2021 FDA Science Forum
Characterization of B-cell Immunodominance in Ever-Changing Enteric Virus Reveal an Additional Mechanism for Emergence of New Variants and New Avenues for Vaccine Development
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Contributing OfficeCenter for Biologics Evaluation and Research
Abstract
Background
A paradigm of RNA viruses is their ability to introduce mutations on antigenic sites that would allow escape from herd immunity. Thus, the holy-grail for vaccine development for such viruses, like influenza or norovirus, is to be able to predict the changes that would emerge in the future. To develop precise models that would predict virus antigenic evolution, we need to understand the mechanisms that govern such diversification. Here, we use GII.4 noroviruses as a model for virus evolution, and show that switches of B-cell immunodominance redirect immune responses that help viral escape from herd immunity, revealing a new mechanism for the antigenic diversification of ever-changing viruses.
Methods
Using population genomics and structural information, we first defined all variable antigenic sites on the capsid protein (VP1) from GII.4 norovirus over 20 years of evolution. We then characterized the antigenic topology using (i) virus-like-particles (VLPs) from wild-type and rationally-designed mutant VLPs with antigenic sites swapped between different variants, (ii) two large panels of MAbs obtained from immunized mice with different wild-type VLPs, and (iii) polyclonal sera raised against different wild-type VLPs. Furthermore, B-cell immunodominance was determined using time-ordered wild-type and corresponding mutant VLPs.
Results
We characterized new antigenic sites and found that a large number of MAbs interacted with multiple variable antigenic sites. Moreover, we observed a remarkable difference between the epitope-binding repertoire for the two panels of MAbs. Thus, MAbs generated against 2004 viruses presented the antigenic site A as immunodominant, while antigenic sites A and G were immunodominant in 2012 virus. These differences on the B-cell immunodominance were confirmed by using polyclonal sera raised against wide-type 2004 and 2012 VLPs in mice and guinea pigs. Further analysis using time-ordered mutant VLPs confirmed the progressive gain of immunodominance of antigenic site G over A.
Conclusions
In addition to point mutations, the change in the epitope-binding repertoire and B-cell immunodominance could be an additional mechanism used by constantly-evolving viruses to escape from herd immunity. Manipulation of the immunodominance hierarchy could provide new avenues for the design of cross-reactive and potent vaccines.
