The spillovers of β-coronaviruses in humans and the emergence of SARS-CoV-2 variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple β-coronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through inhibition of membrane fusion and delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-β-coronavirus vaccines eliciting broad protection.

β-冠状病毒在人类中的溢出和 SARS-CoV-2 变体的出现突出表明需要采取广泛的冠状病毒对策。我们描述了五种单克隆抗体 (mAb) 与从 COVID-19 恢复期个体分离的多种 β-冠状病毒刺突糖蛋白的茎螺旋发生交叉反应。通过结构和功能研究，我们表明具有最大宽度的 mAb (S2P6) 通过抑制膜融合来中和来自三个不同亚属的假型病毒，并描述了其交叉反应性的分子基础。S2P6 通过病毒中和和 Fc 介导的效应子功能降低了受到 SARS-CoV-2 攻击的仓鼠的病毒负荷。茎螺旋抗体很少见，通常特异性较差，可通过体细胞突变获得中和广度。