Abstract:

Vaccines, as a cornerstone of infectious disease prevention and control, have undergone four transformative revolutions throughout their development and application. In recent years, the rapid advancement of computational technologies has further propelled vaccine development into a new era, giving rise to a synthetic biology paradigm centered on structure-guided protein optimization and computational design. This article systematically reviews the applications and significance of three key protein optimization strategies—directed evolution, semi-rational design, and rational design—as well as de novo protein synthesis, with a focus on their roles in vaccine development. At the immunogen design level, strategies such as structural stabilization, epitope focusing, and glycosylation modulation are discussed for their potential to enhance antigen immunogenicity and broaden protective efficacy. At the delivery system level, the unique advantages of protein nanoparticles in eliciting cross-neutralizing antibody responses are emphasized. These nanoparticles utilize high-density antigen presentation and precise geometric conformations, combined with "mosaic" multivalent display technology. Advances in artificial intelligence (AI)-based computational tools have facilitated a paradigm shift from "structural simulation" to "functional customization", thereby significantly promoting the development of structure-guided reverse vaccinology based on antigen-antibody complex structures. The integration of computational epitope screening and de novo protein backbone design has facilitated a transition from natural structures to customized designs in vaccine development. Although challenges remain, such as achieving broad-spectrum protection against highly variable pathogens and accurately simulating dynamic conformations, the deep synergy between vaccine design and computational tools has significantly accelerated the clinical translation of vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV), and established a universal design framework for the prevention and control of future emerging and unknown infectious diseases.

Key words: protein optimization, de novo design, vaccine design, nanoparticle vaccine, reverse vaccinology

摘要：

疫苗作为防控传染性疾病的有力手段，在发展应用过程中经历了四次重要革命。近年来计算工具的迅猛发展更是推动疫苗研发走向新的阶段，形成以结构为导向，蛋白质优化与计算设计为核心的合成生物学研究范式。本文系统介绍了蛋白质优化设计中定向进化、半理性设计和理性设计三种策略与从头合成技术在疫苗研发中的应用与价值。在免疫原设计层面，介绍了结构稳定性改造、表位聚焦、糖基化修饰调控等策略对提升抗原免疫原性与广谱性等特性方面的潜力。在递送系统层面，介绍了蛋白纳米颗粒凭借高密度抗原展示与几何构象优势，结合“马赛克”多价展示技术，对诱导交叉中和抗体生成方面的优势。人工智能计算工具的突破性进展实现了从“结构模拟”到“功能定制”的转变，并极大地推动了以抗原-抗体复合物结构为导向的反向疫苗学的发展。整合表位计算筛选与从头蛋白骨架设计，实现了疫苗从天然结构到定制结构的突破。尽管面临高变异病原广谱保护、动态构象模拟等挑战，疫苗设计与计算工具的深度融合加速了新型冠状病毒、呼吸道合胞病毒等疫苗的临床转化，并为未来新发和突发传染病防控提供了通用设计方法。

关键词: 蛋白质优化, 从头合成, 疫苗设计, 纳米颗粒疫苗, 反向疫苗学