Moderna, Inc.

摘要：本文聚焦纳米材料在疫苗佐剂领域的应用，介绍了纳米佐剂的类型，包括金属及金属氧化物、其他无机纳米颗粒、配位聚合物、脂质体、聚合物纳米颗粒等，阐述其临床应用现状、免疫激活机制，如depot效应、NLRP3 炎症小体激活、靶向 C 型凝集素受体、激活 Toll 样受体、激活 cGAS - STING 信号通路等，同时分析了发展过程中面临的挑战，并展望未来发展趋势，强调纳米材料在疫苗佐剂领域潜力巨大但仍需克服诸多困难 。一、引言：疫苗与纳米材料的相遇疫苗自 1800 年起，在预防传染病等方面发挥关键作用。疫苗通常由抗原和佐剂组成，佐剂能增强疫苗免疫原性 。铝盐是最早获批用于人类的免疫佐剂，过去百年，仅有少数佐剂获许可用于人类疫苗。随着时间推移，疫苗佐剂专利申请数量呈波动变化，自新冠疫情后稳定在每年 400 多项。纳米材料是指至少一维尺度在 1-1000nm 的材料，因其独特的物理化学性质，如长度直径比、表面功能化、比表面积、手性等 ，在生物医学领域应用广泛。在疫苗佐剂方面，纳米材料能更好地保护抗原、延长半衰期、降低生物毒性、促进免疫调节和抗原递送，对激活抗原特异性 T 细胞意义重大，因此在免疫佐剂领域极具应用价值。二、纳米材料基疫苗佐剂：种类繁多各显神通2.1 金属及金属氧化物基疫苗佐剂铝基疫苗佐剂：铝盐是最古老且成熟的疫苗佐剂，安全性高、稳定性好。常见的铝基佐剂有氢氧化铝、磷酸铝和明矾。微米级铝佐剂易引发 Th2 型免疫反应，而铝基纳米颗粒（Al - NPs）可诱导 Th1 型免疫反应，更易促进抗原摄取，诱导平衡免疫反应 。此外，氢氧化铝纳米棒的形状、结晶度、羟基含量，以及羟基磷酸铝纳米颗粒的表面电荷等因素，都会影响其佐剂效果（图 1、图 3）。锰基疫苗佐剂：锰是人体必需微量元素，锰基纳米材料在生物医学领域功能多样。锰能激活 cGAS - STING 通路和 NLRP3 通路，引发细胞免疫，在新冠、肺炎及肿瘤疫苗方面潜力巨大。已有多种锰基纳米佐剂被合成并应用于不同疫苗研发，展现出良好效果（图 4）。贵金属纳米颗粒：金纳米颗粒可控性强，作为佐剂主要用于肿瘤疫苗，可增强免疫反应，其大小和形态会影响抗体产生，右旋手性金纳米颗粒能更有效促进免疫反应 。银纳米颗粒抗菌抗癌活性强，可激活巨噬细胞，但存在生物毒性问题（图 5）。2.2 其他无机纳米颗粒磷酸钙、介孔二氧化硅、氧化锌等无机纳米颗粒也可作为疫苗佐剂。磷酸钙生物相容性好，能促进抗体和细胞因子分泌；介孔二氧化硅可被树突状细胞有效摄取，增强免疫；氧化锌纳米颗粒具有免疫刺激特性，可增强细胞和体液免疫 。2.3 配位聚合物配位聚合物合成简单、成本低，能高效结合抗原，其金属离子可功能化。部分配位聚合物可激活 cGAS - STING 通路，诱导免疫反应，还能使疫苗在常温下储存，减少对冷链的依赖 。2.4 脂质体脂质体具有良好的生物相容性、多样的加载模式和高加载能力 ，作为佐剂可促进抗原与抗原呈递细胞相互作用，降低抗原降解，表面可修饰以增强靶向免疫。阳离子脂质体佐剂效果更佳，目前已应用于多种疫苗，新一代脂质体在新兴疫苗领域潜力巨大，也是 mRNA 疫苗的理想佐剂，但存在稳定性问题（图 5）。2.5 聚合物纳米颗粒壳聚糖：壳聚糖是甲壳素脱乙酰产物，可激活巨噬细胞和树突状细胞，增强抗原特异性 Th1 反应，其纳米颗粒的黏膜粘附性可增强鼻黏膜免疫反应，在多种疾病疫苗中展现出良好应用潜力 。聚乳酸 - 羟基乙酸共聚物（PLGA）：PLGA 生物相容性好，体内可水解代谢，毒性低。PLGA 封装的 α - 生育酚、包裹双链 RNA 佐剂 Riboxxim 等在疫苗中均能有效增强免疫反应，其表面可修饰，应用广泛 。多肽：由疏水氨基酸组成的纳米颗粒可作为高效、无毒、可降解的自佐剂，聚赖氨酸、聚 γ - 谷氨酸等多肽已用于免疫佐剂开发，部分多肽纳米颗粒可诱导强大的细胞免疫反应，在肿瘤预防和治疗方面潜力显著 。三、纳米佐剂在临床试验：探索前行目前，许多新一代佐剂处于临床试验阶段，但纳米佐剂相关临床试验较少。脂质纳米颗粒用于辉瑞和莫德纳的新冠疫苗，可稳定递送 mRNA 并发挥免疫刺激作用；Matrix - M 纳米颗粒可增强免疫细胞浸润和细胞因子释放，促进免疫细胞活化；金纳米颗粒等多种纳米佐剂也在临床试验中探索其效果（表 1、表 2）。四、免疫激活机制：揭秘纳米佐剂的工作原理4.1 depot 效应抗原与佐剂结合可实现持续释放，延长抗原在免疫系统中的停留时间，促进免疫细胞募集，优化抗原呈递条件，从而增强免疫反应。如磷酸铝与抗原制成的凝胶疫苗，可在注射部位形成 depot，缓慢释放抗原（图 1）。4.2 NLRP3 炎症小体激活NLRP3 炎症小体可被病原体或内源性危险信号激活，分为启动信号和激活信号两个步骤。部分纳米颗粒如二氧化钛尖刺颗粒、含内体逃逸肽的纳米颗粒、金纳米颗粒等，可通过不同方式激活 NLRP3 炎症小体，引发下游免疫反应，在肿瘤治疗中与免疫检查点阻断疗法联合效果显著（图 6）。4.3 靶向 CLRs 通路C 型凝集素受体（CLR）是一类重要的模式识别受体，碳水化合物结构物质可激活 CLR，促使抗原呈递细胞内化、处理和呈递抗原，增强适应性免疫反应。不同 CLR 激活后可引发不同信号通路，调节免疫方向。如周期性介孔有机硅、阳离子脂质体佐剂、表面多糖修饰的病毒样颗粒疫苗等，均可通过靶向 CLRs 通路发挥作用（图 6）。4.4 TLRs 激活Toll 样受体（TLR）在先天免疫系统中起关键作用，不同 TLR 被不同物质激活后，可提供病原体信息，促进抗原处理和呈递，调节 B 细胞反应和抗体产生。多种基于 TLR 激活的纳米佐剂在不同疾病疫苗中展现出良好效果，如 TLR4 和 TLR7 配体、TLR7/8 激动剂、TLR9 激动剂等相关纳米佐剂（图 7）。4.5 激活 cGAS - STING 通路cGAS - STING 通路是连接先天免疫和适应性免疫的关键途径，双链 DNA 可激活该通路，促进促炎细胞因子和干扰素生成。锰离子、阳离子壳聚糖、含特定抑制剂和激活剂的纳米佐剂等，均可通过激活 cGAS - STING 通路，增强免疫反应，在肿瘤治疗中效果显著（图 8）。五、挑战与展望：未来之路任重道远尽管纳米材料作为疫苗佐剂展现出良好活性，但仍面临诸多挑战。作用机制方面，纳米材料与免疫细胞的相互作用机制尚不明确，导致部分实验结果矛盾 。安全性方面，纳米佐剂的给药途径和物理化学性质影响其生物分布和安全性，如静脉注射后易在肝脏积累，阳离子脂质体和聚合物存在免疫毒性等，金属基纳米佐剂还可能引发慢性炎症和神经损伤 。此外，癌症纳米佐剂治疗尚不成熟，抗原纯化优化、动物模型构建也存在问题，纳米佐剂的生产和储存也需改进 。未来，纳米佐剂的发展可结合人工智能、机器学习、生物信息学等计算方法，从设计到作用机制进行全面优化。利用人工智能预测抗原和免疫细胞受体结构，理解纳米佐剂作用机制，开发新型纳米佐剂。同时，促进黏膜免疫的纳米佐剂是未来发展趋势之一 。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

CAMBRIDGE, MA, USA I May 23, 2025 I Moderna, Inc. (NASDAQ:MRNA) today announced that it has submitted an application to the U.S. Food and Drug Administration (FDA) for review of its Spikevax 2025-2026 formula, targeting the SARS-CoV-2 variant LP.8.1. The submission is based on guidance from the U.S. FDA, which advised that COVID-19 vaccines should be updated to a monovalent JN.1 lineage, with a preference for the LP.8.1 variant. About Moderna Moderna is a leader in the creation of the field of mRNA medicine. Through the advancement of mRNA technology, Moderna is reimagining how medicines are made and transforming how we treat and prevent disease for everyone. By working at the intersection of science, technology and health for more than a decade, the company has developed medicines at unprecedented speed and efficiency, including one of the earliest and most effective COVID-19 vaccines. Moderna’s mRNA platform has enabled the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases and autoimmune diseases. With a unique culture and a global team driven by the Moderna values and mindsets to responsibly change the future of human health, Moderna strives to deliver the greatest possible impact to people through mRNA medicines. For more information about Moderna, please visit modernatx.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. AUTHORIZED USE IN THE U.S. INDICATION (U.S.) SPIKEVAX (COVID-19 Vaccine, mRNA) is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older. IMPORTANT SAFETY INFORMATION Contraindications Warnings and Precautions Adverse Reactions The most commonly reported (≥10%) adverse reactions following any dose in any indicated patient population were pain at the injection site, headache, fatigue, myalgia, chills, arthralgia, axillary swelling/tenderness, nausea/vomiting, swelling at the injection site, erythema at the injection site, and fever. Reporting Adverse Events and Vaccine Administration Errors The vaccination provider is responsible for mandatory reporting of certain adverse events to the Vaccine Adverse Event Reporting System (VAERS) online at https://vaers.hhs.gov/reportevent.html or by calling 1-800-822-7967. Please see the SPIKEVAX Full Prescribing Information . Please see the Moderna COVID-19 Vaccine Fact Sheet for Healthcare Providers Administering Vaccine for more information . SOURCE: Moderna Therapeutics

Phase 1/2 H5 avian flu vaccine study shows positive interim results Company has been notified that HHS will terminate Moderna’s award for late-stage development of pre-pandemic influenza vaccines CAMBRIDGE, MA, USA I May 28, 2025 I Moderna, Inc. (NASDAQ:MRNA) today announced positive interim data from a Phase 1/2 clinical study ( NCT05972174 ) evaluating the safety and immunogenicity of its investigational pandemic influenza vaccine, mRNA-1018, in approximately 300 healthy adults aged 18 years and older. The interim results focus on a vaccine candidate targeting the H5 avian influenza virus subtype. The Company had previously expected to advance the program to late-stage development with the U.S. Department of Health and Human Services (HHS); however, today Moderna received notice that HHS will terminate the award for the late-stage development and right to purchase pre-pandemic influenza vaccines. “While the termination of funding from HHS adds uncertainty, we are pleased by the robust immune response and safety profile observed in this interim analysis of the Phase 1/2 study of our H5 avian flu vaccine and we will explore alternative paths forward for the program,” said Stéphane Bancel, Chief Executive Officer of Moderna. “These clinical data in pandemic influenza underscore the critical role mRNA technology has played as a countermeasure to emerging health threats.” The Phase 1/2 study evaluated a two-dose regimen of Moderna’s investigational avian influenza vaccine. mRNA-1018 demonstrated a rapid, potent and durable immune response. At baseline, pre-existing immunity was minimal, with only 2.1% of participants showing hemagglutination inhibition (HAI) antibody titers ≥1:40, an HAI titer considered to correlate with protection. At Day 43, three weeks after the second vaccination, 97.8% of participants achieved titers ≥1:40 with a 44.5-fold increase of titers from baseline. The investigational vaccine was generally well-tolerated, with no dose-limiting tolerability concerns observed. Most solicited adverse reactions were Grade 1 or 2 and did not increase significantly with number of doses or between first and second doses. Further data is expected to be submitted for presentation at an upcoming scientific meeting. Moderna will explore alternatives for late-stage development and manufacturing of the H5 program consistent with the Company’s strategic commitment to pandemic preparedness. About Moderna Moderna is a leader in the creation of the field of mRNA medicine. Through the advancement of mRNA technology, Moderna is reimagining how medicines are made and transforming how we treat and prevent disease for everyone. By working at the intersection of science, technology and health for more than a decade, the company has developed medicines at unprecedented speed and efficiency, including one of the earliest and most effective COVID-19 vaccines. Moderna’s mRNA platform has enabled the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases and autoimmune diseases. With a unique culture and a global team driven by the Moderna values and mindsets to responsibly change the future of human health, Moderna strives to deliver the greatest possible impact to people through mRNA medicines. For more information about Moderna, please visit modernatx.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. SOURCE: Moderna Therapeutics