1)厦门大学公共卫生学院,国家传染病诊断试剂与疫苗工程技术研究中心,厦门 361102;2)翔安创新实验室,传染病疫苗研发全国重点实验室,厦门 361102
国家自然科学基金(82171821)和中央高校基本科研业务费专项(20720250004)资助。
1)National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China;2)National Key Laboratory for Vaccine Development against Infectious Diseases, Xiang’an Innovation Laboratory, Xiamen 361102, China
This work was supported by grants from The National Natural Science Foundation of China (82171821) and Special Fund for Basic Scientific Research of Central Universities (20720250004).
人类免疫缺陷病毒(HIV)自20世纪80年代出现以来,已在全球范围内广泛流行,给人类生命健康和社会发展带来巨大威胁。尽管暴露前预防能有效遏制HIV传播,抗逆转录病毒治疗显著延长了患者生存期,但疫苗仍是阻断传播、终结流行的关键工具。HIV-1的高度遗传变异性、包膜糖蛋白的聚糖屏蔽以及体内潜伏库的长期稳定存在,使传统疫苗策略屡遭瓶颈。近年来,mRNA技术凭借序列可编程、生产周期短、天然构象表达及自佐剂效应等优势,为破解上述难题提供了全新思路。本文系统梳理mRNA技术在HIV-1疫苗开发中的最新研究进展,重点剖析诱导广谱中和抗体及有效T细胞应答面临的独特免疫障碍,阐述了基于RV144疫苗的mRNA革新、颗粒化mRNA疫苗设计、种系靶向mRNA疫苗研发和HIV治疗性疫苗4大核心研究方向的成果。同时对比mRNA与传统疫苗平台的关键免疫学差异,揭示其在免疫原递送中的独特价值,深入探讨mRNA疫苗诱导广谱中和抗体的核心机制创新,分析其临床转化中面临的免疫应答持久性、特殊人群适配性、递送系统规模化等核心挑战并提出靶向突破策略。
Since its emergence in the 1980s, the human immunodeficiency virus (HIV) has caused a global pandemic, posing a severe threat to human life and health as well as social development. Although pre-exposure prophylaxis (PrEP) effectively curbs HIV transmission and antiretroviral therapy (ART) significantly extends the lifespan of patients, vaccines remain a pivotal tool for blocking transmission and ending the pandemic. The high genetic variability of HIV-1, the glycan shield of its envelope glycoproteins, and the long-term persistence of latent reservoirs have repeatedly led to bottlenecks in traditional vaccine strategies. In recent years, mRNA technology has offered a novel approach to addressing these challenges, leveraging advantages such as sequence programmability, short production cycles, native conformational expression of antigens, and self-adjuvant effects. In recent years, mRNA vaccine technology has emerged as a transformative solution to longstanding vaccinology challenges, characterized by its sequence programmability, rapid production cycles, native conformational antigen expression, and intrinsic self-adjuvanting properties. Unlike traditional platforms reliant on pathogen culture or recombinant proteins, mRNA vaccines can be expeditiously designed and updated based solely on viral genomic sequences. Lipid nanoparticle (LNP)-encapsulated mRNA facilitates endogenous antigen expression and presentation, simultaneously eliciting potent humoral and cellular immune responses. Within this landscape, self-amplifying mRNA (saRNA) further extends in vivo antigen expression to enhance the persistence of immune responses. Moreover, the LNP delivery system not only protects mRNA from degradation and mediates endosomal escape but also synergizes with mRNA to optimize immune activation via self-adjuvant effects. Importantly, mRNA platforms circumvent the pre-existing immunity associated with viral vectors and the genomic integration risks of DNA vaccines, positioning them as a cornerstone for global pandemic preparedness. This review systematically delineates recent advances in mRNA technology for HIV-1 vaccine development, focusing on four pivotal research frontiers. First, mRNA innovations building upon the RV144 trial optimize antigens through codon modification and multivalent designs to induce more durable and broad-spectrum immunity. Second, particulate mRNA vaccine strategies, utilizing virus-like particles (VLPs) and ferritin nanoparticles, achieve in situ antigen self-assembly, significantly enhancing B cell activation and reducing infection risks in non-human primate models. Third, germline-targeting mRNA vaccines address the low-affinity barrier of broadly neutralizing antibody (bNAp) precursors, efficiently activating rare precursor B cells and promoting affinity maturation. Fourth, therapeutic mRNA vaccines offer unique advantages for an HIV functional cure; combining immunogens with mRNA-encoded adjuvants potentiates cellular immunity, while LNP-mediated “shock-and-kill” strategies specifically activate latent reservoirs to guide immune clearance. Comparative analyses with traditional platforms reveal that mRNA technology redefines antigen production and presentation, simulating chronic infection through sustained expression and enabling dual-pathway presentation via endogenous synthesis. Furthermore, we explore the mechanistic innovations of mRNA vaccines in inducing bNAps: sustained in vivo production prolongs the activation window for precursor B cells and maintains germinal center (GC) reactions; endogenously expressed antigens adopt native conformations to expose conserved epitopes; and self-adjuvanting effects modulate the functions of antigen-presenting cells (APCs) and follicular helper T cells (Tfh), driving somatic hypermutation and affinity maturation. We also address critical clinical translation challenges, including immune durability, adaptability to special populations, and large-scale LNP manufacturing, while proposing targeted optimization strategies. In conclusion, this review establishes a theoretical framework for utilizing mRNA technology to overcome HIV-1 immune escape, transitioning from a descriptive paradigm to a problem-solving-based synthesis of evidence. By integrating preclinical and early clinical data, we bridge the gap between basic design and translational verification. mRNA technology is poised to become a central pillar in HIV-1 prevention and therapy, providing a robust toolset to achieve the global goal of ending the AIDS pandemic and offering a blueprint for vaccine development against other recalcitrant infectious diseases.
刘佩,方中岳,陈欣欣,李少伟,顾颖.基于mRNA平台的人类免疫缺陷病毒1疫苗策略[J].生物化学与生物物理进展,2026,53(4):826-839
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