DATA PORTAL LOGIN
Recent technological advances in antigen discovery, structural biology, genomics, immune monitoring and bioinformatics, has led to the establishment of the Human Vaccines Project (Project), a global public-private partnership with the goal of accelerating development of new and improved vaccines and immunotherapies for global infectious diseases and cancers by deciphering the human immunome and elucidating the rules of immunogenicity. Advances in the speed and accuracy of next-generation DNA sequencing technologies now allow exploration of the enormous diversity of variable genes encoding immune repertoires at unprecedented depth.
The human genome has been sequenced, but there is a special part of the genome in humans that is still not fully defined, which we have termed the HUMAN IMMUNOME, to designate the vast repertoire of expressed B and T cell receptors in humans. Unlike any other human genes, human antibody and T cell receptor genes (which encode the proteins of the adaptive immune response that recognize foreign invaders) are combinations of genes, and in addition the antibody variable genes are subject to high frequency of somatic mutation. The potential combinatorial diversity of immune genes (potential variable, N addition, diversity and joining gene [VH-N-DH-N-JH and VL-N-JL] combinations) is enormous, but many or even most of the combinations probably never exist as expressed proteins because they misfold (leading to elimination of those cells without surface receptors), fail to pair as a heavy/light chain combination, or they recognize our own tissues (they are autoreactive, and become eliminated or made anergic). Essentially, we do not yet know the “parts list” of the adaptive human immune system, with which we can design vaccines.
Current approaches to developing vaccines are empiric, since we don’t fully understand all of the structural components of the human adaptive immune system that function in molecular recognition of pathogens. In order to move forward to rational vaccine design, we need a complete database of all of the antibody and T cell sequences, and ultimately structures, which are made naturally in humans, across genders, ages, ethnicities and geography. With a complete HUMAN IMMUNOME deciphered, we could begin to use exciting new techniques for structure-based computational design of new antigens for difficult targets by considering the available immune molecules that can respond to such antigens.
Pre-pilot phase (2016)
- Definiton of HUMAN IMMUNOME in a small cohort of healthy subjects.
Pilot phase I (2017)
- Expand numbers of subjects in the HUMAN IMMUNOME cohort of healthy subjects.
- One year follow up of pre-pilot participants to determine stability of repertoires.
- Immunomes of subjects enrolled in a detailed study of hepatitis B vaccine, to extend the studies to a virus-specific context.
- Definiton of HUMAN IMMUNOME in small cohorts of disease states.
VUMC INSTITUTIONAL AFFILIATION
|James E. Crowe, Jr., MD||VVC||Director, Vanderbilt Vaccine Ctr PI, Human Immunome Program|
|Cinque Soto, Ph.D.||VVC||Bioinformatics/data processing|
|Robin Bombardi||VVC||Sequencing Core Manager; Immunome sequencing specialist|
|Andre Branchizio||VVC||Bioinformatics System Engineer|
|Ross Troseth||VVC||Bioinformatics System Engineer|
|Mahsa Majedi||VVC||Research Assistant|
|Pranathi Matta||VVC||Research Assistant|
|Nurgun Kose||VVC||Research Assistant, sample processing|
|Merissa Mayo||VVC||Project Manager|
|Simon Mallal, M.B.B.S.||Medicine||Director, VANTAGE core; TCR sequencing specialist|
|Mark Pilkinton, M.D., Ph.D.||Medicine||Bioinformatics/data processing|
VVC: Vanderbilt Vaccine Center, Nashville, TN, USA
VUMC: Vanderbilt University Medical Center, Nashville, TN, USA
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
|Name, Position||UBC Affiliations||Role||Description of Contribution/Reason for Inclusion|
|R. E.W. Hancock, PhD||Professor Dept. of Microbiology & Immunology||Co-I||Expert in systems biology and immunology|
|T.R. Kollmann, MDPhD||Professor Dept. of Pediatrics||PI||Expert in immune ontogeny and infectious disease|
|L. Foster, PhD||Professor & Interim Head Dept. Biochemistry||Co-I||Expert in proteomics & metabolomics|
|S. Tebbutt, PhD||Assoc. Professor; Dept. Medicine||Co-I||Expert in systems biology and biomarkers|
|R.R. Brinkman, PhD||Professor Dept. Medicine; BC Cancer Research Institute||Co-I||Expert in flow cytometry and bioinformatics|
|M. Kobor, PhD||Professor Dept. Medical Genetics||Co-I||Expert in epigenetics|
|M. Sadarangani, MDPhD||Assoc. Professor Department of Pediatrics||Co-I||Expert in vaccine studies and infectious disease; Director of Vaccine Evaluation Unit|
|M. Krajden, MD||Professor Dept. Medicine; Director BCCDC Lab.||Co-I||Expert in hepatitis and adult infectious diseases|
|G. Ogilvie, MD||Professor Dept. Medicine; School of Public Health||Co-I||Expert in vaccine studies and infectious disease|
ImmPort Vaccine Data
The ImmPort resource allows access to shared biomedical research data and metadata from generated by public and non-public funds. This project involves loading the relevant data from vaccine response studies in humans available within Immport (see below). Including these data in downstream bioinformatics workflows as part of a meta-analysis will improve the reliability of our results, generate testable hypotheses, and enable subsequent data-mining projects. We anticipate that integrating experimental results from these datasets will augment our knowledge of the human immune response after vaccination.
To view the study design and metadata associated with these studies, please open the following link: http://www.immport.org/immport-open/public/home/studySearch. Then select the checkboxes for "Vaccine Response" and "Homo sapiens" in the filter options on the left side of the page.