Walls Alexandra C, Miranda Marcos C, Schäfer Alexandra, Pham Minh N, Greaney Allison, Arunachalam Prabhu S, Navarro Mary-Jane, Tortorici M Alejandra, Rogers Kenneth, O'Connor Megan A, Shirreff Lisa, Ferrell Douglas E, Bowen John, Brunette Natalie, Kepl Elizabeth, Zepeda Samantha K, Starr Tyler, Hsieh Ching-Lin, Fiala Brooke, Wrenn Samuel, Pettie Deleah, Sydeman Claire, Sprouse Kaitlin R, Johnson Max, Blackstone Alyssa, Ravichandran Rashmi, Ogohara Cassandra, Carter Lauren, Tilles Sasha W, Rappuoli Rino, Leist Sarah R, Martinez David R, Clark Matthew, Tisch Roland, O'Hagan Derek T, Van Der Most Robbert, Van Voorhis Wesley C, Corti Davide, McLellan Jason S, Kleanthous Harry, Sheahan Timothy P, Smith Kelly D, Fuller Deborah H, Villinger Francois, Bloom Jesse, Pulendran Bali, Baric Ralph S, King Neil P, Veesler David
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Cell. 2021 Oct 14;184(21):5432-5447.e16. doi: 10.1016/j.cell.2021.09.015. Epub 2021 Sep 15.
Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.
了解疫苗引发的针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变异株及其他沙贝病毒的保护作用是指导公共卫生政策的关键。我们发现，一种临床阶段的多价SARS-CoV-2刺突受体结合域纳米颗粒（RBD-NP）疫苗单次免疫后可保护小鼠免受SARS-CoV-2攻击，这表明存在一种潜在的节省剂量策略。我们使用一组循环突变体，在非人类灵长类动物中比较了RBD-NP诱导的血清中和活性与一种主要的预融合稳定SARS-CoV-2刺突（六聚体）的血清中和活性。两种疫苗诱导的多克隆抗体对所测试的许多RBD残基替换同样具有抗性，尽管484位及其周围的突变对中和作用有负面影响。展示多种沙贝病毒RBD的嵌合和混合纳米颗粒免疫原在小鼠中引发广泛的中和活性，即使疫苗中不存在SARS-CoV RBD，也能保护小鼠免受SARS-CoV攻击。本研究提供了原理证明，即多价沙贝病毒RBD-NP可诱导异型保护，并推动将这种具有广泛保护作用的沙贝病毒疫苗推进到临床阶段。
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