Revolution in vaccine development led by protein optimization design and <italic style="font-style: italic">de novo</italic> synthesis

CHEN Tao; LAI Jintao; HU Meilin; MA Xiancai

doi:10.12211/2096-8280.2025-068

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Revolution in vaccine development led by protein optimization design and de novo synthesis

Invited Review | 更新时间：2026-03-07

- Revolution in vaccine development led by protein optimization design and de novo synthesis
- Synthetic Biology Journal Vol. 7, Issue 1, Pages: 152-176(2026)
- 作者机构：
  
  1.广州国家实验室，广东广州 510005
  2.中山大学，中山医学院，广东广州 510080
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2025-068
  CLC： Q816
- Received：30 June 2025，
  
  Revised：2025-08-19，
  
  Published：28 February 2026
- 稿件说明：
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陈涛，赖锦涛，胡美林，马显才. 蛋白质优化设计与从头合成引领的疫苗研发革命［J］. 合成生物学， 2026， 7（1）： 152-176

CHEN Tao， LAI Jintao， HU Meilin， MA Xiancai. Revolution in vaccine development led by protein optimization design and de novo synthesis［J］. Synthetic Biology Journal， 2026， 7（1）： 152-176
陈涛，赖锦涛，胡美林，马显才. 蛋白质优化设计与从头合成引领的疫苗研发革命［J］. 合成生物学， 2026， 7（1）： 152-176 DOI： 10.12211/2096-8280.2025-068.

CHEN Tao， LAI Jintao， HU Meilin， MA Xiancai. Revolution in vaccine development led by protein optimization design and de novo synthesis［J］. Synthetic Biology Journal， 2026， 7（1）： 152-176 DOI： 10.12211/2096-8280.2025-068.

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，在诱导交叉中和抗体生成方面具有独特的优势。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。

Abstract

Vaccines

as a cornerstone of infectious disease prevention and control

have undergone four transformative revolutions throughout their development and applications. 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 potentials 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 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 accelerat

ed 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.

关键词

Keywords

references

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LAI Jingtao

TONG Yigang

XU Shan

ZHANG Jingming

YANG Lu

ZHU Yun

JIANG Shibo

LU Lu

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State Key Laboratory of Green Biomanufacturing， College of Life Science and Technology， Beijing University of Chemical Technology

Institute of Advanced Medicine and Regenerative Medicine， Institute of Health and Medicine， Hefei Comprehensive National Science Center

School of Basic Medical Sciences， Fudan University

Department of Pharmacology， School of Pharmacy， Fudan University

Institute of Biophysics， Chinese Academy of Sciences

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Revolution in vaccine development led by protein optimization design and de novo synthesis

DOI：10.12211/2096-8280.2025-068

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