Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Nat Commun. 2024 Feb 20;15(1):1553. doi: 10.1038/s41467-024-45404-x.
Ever-evolving SARS-CoV-2 variants of concern (VOCs) have diminished the effectiveness of therapeutic antibodies and vaccines. Developing a coronavirus vaccine that offers a greater breadth of protection against current and future VOCs would eliminate the need to reformulate COVID-19 vaccines. Here, we rationally engineer the sequence-conserved S2 subunit of the SARS-CoV-2 spike protein and characterize the resulting S2-only antigens. Structural studies demonstrate that the introduction of interprotomer disulfide bonds can lock S2 in prefusion trimers, although the apex samples a continuum of conformations between open and closed states. Immunization with prefusion-stabilized S2 constructs elicits broadly neutralizing responses against several sarbecoviruses and protects female BALB/c mice from mouse-adapted SARS-CoV-2 lethal challenge and partially protects female BALB/c mice from mouse-adapted SARS-CoV lethal challenge. These engineering and immunogenicity results should inform the development of next-generation pan-coronavirus therapeutics and vaccines.
不断进化的严重急性呼吸综合征冠状病毒 2 型变异株（VOC）降低了治疗性抗体和疫苗的有效性。开发一种能够针对当前和未来的 VOC 提供更广泛保护的冠状病毒疫苗，将消除对 COVID-19 疫苗进行重新配方的需要。在这里，我们对 SARS-CoV-2 刺突蛋白的序列保守 S2 亚基进行了合理的工程改造，并对由此产生的 S2 单体抗原进行了表征。结构研究表明，引入同二硫键可以将 S2 锁定在预融合三聚体中，尽管尖峰样本在开放和闭合状态之间呈现连续的构象。用预融合稳定的 S2 构建体免疫可引发针对几种sarbecovirus 的广泛中和反应，并保护雌性 BALB/c 小鼠免受适应小鼠的 SARS-CoV-2 致死性挑战，并部分保护雌性 BALB/c 小鼠免受适应小鼠的 SARS-CoV 致死性挑战。这些工程和免疫原性结果应能为下一代泛冠状病毒治疗药物和疫苗的开发提供信息。
