Bioinformatics Data Hub Project

Human Immunome Program

Sequencing and data analysis to better understand B and T cell receptors.

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.

Scope Of Work

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.

Project Leadership

Primary Investigator

James E. Crowe, Jr., MD

Director, Vanderbilt Vaccine Center
Project Manager

Merissa Mayo

Vanderbilt Vaccine Center
Project Team

Cinque Soto, Ph.D.

Bioinformatics/data processing, Vanderbilt Vaccine Center

Robin Bombardi

Sequencing Core Manager & Immunome sequencing specialist, Vanderbilt Vaccine Center

Andre Branchizio

Bioinformatics System Engineer, Vanderbilt Vaccine Center

Ross Troseth

Bioinformatics System Engineer, Vanderbilt Vaccine Center

Mahsa Majedi

Research Assistant, Vanderbilt Vaccine Center

Pranathi Matta

Research Assistant, Vanderbilt Vaccine Center

Nurgun Kose

Research Assistant & Sample Processing, Vanderbilt Vaccine Center

Simon Mallal, M.B.B.S.

Director at VANTAGE Core & TCR sequencing specialist, Vanderbilt University Medical Center

Mark Pilkinton, M.D., Ph.D.

Bioinformatics/data processing, Vanderbilt University Medical Center