Research

We research the population and evolutionary dynamics of host-pathogen interactions using computational and mathematical models. We collaborate closely with experimental immunologists and epidemiologists. Our work involves three overlapping themes:

Ecology and evolution of influenza and other multistrain pathogens

We are working to explain the spatiotemporal diversity of influenza and other pathogens composed of multiple strains, especially strains that appear somewhat distinct to the immune system. Protective immunity can be a strong evolutionary pressure, as in influenza, and it can also stabilize the dynamics of competing strains and promote coexistence. We are interested in how immune pressure interacts with strains' transmission dynamics and evolution to lead to the diversity of pathogens that infect us today. Understanding the interplay of these forces is essential for the development of effective vaccination strategies, which can alter the strength and type of immune selection. It can also help us understand variation in epidemic sizes in space and time.

Examples:

Evolution of the antibody response

A host's primary means of protection to pathogens like influenza is through antibodies, which themselves evolve rapidly by natural selection as B cell receptors. Understanding the dynamics of antibody repertoires is thus key to understanding much pathogen evolution and variation in susceptibility between people. B cells are also a unique example of evolved evolvability that have received relatively little attention from evolutionary biologists. We are investigating the evolutionary dynamics of primary B cell responses to quantify the contributions of chance, competition, and evolutionary constraints on the primary immune response. We are also investigating secondary responses to measure the strength of competition between pre-existing and new responses. This competition between memory and naïve responses underpins a phenomenon known as "original antigenic sin" or possibly "immune imprinting" in influenza, and potentially influences susceptibility. We are investigating the evolution of the antibody response by fitting longitudinal models to individuals and birth year cohorts over time, and also by analyzing serology.

Examples:

Effectiveness and effects of the seasonal influenza vaccine

The low effectiveness of the seasonal influenza vaccine is often attributed to poor strain selection due to influenza's fast evolution. Our simulations suggest if antigenic mismatch were the only source of low vaccine effectiveness, then stopping seasonal influenza transmission with the seasonal vaccine might be easier than thought. In practice, intrinsically limited vaccine-induced protection might make eradication harder. Several groups, including ours, have shown that the vaccine response is influenced by the same factors that shape specificity in natural infection, especially exposure history: adults have qualitatively different responses compared to naïve animals after influenza vaccination, and vaccination history affects the specificity of the response to recent seasonal vaccines. We think this might explain the unexpected failure of the vaccine in some age groups in some seasons, but there are also statistical uncertainties underlying many estimates of vaccine effectiveness. Another focus is how widespread vaccination might affect influenza's evolution.

Examples: