Mapping the landscape of human norovirus antigens during infection reveals the timing and breadth of the humoral immune response among individuals


Human noroviruses (HuNoVs) are the leading cause of vomiting, diarrhea, and foodborne diseases worldwide. HuNoV infections result in the global financial costs of 60 billion USD and the public health burden of ~200,000 deaths. Currently, there is still no licensed vaccine due to the difficulties in developing a vaccine that is able to overcome the wide genetic and antigenic diversity of noroviruses with multiple variants of various genotypes.

A thorough understanding of the humoral immune response against HuNoV infections is critical in the design of a protective vaccine as humoral immunity plays a critical role in viral clearance. To facilitate this, we sought to build a comprehensive antigenic map of HuNoV during infections. An antigenic map could answer questions such as what epitopes are recognized during an infection, how does our immune profile differ from one another, does the antigenic landscape change throughout the course of an infection, and are there conserved and immunodominant epitopes among HuNoVs.

In our recently published study, we performed phage display affinity selections coupled with deep sequencing on human sera of individuals infected with HuNoVs to characterize the repertoire of antibodies produced by the humoral immune response. Our first key finding revealed both common and unique epitopes that were distributed among both the HuNoV nonstructural proteins and the major capsid protein VP1. The common epitopes suggest the presence of immunodominant antibodies among the infected individuals. Several epitopes were also previously identified as neutralizing.

Secondly, a longitudinal analysis from three individuals showed the presence of pre-existing epitopes in the pre-infection sera, emergence of de novo epitopes post infection, and the persistence of both the pre-existing and the de novo epitopes by 180 days post-infection. The presence of pre-existing epitopes suggests prior HuNoV infections in all three individuals and the persistence of both pre-existing and de novo epitopes throughout the course of infection suggests a “back-boosting” effect of the humoral immune response during HuNoV infection. Lastly, we identified cross-reactive epitopes between different genogroups and genotypes of HuNoVs with high levels of sequence conservation.

In summary, our findings could be applied to the design of a potentially protective vaccines with conserved and possibly neutralizing epitopes. If the vaccine could elicit the production of antibodies with a “back-boosting” effect, where both the immunity targeting the past and present infections are induced, the vaccine could also contribute to the broad and prolonged protection of the immune response. Other than uncovering a comprehensive antigenic map of HuNoV, our approach could also be utilized to identify important epitopes in other disease models for the development of broadly protective vaccines and even diagnostics and antibody-based therapies.

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