Cohen Alexander A, van Doremalen Neeltje, Greaney Allison J, Andersen Hanne, Sharma Ankur, Starr Tyler N, Keeffe Jennifer R, Fan Chengcheng, Schulz Jonathan E, Gnanapragasam Priyanthi N P, Kakutani Leesa M, West Anthony P, Saturday Greg, Lee Yu E, Gao Han, Jette Claudia A, Lewis Mark G, Tan Tiong K, Townsend Alain R, Bloom Jesse D, Munster Vincent J, Bjorkman Pamela J
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
bioRxiv. 2022 Mar 28:2022.03.25.485875. doi: 10.1101/2022.03.25.485875.
To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.
为了对抗未来的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变种以及威胁全球健康的类似SARS的β冠状病毒（沙贝病毒）的溢出，我们设计了镶嵌纳米颗粒，这些颗粒呈现随机排列的沙贝病毒刺突受体结合域（RBD），以引发针对保守/相对隐蔽而非可变/免疫显性/暴露表位的抗体。我们比较了镶嵌8（SARS-CoV-2和七种动物沙贝病毒）和同型（仅SARS-CoV-2）RBD纳米颗粒在小鼠和猕猴中引发的免疫反应，观察到镶嵌8对包括SARS-CoV和动物沙贝病毒在内的不匹配（不在纳米颗粒上）毒株引发的反应更强。镶嵌8免疫显示出对包括奥密克戎在内的SARS-CoV-2变种具有同等的中和作用，并能抵御SARS-CoV-2和SARS-CoV的攻击，而同型SARS-CoV-2免疫仅能抵御SARS-CoV-2的攻击。表位图谱显示，镶嵌8免疫后对保守表位的靶向性增加。总之，这些结果表明镶嵌8 RBD纳米颗粒可以预防SARS-CoV-2变种和未来的沙贝病毒溢出。
