Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Institute for Protein Design, University of Washington School of Medicine, Seattle, WA, USA.
Nat Commun. 2023 Oct 4;14(1):6195. doi: 10.1038/s41467-023-41661-4.
Multivalent antigen display is a fast-growing area of interest toward broadly protective vaccines. Current nanoparticle-based vaccine candidates demonstrate the ability to confer antibody-mediated immunity against divergent strains of notably mutable viruses. In coronaviruses, this work is predominantly aimed at targeting conserved epitopes of the receptor binding domain. However, targeting conserved non-RBD epitopes could limit the potential for antigenic escape. To explore new potential targets, we engineered protein nanoparticles displaying coronavirus prefusion-stabilized spike (CoV_S-2P) trimers derived from MERS-CoV, SARS-CoV-1, SARS-CoV-2, hCoV-HKU1, and hCoV-OC43 and assessed their immunogenicity in female mice. Monotypic SARS-1 nanoparticles elicit cross-neutralizing antibodies against MERS-CoV and protect against MERS-CoV challenge. MERS and SARS nanoparticles elicit S1-focused antibodies, revealing a conserved site on the S N-terminal domain. Moreover, mosaic nanoparticles co-displaying distinct CoV_S-2P trimers elicit antibody responses to distant cross-group antigens and protect male and female mice against MERS-CoV challenge. Our findings will inform further efforts toward the development of pan-coronavirus vaccines.
多价抗原展示是广泛保护性疫苗研究的一个快速发展领域。目前基于纳米颗粒的疫苗候选物表现出能够针对明显具有突变性的不同病毒株提供抗体介导的免疫的能力。在冠状病毒中,这项工作主要针对针对受体结合域的保守表位。然而,针对保守的非 RBD 表位可能会限制抗原逃逸的潜力。为了探索新的潜在靶标,我们设计了展示来自 MERS-CoV、SARS-CoV-1、SARS-CoV-2、hCoV-HKU1 和 hCoV-OC43 的冠状病毒预融合稳定化刺突(CoV_S-2P)三聚体的蛋白纳米颗粒,并在雌性小鼠中评估了它们的免疫原性。单型 SARS-1 纳米颗粒引发针对 MERS-CoV 的交叉中和抗体,并可预防 MERS-CoV 感染。MERS 和 SARS 纳米颗粒引发针对 S1 的抗体反应,揭示了 S N 末端结构域上的一个保守位点。此外,共同展示不同 CoV_S-2P 三聚体的嵌合纳米颗粒引发针对远交群抗原的抗体反应,并可保护雄性和雌性小鼠免受 MERS-CoV 感染。我们的研究结果将为开发泛冠状病毒疫苗提供进一步的信息。
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