Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Scott E. Hensley

Abstract

Antibodies (Abs) elicited by influenza viruses often bind with higher affinities to past influenza strains than to the current strain. This has been associated with the hypothesis of “original antigenic sin” which postulates that B cell clones elicited by prior exposure are recalled at the expense of generating a strain-specific response to the current strain. It is clear that prior exposures to influenza viruses focus the response on conserved epitopes of influenza’s hemagglutinin (HA) glycoprotein. Here, pre-exposure to influenza is shown to affect Ab fine specificity and Ab mediated protection in mice, ferrets, and humans. Sequential vaccination of mice with antigenically drifted strains of influenza virus elicited a large proportion of cross-reactive Abs, but also recalled Abs that have a higher affinity for the priming strain while binding to the same region of HA with different fine specificities. These fine specificities were modified by somatic hypermutation, which affected the degree of cross-reactivity. Surprisingly, Abs that bound with relatively low affinities to an antigenically drifted strain effectively neutralized the drifted strain following passive transfer. This indicates that Abs expressed by recalled B cell clones share some level of cross-reactivity between antigenically drifted priming and recall strains. This was also observed by measuring the reactivity of sera to HA of antigenically drifted influenza strains. Similarly, ferrets and humans sequentially exposed to influenza viruses had Ab repertoires that were focused on epitopes conserved between recent strains and earlier strains that circulated during their childhood. As influenza viruses continually mutate, humans had Ab repertoires that were focused on different regions of the HA, potentially due to unique pre-exposure histories. A recently acquired HA mutation abrogated binding of Abs predominantly found in middle-aged adults that were unusually susceptible to influenza infection during the 2013-2014 influenza season. These findings highlight that while weakly cross-reactive Abs can protect against antigenically drifted strains, shifting the Ab repertoire to partially conserved sites can focus the response on regions of the virus that undergo continual antigenic drift. Recall of cross-reactive Abs can thus result in protection or susceptibility to influenza, depending upon the exposure history and Ab fine specificities.

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