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

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.

Rotavirus infection

“…Thus, safer replication-incompetent rotavirus vaccines are required. One study identified memory B cells in the submucosa of adult intestinal tissue that produced broadly cross-reactive and cross-neutralizing antibodies specific to VP5*; accordingly, recombinant VP5* might represent a broadly efficient candidate for a rotavirus vaccine 191 .…”

A G3P[13] porcine group A rotavirus emerging in China is a reassortant and a natural recombinant in the VP4 gene

“…However, many neutralizing antigen epitope differences were identified on the VP4 protein between the Chinese PoRV strains and the RCE strains, suggesting the reduced effectiveness of the RCE strains. Rotavirus antigens and serotypes are diverse, suggesting that obtaining extensive protective immunity requires immunization or infection with multiple antigens (Nair et al., ). More information is needed to understand the diversity of field strains and to develop an effective polyvalent vaccine as a possible means of PoRV control in China.…”

The Role of Innate Immunity in Regulating Rotavirus Replication, Pathogenesis, and Host Range Restriction and the Implications for Live Rotaviral Vaccine Development

“…Other potential disadvantages of inactivated vaccines become apparent when the antigen or antigens required to induce protective immunity are difficult to synthesize artificially or when immunity is most potent when it is directed at multiple antigens that are correctly folded only on the actual or recombinant multiprotein viral particle. Of note, RVs have at least two separate proteins (VP4 and VP7) that are targets of protective antibodies, and VP4 is cleaved by enteric trypsin into two separate protein components: VP8* and VP5* [78]. Both VP8* and VP5* are individually targeted by protective antibody responses.…”