The Effect of Memory B cells on Influenza Vaccination, Immune Focusing, and Implications on Vaccine Design

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology & Immunology, 2017.Influenza A viruses periodically jump from animals to humans resulting in world-wide pandemics. As immunity to the virus rises in the population, either through infection or vaccination, the virus changes its shape (drift) in order to escape population immunity. Vaccination to the original virus is based on a simple observation that exposure to a dead or attenuated virus increases immunity to that virus. As the vaccine drifts (or if a new virus enters the population) the new virus is used to create a vaccine and the vaccine is re-administered to the population. In people with prior exposure to influenza, the antibody (immune) responses to subsequent immunization or infection are typically qualitatively and quantitatively different than in those who are immunologically naïve. Repeated exposure to antigenically similar (but not identical) viruses can also result in the focusing of the response to narrow regions of the virus, a phenomenon we call immune focusing. This can contribute to escape of the viruses from the immune response, diminishing vaccine efficacy and increasing risk of infection. Unfortunately, the mechanisms that explain these differences are not well understood, and it is currently difficult or impossible to predict how each individual will respond to a given vaccine or virus strain. Data in this dissertation and in the literature suggest that prior immunity in the form of antibodies or memory B cells alters responses to later virus strains. To better understand and predict responses to influenza in people with different prior exposures, simulations were performed using a simplified computer model of the humoral (B cell and antibodies) immune system. It was found that pre-existing memory B cells and antibody affected the responses to vaccination. Knowledge of the prior B cell memory and its specificity improve prediction of antibody responses to different influenza strains used in the simulations, and later verified by experimentation. Extension of these principles to human influenza immunity has implications for explaining defects in the current vaccine strategy, as well as potential to suggest altered strategies to improve protective immunity to the virus