Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation

• DOI: 10.1371/journal.ppat.1002705
• Publication Date: 2012-05-17T21:02:06Z
• Authors: Lisa C. Lindesmith; Martina Beltramello; Eric F. Donaldson; Davide Corti; Jesica Swanstrom; Kari Debbink; Antonio Lanzavecchia; Ralph S. Baric
• Keywords: 0301 basic medicine; B-Lymphocytes; QH301-705.5; Norovirus; Antibodies, Monoclonal; RC581-607; Antibodies, Viral; Antigenic Variation; Gastroenteritis; 3. Good health; Evolution, Molecular; Epitopes; 03 medical and health sciences; Antibody Specificity; Humans; Capsid Proteins; Amino Acid Sequence; Vaccines, Virus-Like Particle; Immunologic diseases. Allergy; Biology (General); Antigens, Viral; Cells, Cultured; Research Article; Caliciviridae Infections

Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% infections. The major capsid protein is evolving rapidly, resulting in new altered antigenic potentials. To test if drift may contribute to persistence, human memory B cells were immortalized and monoclonal antibodies (mAbs) characterized reactivity a panel time-ordered virus-like particles (VLPs). Reflecting complex exposure history volunteer, anti-GII.4 mAbs grouped into three VLP patterns; ancestral (1987–1997), contemporary (2004–2009), broad (1987–2009). NVB 114 reacted exclusively earliest VLPs by EIA blockade. 97 specifically bound blocked only VLPs, while NBV 111 43.9 variants GII.4.2006 Minerva strain. Three had reactivity. Two, 37.10 61.3, also detected other genogroup II but did not block any interactions carbohydrate ligands. 71.4 cross-neutralized as measured VLP-carbohydrate blockade assays. Using mutant designed alter predicted epitopes, two evolving, GII.4-specific, epitopes mapped. Amino acids 294–298 368–372 required binding 114, mAbs. 393–395 essential 97, supporting earlier correlations between antibody escape variation. These data inform vaccine design, provide strategy expanding cross-blockade potential chimeric vaccines, identify an broadly neutralizing therapeutic treatment disease. Moreover, these support hypothesis that norovirus evolution heavily influenced variation consequently, antibody-driven receptor switching; thus, protective herd immunity driving force molecular evolution.