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The Human Vaccines Project currently has three programs: 1) The Human Immunome Program, with the goal of deciphering the complete repertoire of B and T cell receptors across the human population, 2) The Rules of Immunity Program, with the goal of understanding the key principles of how a vaccine elicits a protective and durable response using a systems biology approach, and 3) The Universal Influenza Vaccine Initiative (UIVI), with the goal of conducting experimental clinical trials to understand the influence of influenza pre-exposures on subsequent influenza immunization and the mechanisms of protection.

The Human Immunome Program

The Human Immunome Program involves an unprecedented level of sequencing and data analysis to better understand the global repertoire of B and T cell receptors within each person, the degree to which individual B and T cell repertoires are unique, and the percentage of B and T cell clonotypes that are shared among all individuals. The processing and analysis of the transcripts sequenced in this program is facilitated by the expertise and computing capacity of the J. Craig Venter Institute (JCVI) and the San Diego Super Computer Center (SDSC). An additional goal of the Human Immunome Program is to understand the differences in the immunomes of healthy vs diseased individuals, and the immunomes from individuals with multiple sclerosis are currently being sequenced for comparison to non-diseased individuals. We are also sequencing the immunomes from newborn cord blood to determine the repertoire of B and T cells receptors that humans are born already possessing as well as the immunomes from people over 100 years old. The overarching objective of the Human Immunome Program is to create a sequence database compiled from these various areas of inquiry that will allow us to more fully understand the adaptive immune system in health and in disease, in the young and in the old, and inform future vaccine discovery and development efforts.
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BACKGROUND

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.

BACKGROUND

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

Name Affiliations Role
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
CTC: Clinical Trials Center, Nashville, TN, USA
VVC: Vanderbilt Vaccine Center, Nashville, TN, USA
VUMC: Vanderbilt University Medical Center, Nashville, TN, USA

The Rules of Immunity Program

The Rules of Immunity Program involves conducting experimental clinical trials using licensed vaccines as probes to perform comprehensive omics and immunoassays to uncover the components the immune system responsible for generating a protective and durable response using a systems biology approach. Unlike most vaccine clinical trials, we are specifically interested at very early events immediately following immunization to allow for the measurement of innate immune responses and the assessment of innate signatures and novel transcriptional activation patterns that can be directly correlated with subsequent adaptive responses and seroconversion. The extensive series of assays that we conduct include: antibody responses (serology, sub-class, avidity), B cell analysis (B cell ELISpot, NextGen sequencing of IgG memory B cells), flow cytometry immunophenotyping (FlowBin analysis), cell-mediated immunity (ELISpot), single-cell RNA-sequencing of several innate cell populations, transcriptomics, proteomics, metabolomics, epigenetics, microbiome analysis (stool, nose, mouth, skin), as well as analysis of tissue-specific responses from lymph node and bone marrow biopsies post vaccination.

The strength of the systems biology approach in the Rules of Immunity programs lies in both the comprehensive set of assays that are performed and in the use of advanced computational methods that integrate across multiple data sets to identify novel or emergent patterns in the immune response that are evident only when the data are analyzed as a unified system. Additionally, we employ techniques used in the field of high dimensional statistics to identify relevant variables and consistent interactions in large data sets despite a small sample size. The information and insight gained from the Rules of Immunity program will not only set new standards for systems vaccinology research, but will also lead to groundbreaking discoveries about the human immune response to vaccination which will transform the way that we develop, test and administer vaccines in the coming decades.
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BACKGROUND

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

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

The Universal Influenza Vaccine Initiative (UIVI)

The third program of the Human Vaccines Project is the Universal Influenza Vaccine Initiative, with the purpose to understand the underlying immune mechanisms involved in the response to influenza in order to facilitate the research and development of universal influenza vaccines. Because current seasonal influenza vaccines are consistently ineffective due to antigenic drift, and because the potential for pandemic influenza outbreaks remains a threat, the UIVI has begun planning experimental clinical trials designed to increase our understanding of the mechanisms that underlie the immune response to initial influenza exposure (infant cohort) and more fully elucidate the mechanisms of how B and T cell memory responses (older adults) affect subsequent responses to influenza immunization. The information gained by conducting these experimental influenza trials that will also involve in-patient challenge studies, which are desperately needed if we are to make any significant gains in the development of a vaccine that will be broadly efficacious in all populations, regardless of previous influenza exposures.

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.

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