Serum Immunoglobulin A Cross-Strain Blockade of Human Noroviruses

Abstract

Background. Human noroviruses are the leading cause of acute viral gastroenteritis, justifying vaccine development despite a limited understanding of strain immunity. After genogroup I (GI).1 norovirus infection and immunization, blockade antibody titers to multiple virus-like particles (VLPs) increase, suggesting that GI cross-protection may occur.Methods. Immunoglobulin (Ig)A was purified from sera collected from GI.1-infected participants, and potential neutralization activity was measured using a surrogate neutralization assay based on antibody blockade of ligand binding. Human and mouse monoclonal antibodies (mAbs) were produced to multiple GI VLPs to characterize GI epitopes.Results. Immunoglobulin A purified from day 14 post-GI.1 challenge sera blocked binding of GI.1, GI.3, and GI.4 to carbohydrate ligands. In some subjects, purified IgA preferentially blocked binding of other GI VLPs compared with GI.1, supporting observations that the immune response to GI.1 infection may be influenced by pre-exposure history. For other subjects, IgA equivalently blocked multiple GI VLPs. Only strain-specific mAbs recognized blockade epitopes, whereas strain cross-reactive mAbs recognized nonblockade epitopes.Conclusions. These studies are the first to describe a functional role for serum IgA in norovirus immunity and the first to characterize human monoclonal antibodies to GI strains, expanding our understanding of norovirus immunobiology.

Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades

“…Moreover, the protective role of IgA was also found to be associated with protection against a GI.1 NoV infection (41). In another study, IgA purified from convalescent-phase sera of GI.1 NoV-challenged individuals was shown to block binding of NoV VLPs to PGM (42). Further, a recent study showed that the IgA isotype in human B cells encoding norovirus-specific monoclonal antibodies could frequently block binding of VLPs to HBGA in comparison to antibodies having IgG specificity (43).…”

Antiviral targets of human noroviruses

“…HBGA-blocking antibodies can vary in specificity, from genotype-specific to variant-specific and even strain-specific among the globally prevalent GII.4 NoVs, further emphasizing a correlated interplay between antigenicity and HBGA specificity in the evolution of NoVs [12,13,50]. Human monoclonal antibodies that block HBGA binding have been isolated and produced from the peripheral blood mononuclear cells of blood donors, and the few that have been characterized to date appear to be genotype-specific [51]. In addition, nanobodies that block HBGA binding in GI.1 and GII.4 VLPs, have been identified and characterized [52*].…”

Norovirus-specific mucosal antibodies correlate to systemic antibodies and block norovirus virus-like particles binding to histo-blood group antigens

“…However, there are subtle differences in IgG and IgA induction and duration after acute infection that should be taken into account; i.e. NoV-specific IgG peaks after IgA and is more longlasting [42,[56][57][58]. A limitation of our current study was the lack of infection-related samples and therefore we were unable to test the antibody levels in response to infection.…”

“…We also detected small amount of SIgA in serum, which happens when mucosal SIgA leaks back into systemic circulation [63]. What role does the SIgA play in systemic immunity is not clear, but others have shown that purified serum anti-NoV IgA confers cross-strain blocking activity [58].…”