Potent monoclonal antibody–mediated neutralization of a divergent Hendra virus variant

Significance A new Hendra virus variant (HeV-g2) has been recently identified in two independent studies, increasing the concern of HeV spillover. Here, we show that HeV-g2 utilizes the same host receptor as HeV and that a panel of previously described HeV neutralizing antibodies cross-neutralizes HeV-g2 potently. Furthermore, we describe a monoclonal antibody (hAH1.3) neutralizing HeV and HeV-g2 and reveal its epitope using X-ray crystallography. We show that targeting four nonoverlapping epitopes on the HeV attachment protein simultaneously leads to potent HeV and HeV-g2 neutralization, supporting the development of a tetravalent monoclonal antibody cocktail. Collectively, our data provide a comprehensive assessment of available countermeasures against this newly described HeV-g2 variant and delineate multiple strategies for pandemic preparedness.