics Data Hub Project

Rules of Immunity Program

Using systems biology to identify emergent patterns in immune response to vaccines.

Systems Biology to Identify Biomarkers of Vaccine Immunogenicity Across the Human Lifespan

Vaccine preventable infections remain a major cause of morbidity and mortality, especially at the extreme ends of life and in resource-limited populations. This likely relates to the suboptimal response to vaccination especially of subjects at the extreme ends of life and in resource-poor environments. To improve vaccine-mediated protection in these vulnerable groups, we will need to garner insight into the underlying cause. Systems biology approaches (OMICs) applied to vaccinology (systems vaccinology) has revolutionized the field with an unbiased identification of pathways relevant to vaccine-induced immune responses. However, systems vaccinology has focused primarily on adults in resource-rich populations. We successfully adapted the experimental platforms to be fully operational within the small blood volumes obtainable from e.g. newborns and infants.

Our pilot data prove feasibility of collecting high-quality samples across multiple study sites according to our stringently controlled standard operating procedures. As a result, we have been awarded a NIH Human Immunology Project Consortium (HIPC) grant to study the immune response to Hepatitis B Virus vaccine (HBV) of newborns in resource-limited areas of Africa and Australasia. The Human Vaccines Project (HVP), a global not-for-profit, public-private partnership of leading academic centers and vaccine manufacturers has offered to fund an extension of our HIPC study to focus on high resourced areas (BC, Canada) and to broaden it to include the entire age spectrum not just the newborn. This would be the first comprehensive study of the immune response to vaccination across the entire age spectrum, contrasting subjects from low vs. high resourced areas. As in our NIH-peer reviewed HIPC grant, we will determine the molecular pathways associated with successful immunization with HBV. HBV is the ideal model because it is highly (>90%) effective and has a well-established, quantitative correlate of protection (CoP). As complex networks of functional interactions among genes, proteins, metabolites and their regulation (e.g. epigenetics) drive the response to immunization, we will integrate transcriptomic, proteomic, metabolomic, epigenetic and immune phenotyping approaches to determine the rules of HBV immunogenicity across the age- and resource-spectrum addressing these Specific Aims:

  • Aim 1. Characterize pre-vaccine OMIC and immune signatures that predict immunogenicity of HBV in humans across age- and resource-spectrum. In adult systems vaccinology studies, baseline immune status (i.e. pre-vaccine) of vaccine recipients was highly predictive of vaccine immunogenicity. We will characterize pre-vaccine whole blood gene expression, epigenetics, plasma proteome and metabolome as well as white blood cell composition in relation to the established CoP for HBV.
  • Aim 2. Characterize the post-vaccine impact of HBV on OMIC and immune signatures that predict immunogenicity of HBV. Analysis of vaccine-induced signatures (i.e. post-vaccine) in adults has provided new insights into mechanisms driving immunogenicity. We will characterize whole blood gene expression, epigenetics, plasma proteome and metabolome as well as white blood cell composition and functional status on Days 1, -3 , -7 and -14 post-vaccine and correlate this with the HBV CoP.
  • Aim 3. Explore the role of the microbiome as well as correlations of vaccine-induced changes in lymph node vs. blood on vaccine responses. Recent data from animal models suggest a powerful influence of the microbiome on vaccine responses. Furthermore, vaccine induced changes in draining lymphnodes of monkeys provide better predictors of immunogenicity than changes in peripheral blood. Neither of these aspects has been systematically investigated in the human setting. We will begin to explore these in this project

Collaborators

Primary Investigator

T.R. Kollmann, MD PhD

Professor, Dept. of Microbiology & Immunology, UBC
Expert in immune ontogeny and infectious disease
Co-Investigators

R. E.W. Hancock, PhD

Professor, Dept. of Microbiology & Immunology, UBC
Expert in systems biology and immunology

L. Foster, PhD

Professor & Interim Head, Dept. Biochemistry, UBC
Expert in proteomics & metabolomics

S. Tebbutt, PhD

Assoc. Professor, Dept. Medicine, UBC
Expert in systems biology and biomarkers

R.R. Brinkman, PhD

Professor, Dept. Medicine & BC Cancer Research Institute, UBC
Expert in flow cytometry and bioinformatics

M. Kobor, PhD

Professor, Dept. Medical Genetics, UBC
Expert in epigenetics

M. Sadarangani, MDPhD

Assoc. Professor, Department of Pediatrics, UBC
Expert in vaccine studies and infectious disease; Director of Vaccine Evaluation Unit

M. Krajden, MD

Professor, Dept. Medicine & Director BCCDC Lab., UBC
Expert in hepatitis and adult infectious diseases

G. Ogilvie, MD

Professor, Dept. Medicine & School of Public Health, UBC
Expert in vaccine studies and infectious disease