MOLECULAR DETERMINANTS OF HUMAN ANTIBODY MEDIATED INHIBITION OF HUMAN NOROVIRUS

Abstract

Human noroviruses (HuNoVs) are the leading cause of acute nonbacterial gastroenteritis and are responsible for 19-21 million cases of infection in the U.S. each year. There are currently no licensed vaccines, therapeutics, or prophylactics available to prevent or treat NoV infection. NoVs are classified into at least 6 phylogenetically distinct genogroups and are further subdivided into more than 31 genotypes. Viruses of genogroup I (GI) and a rapidly evolving genogroup II (GII) account for nearly all human infections. The antigenic variation among HuNoV strains has made developing an effective broadly cross-protective vaccine extremely challenging. Identifying the determinants of human antibody-antigen recognition and mapping blockade epitopes will define the HuNoV antigenic sites that could be used to design broadly protective vaccine candidates. I hypothesized that NoV infection induces genotype-specific and inter- or intra-genogroup I and II cross-reactive broadly blocking, or neutralizing, human antibodies, and that neutralization is mediated by Abs binding near the receptor binding domain. Several genotype-specific or cross-reactive broadly binding and broadly neutralizing human mAbs were identified and three-dimensional structural studies determined neutralizing epitopes on both a GI and GII variants. All isolated human mAbs also have the potential to be used for diagnostic or therapeutic purposes. Identifying anti-NoV human mAbs and defining blockade epitopes can provide valuable necessary insight for rational vaccine design efforts.