DYNAMICS AND EVOLUTION OF IMMUNE RESPONSES TO INFLUENZA VIRUSES

PROJECT SUMMARY/ABSTRACT
Our goal is to develop a quantitative framework for the generation, boosting and maintenance of
immunological memory. Mathematical models are useful because immunization and infection involve the
interaction of rapidly changing populations of virus and multiple populations of immune cells. We first
develop and validate models using experiments in mice. We then use these validated models to analyze
data from human vaccination studies.
Aim 1 asks how prior immunity affects and potentially limit the boosting of immunity and apply this to
influenza. Our approach is to develop models to understand why prior immunity limits boosting of
antibodies to conserved regions of the virus. Specifically, we use our models to better understand how
prior immunity might limit boosting of antibody responses to conserved regions on the stem of the
hemagglutinin molecule that is the focus of universal influenza vaccines.
Aim 2 considers the factors that affect the durability of humoral immune memory, and address questions
such as why memory generated by immunization with protein antigens is less durable than immunity
generated by virus infection, and how prior immunity can differentially affect the boosting and generation
of memory to new strains of influenza.
Aim 3 considers the generation of CD8 T cell memory to influenza and yellow fever. We will determine
how repeated exposure to influenza affects the diversity of the CD8 T cell responses generated. We have
access to a unique dataset that follows the number of YFV-specific CD8 T cells, changes in their
phenotype, and their turnover from heavy water labelling studies for a period of over one year. Our analysis
of this dataset will allow us to address an ongoing controversy regarding whether are long-term memory
CD8 memory stem cells are generated rapidly after immunization or only gradually over time.
Aim 4 describes computational tools that we will build for B cell receptor sequence analysis and
visualization, and for simulation of the dynamics of immune responses. These tools will be widely
accessible online, and promoted at workshops and scientific symposia we organize.

Grant Number: 5U01AI150747-05
NIH Institute/Center: NIH
Principal Investigator: RUSTOM ANTIA