Research ArticleInfectious diseases

VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans

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Science Translational Medicine  21 Jun 2017:
Vol. 9, Issue 395, eaam5434
DOI: 10.1126/scitranslmed.aam5434

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Investigating heterotypic immunity to rotavirus

There are many serotypes of rotavirus, and currently available vaccines include only one or a handful of different strains. However, these vaccines are generally able to induce cross-reactive immunity that prevents diarrheal disease in young children. To get a better understanding of heterotypic immunity, Nair et al. isolated rotavirus-specific B cells from human intestinal tissue and cloned the antibodies for functional analyses. They discovered that heterotypic immunity was often derived from antibodies targeting the VP5* stalk epitope. Although only a small number of antibodies were studied, these results suggest that vaccines focused on the VP5* region may be better able to induce broadly protective immunity to rotavirus.

Abstract

Human rotaviruses (RVs) are the leading cause of severe diarrhea in young children worldwide. The molecular mechanisms underlying the rapid induction of heterotypic protective immunity to RV, which provides the basis for the efficacy of licensed monovalent RV vaccines, have remained unknown for more than 30 years. We used RV-specific single cell–sorted intestinal B cells from human adults, barcode-based deep sequencing of antibody repertoires, monoclonal antibody expression, and serologic and functional characterization to demonstrate that infection-induced heterotypic immunoglobulins (Igs) primarily directed to VP5*, the stalk region of the RV attachment protein, VP4, are able to mediate heterotypic protective immunity. Heterotypic protective Igs against VP7, the capsid glycoprotein, and VP8*, the cell-binding region of VP4, are also generated after infection; however, our data suggest that homotypic anti-VP7 and non-neutralizing VP8* responses occur more commonly in people. These results indicate that humans can circumvent the extensive serotypic diversity of circulating RV strains by generating frequent heterotypic neutralizing antibody responses to VP7, VP8*, and most often, to VP5* after natural infection. These findings further suggest that recombinant VP5* may represent a useful target for the development of an improved, third-generation, broadly effective RV vaccine and warrants more direct examination.

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