Shen Zhaoling, Li Cheng, Song Wenping, Liu Litong, Kong Yu, Huang Ailing, Bao Qingui, Ying Tianlei, Wu Yanling
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai, China.
College of Life Sciences, Hebei Agricultural University, Baoding, China.
PLoS Pathog. 2025 Jan 8;21(1):e1012845. doi: 10.1371/journal.ppat.1012845. eCollection 2025 Jan.
Vaccines are widely regarded as one of the most effective strategies for combating infectious diseases. However, significant challenges remain, such as insufficient antibody levels, limited protection against rapidly evolving variants, and poor immune durability, particularly in subunit vaccines, likely due to their short in vivo exposure. Recent advances in extending the half-life of protein therapeutics have shown promise in improving drug efficacy, yet whether increasing in vivo persistence can enhance the efficacy of subunit vaccines remains underexplored. In this study, we developed two trimeric SARS-CoV-2 subunit vaccines with distinct pharmacokinetic profiles to evaluate the impact of vaccine persistence on immune efficacy. A self-assembling trimeric subunit vaccine (RBD-HR/trimer) was designed, followed by an extended-persistence variant (RBD-sFc-HR/trimer) incorporating a soluble monomeric IgG1 fragment crystallizable. We demonstrated that RBD-sFc-HR/trimer elicited more robust and higher levels of neutralizing antibodies, with potent and broad neutralization activity against multiple SARS-CoV-2 variants. Notably, RBD-sFc-HR/trimer induced a durable immune response, significantly increasing the number of memory B cells and T cells. This study provides critical insights for designing vaccines that achieve potent and long-lasting immune responses against infectious diseases.
疫苗被广泛认为是对抗传染病最有效的策略之一。然而，重大挑战依然存在，比如抗体水平不足、对快速演变的变体的保护有限以及免疫持久性差，特别是在亚单位疫苗中，这可能是由于它们在体内的暴露时间较短。延长蛋白质疗法半衰期的最新进展已显示出改善药物疗效的前景，但增加体内持久性是否能提高亚单位疫苗的疗效仍未得到充分探索。在本研究中，我们开发了两种具有不同药代动力学特征的三聚体 SARS-CoV-2 亚单位疫苗，以评估疫苗持久性对免疫效果的影响。设计了一种自组装三聚体亚单位疫苗（RBD-HR/三聚体），随后是一种包含可溶性单体 IgG1 可结晶片段的延长持久性变体（RBD-sFc-HR/三聚体）。我们证明，RBD-sFc-HR/三聚体引发了更强且更高水平的中和抗体，对多种 SARS-CoV-2 变体具有强大而广泛的中和活性。值得注意的是，RBD-sFc-HR/三聚体诱导了持久的免疫反应，显著增加了记忆 B 细胞和 T 细胞的数量。这项研究为设计针对传染病实现强效和持久免疫反应的疫苗提供了关键见解。
