Atomic resolution structures of neutralizing antibodies bound to immunodominant epitopes provides new insights into GII.4 norovirus immune evasion

Anisa Ghosh, University of California,Santa Cruz

Anisa Ghosha, Kelsey A. Pilewskib, Kentaro Tohmab, Michael Landivarb, Gabriel I. Parrab, Rebecca M. DuBoisa a Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA. b Division of Viral Products, CBER, US. Food and Drug Administration, Maryland, USA.

Vaccines and immunity

GII.4 noroviruses are a leading cause of acute gastroenteritis worldwide. Their prevalence in humans is attributed to the continuous emergence of new variants that evade herd immunity. Understanding the mechanisms governing this immune evasion is crucial for developing broadly protective vaccines. Large-scale genomics studies identified variable antigenic sites on the norovirus capsid, with antigenic site A showing continuous diversification and playing a major role on HBGA-blocking responses, while antigenic site G exhibits time-restricted changes and has recently emerged as an immunodominant site. Despite the relevance of these antigenic sites in virus neutralization, the structural basis of antibody recognition at these sites remains largely unelucidated. Here, we present the first high-resolution crystal structures of two neutralizing and HBGA blocking monoclonal antibodies, 24C10 and 17A5, whose binding has been shown to be affected by changes in sites A/G and G, respectively. The structures revealed atomic-level interactions with residues from multiple antigenic sites, supporting initial data that immune escape results from synchronized changes at several neutralizing epitopes. Furthermore, these structures identified new variable residues associated with canonical antigenic sites. The buried surface area and the “angle of attack” by which these antibodies bind to the norovirus capsid protein suggest different mechanisms of HBGA-blockade. Notably, while ~60% of the residues involved in these epitopes mapped to conserved sites of the capsid only a subset of (variable) residues resulted in immune escape. A better understanding of the interaction of antibodies mapping to immunodominant epitopes could provide new avenues for the development of structure-guided vaccine candidates.