# Structural basis for recognition of Rift Valley fever virus Gn protein by a human neutralizing monoclonal antibody with a kappa light chain

## TL;DR

This study reveals how a human antibody recognizes a key protein on the Rift Valley fever virus, offering insights for vaccine design.

## Contribution

The paper provides a novel structural analysis of a unique human monoclonal antibody with a kappa light chain targeting the RVFV Gn protein.

## Key findings

- RVFV-379 uses an oblique angle of approach to bind the Gn protein, differing from other antibodies.
- RVFV-379 has a larger epitope footprint involving both light and heavy chains.
- The antibody exhibits limited neutralization breadth across RVFV strains due to epitope variability.

## Abstract

Rift Valley fever virus (RVFV) poses a continued threat to human health and animal husbandry. Two neutralizing and protective human monoclonal antibodies (mAbs), RVFV-268 and RVFV-379, exhibit similar affinities and epitope footprints on the Gn glycoprotein component of the RVFV Gn-Gc capsomeric lattice. Here, we define fine details of the biophysical determinants of Gn recognition used by RVFV human monoclonal antibodies through studying an antibody encoded by a set of recombined genes not previously identified in RVFV antibodies. We find that RVFV-379 exhibits a larger footprint than that observed for RVFV-268 and other antibodies targeting the same region, which involves major contributions of both the light and heavy chains. RVFV-379 also uses an oblique angle of approach towards the virion surface that contrasts with the perpendicular angle of engagement observed for some other potently neutralizing human mAbs. Further, consistent with amino acid sequence variation within and proximal to the RVFV-379 epitope, in vitro neutralization screening reveals a limited degree of neutralization breadth across prevalent RVFV strains, suggesting that RVFV has fewer functional constraints at this region of the virus envelope. By dissecting the molecular determinants of mAb recognition of Gn, this integrated analysis refines strategies needed for the rational design of vaccines that can elicit a potent and species-wide protective antibody immune response to this important re-emerging pathogen.

Rift Valley fever virus (RVFV) constitutes a continued threat to human health and animal husbandry. While the humoral response against RVFV in humans is known to elicit potently neutralizing and protective antibodies, a comprehensive understanding of the molecular determinants of neutralization remains incompletely defined and is essential for addressing this threat. Here, we describe a protective human monoclonal antibody (mAb) termed RVFV-379, which is encoded by a kappa light chain gene and potently neutralizes RVFV. We structurally characterize this unique mAb in complex with a major antigenic target on RVFV, the Gn glycoprotein, and reveal a binding pose distinct to other reported human mAbs directed against Gn. Through examination of the specificity underlying this antibody-antigen interaction, we refine our knowledge about a key site of vulnerability on the RVFV surface. Further, this integrated functional and structural study provides a template that informs upon determinants of cross-protection against prevalent RVFV strains, an essential consideration for rational vaccine design.