呼吸道病毒黏膜疫苗的递送制剂技术与药学研究进展

Advances in Delivery and Formulation Technologies and Pharmaceutical Research for Mucosal Vaccines against Respiratory Viruses

摘要

呼吸道病毒感染是全球重大公共卫生威胁。当前大多数呼吸道病毒疫苗采用肌内注射途径给药，主要诱导以血清中和抗体为代表的系统性免疫应答，在预防重症以及降低住院风险和死亡风险方面发挥了重要作用。然而，鼻腔、鼻咽部等部位的呼吸道黏膜既是呼吸道病毒入侵机体的主要门户，也是病毒早期复制的重要场所。由于肌内注射疫苗在诱导呼吸道黏膜局部分泌型免疫球蛋白 A（secretory immunoglobulin A，sIgA）、组织驻留记忆 T 细胞（tissue-resident memory T cell，TRM）及局部固有免疫应答的能力相对有限，因此难以在病毒早期入侵时建立有效的黏膜免疫屏障。因此，尽管肌内注射疫苗能够有效预防重症，但其在阻断上呼吸道感染及病毒早期复制、减少病毒排出和遏制人际传播方面仍存在一定局限。近年来，基于病毒载体、脂质纳米颗粒（lipid nanoparticles，LNPs）及新型佐剂等多种递送平台已在流感病毒、呼吸道合胞病毒及严重急性呼吸系统综合征冠状病毒 2 型（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）疫苗的研发中展现出显著潜力。然而，黏膜递送系统效率不足、制剂稳定性差、佐剂的安全性与免疫原性难以平衡，以及生产质控体系不完善等药学关键问题，仍严重制约黏膜疫苗的临床转化进程。通过系统综述呼吸道病毒黏膜疫苗的主流递送制剂技术平台，阐述不同递送系统诱导黏膜免疫的作用机制，并探讨当前面临的核心药学挑战与未来研究方向，以期为高效黏膜疫苗的制剂开发与临床转化提供参考。

Abstract

Respiratory viral infections pose a major threat to global public health. Most currently available vaccines against respiratory viruses are administered intramuscularly and primarily induce systemic immune responses, particularly serum neutralizing antibodies, thereby playing an important role in preventing severe disease and reducing the risks of hospitalization and death. However, the respiratory mucosa of the nasal cavity, nasopharynx, and other sites serves not only as the primary portal of entry for respiratory viruses but also as a major site of early viral replication. Because intramuscular vaccines have a relatively limited capacity to induce local secretory immunoglobulin A (sIgA), tissue-resident memory T cell (TRM), and innate immune responses in the respiratory mucosa, they are unlikely to establish an effective mucosal immune barrier during the early stages of viral invasion. Consequently, although intramuscular vaccines are effective in preventing severe disease, their ability to prevent upper respiratory tract infection and early viral replication, reduce viral shedding, and curb person-to-person transmission remains limited. Mucosal vaccines, delivered via optimized respiratory routes such as intranasal spray and aerosol inhalation, are designed to mimic the natural process of pathogen infection. In addition to inducing systemic immunity, they promote local sIgA production, recruit TRM cells, and induce trained immunity in the respiratory mucosa, thereby establishing a multilayered immune barrier. In recent years, various delivery platforms based on viral vectors, lipid nanoparticles (LNPs), and novel adjuvants have demonstrated considerable potential in the development of vaccines against influenza viruses, respiratory syncytial virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nevertheless, critical pharmaceutical challenges, including the insufficient efficiency of mucosal delivery systems, poor formulation stability, the difficulty of balancing adjuvant safety and immunogenicity, and inadequate manufacturing and quality control systems, continue to severely hinder the clinical translation of mucosal vaccines. This review systematically summarizes the major delivery and formulation technology platforms for mucosal vaccines against respiratory viruses, elucidates the mechanisms by which different delivery systems induce mucosal immunity, and discusses the key pharmaceutical challenges and future research directions, with the aim of providing a reference for the formulation development and clinical translation of effective mucosal vaccines.

关键词

呼吸道病毒 / 黏膜疫苗 / 黏膜免疫 / 递送系统 / 疫苗制剂

Key words

respiratory viruses / mucosal vaccines / mucosal immunity / delivery systems / vaccine formulations

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基金资助

国家重点研发计划资助项目(2023YFC2307900)