The Gn subcomponent of the Gn-Gc assembly that envelopes the human and animal
pathogen, Rift Valley fever virus (RVFV), is a primary target of the neutralizing
antibody response. To better understand the molecular basis for immune recognition, we
raised a class of neutralizing monoclonal antibodies (nAbs) against RVFV Gn, which
exhibited protective efficacy in a mouse infection model. Structural characterization
revealed that these nAbs were directed to the membrane-distal domain of RVFV Gn and
likely prevented virus entry into a host cell by blocking fusogenic rearrangements of the
Gn-Gc lattice. Genome sequence analysis confirmed that this region of the RVFV Gn-Gc
assembly was under selective pressure and constituted a site of vulnerability on the virion
surface. These data provide a blueprint for the rational design of immunotherapeutics and
vaccines capable of preventing RVFV infection and a model for understanding Abmediated neutralization of bunyaviruses more generally.