Influenza vaccine(Seqirus GmbH)

亚单位疫苗佐剂研究进展赵鹏举1，2，辛洪亮1*1南京医科大学 药学院，南京医科大学 国家疫苗研发创新平台 南京 211166；2简达生物医药（南京）有限公司，南京 210032摘 要  接种疫苗是预防、控制甚至消灭传染病最有效的方法。近年来，随着DNA重组技术的发展，重组亚单位疫苗等新型疫苗的研究取得快速发展。亚单位疫苗由病原体的免疫活性片段制备而成，具有制备简单、安全性高等优点，成为新型疫苗的研究开发热点。然而，亚单位疫苗抗原的免疫原性较弱，常需添加佐剂系统增强其免疫作用。因此，本文将对亚单位疫苗中的常用佐剂和新型佐剂研究进展进行综述与分析，旨在为亚单位疫苗的研发提供理论依据。关键词  亚单位疫苗；佐剂；纳米材料推荐阅读：鸡胚“亚单位”VS杆状病毒重组亚单位流感疫苗：一场“真假亚单位”的科学审视疫苗接种是预防传染病最有效和最经济的方法之一，尤其是在新型冠状病毒肺炎爆发后，疫苗的快速开发显得尤为重要。亚单位疫苗通常是指通过基因工程，获得微生物病原体的抗原成分制备而成的疫苗，不含遗传物质，可诱导机体产生免疫反应[1]。亚单位疫苗抗原成分明确、纯度高、安全性好，减少了人工减毒、灭活等方法制备疫苗可能发生的低热、恶心、头晕等不良反应。另一方面，其生产过程中不涉及活的病原微生物，从而消除了接触性传染风险[2]，随着用于疫苗设计的生物信息学和免疫信息学等相关学科的快速发展，目前可以组合各种编码序列生成多表位疫苗[3]，成为疫苗研究开发的热点。然而，亚单位疫苗免疫原性通常不强，需要合适的佐剂以获得理想的免疫效果。目前已成熟的佐剂系统和产品归纳于表1。　　除上述佐剂系统外，国内外正在开发多种具有佐剂特性的疫苗递送系统，它们能够有效增强亚单位疫苗的免疫反应，例如病毒样颗粒（virus-like particles，VLPs），其形貌和大小与病毒颗粒类似，不仅可以结合装载大量的抗原成分用于抗原的递送，还可以模拟病毒的自然免疫过程，增强抗原的免疫反应[4]。又如，利用多肽的结构多功能性，通过分子间相互作用自发地组装成纳米结构聚集体，也可以用于亚单位抗原递送和佐剂系统[2]。因此，本文针对亚单位疫苗中的常用佐剂和新型佐剂系统进行综述与分析，旨在为我国亚单位疫苗的研发提供参考。1传统亚单位疫苗的佐剂　　疫苗的传统佐剂按作用机制可以分为递送系统佐剂和免疫增强型佐剂。递送系统佐剂主要通过增强抗原向抗原呈递细胞（antigen-presenting cells，APC）传递，从而导致更广泛和持久的免疫反应，如铝佐剂、MF59和AS03等；免疫增强型佐剂通过激活APC上的模式受体（pattern recognition receptor，PRR），从而促进主要组织相容性复合体（major histocompatibility complex，MHC）的抗原呈递，如Toll样受体（toll-like receptor，TLR）激动剂。1.1　递送系统佐剂1.1.1　铝佐剂　铝佐剂是疫苗开发中最常用的佐剂，被广泛用于传染病疫苗中。疫苗用铝佐剂主要有氢氧化铝、磷酸铝和明矾3种，其中，氢氧化铝是最常见的铝佐剂。虽然铝盐作为佐剂使用已有几十年历史，但是其增强抗原免疫作用机制尚无定论，可能的机制之一是储存库效应[5]，即抗原被佐剂吸附积累，然后缓慢从免疫接种部位释放。另一种可能的机制是激活核苷酸结合寡聚化结构域（nucleotide-binding oligomerization domain，NOD）样受体热蛋白结构域相关蛋白3（NOD-like receptor thermal protein domain associated protein 3,NLRP3）通路[6]，通过抗原呈递细胞的模式识别受体和NOD样受体（NOD-like receptors，NLRs）发挥作用，后者增加促炎细胞因子IL-1β和IL-18的分泌，诱导中性粒细胞、嗜酸性粒细胞、单核细胞和树突状细胞（dendritic cell，DC）等免疫细胞募集到注射部位，增加MHC Ⅱ的表达，并增加抗原特异性IgG1的产生。铝佐剂还可以与细胞膜脂质相互作用，激活磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase，PI3K）和钙调磷酸酶-活化T细胞核因子（nuclear factor of activated T-cells，NFAT）信号通路，并诱导IL-2的分泌[7]。有研究发现[8]，铝佐剂可激活Th2型免疫应答（促进IgG1、IgE、IL-4、IL-5分泌以及活化嗜酸性粒细胞等）从而促进体液反应，用铝配制的急性呼吸系统综合征冠状病毒疫苗可以诱导小鼠发生特异性Th2反应，并诱导肺部嗜酸性粒细胞浸润。　　影响铝佐剂免疫效应的因素包括抗原的吸附率与吸附强度、抗原的释放能力、铝盐的颗粒大小与均匀度、抗原特性等，在具体应用中，仍需进行细致的处方筛选与制备工艺优化。虽然以铝盐为佐剂的疫苗被广泛用于临床，但含铝佐剂的疫苗可导致如红斑、皮下结节、接触性超敏、肉芽肿等局部不良反应。所以，还需深入研究含铝佐剂的疫苗配方、铝佐剂本身性能。例如，将铝佐剂纳米化后，对于注射常规铝佐剂时皮下经常产生的肉芽肿等过度炎症反应也有所减轻。1.1.2　MF59　MF59是诺华和Seqirus公司共同开发的水包油乳液，其配方为吐温-80、司盘-85、角鲨烯油和柠檬酸缓冲液，安全无毒且可完全降解，是目前欧盟批准用于人体的佐剂，已广泛应用于流感、乙肝、结核病及肿瘤疫苗的制备。　　DUPUIS M等[9]研究发现，MF59不直接活化DC，而是通过刺激单核细胞、巨噬细胞和粒细胞来产生趋化因子，进而影响APC对抗原的摄取，并转移到引流淋巴结。此外，MF59还可以上调含有半胱氨酸蛋白酶募集结构域（apoptosis-associated speck-like protein containing a caspase recruitment domain，ASC）的凋亡相关斑点样蛋白表达，激活IL-4和Stat-6信号传导，同时还可以显著提高IL-5和IL-6水平。基于MF59良好的佐剂特性，四川大学华西医院研发的重组新型冠状病毒疫苗中使用了新型水包油乳剂佐剂WGa01（基于MF59配方的角鲨烯水包油乳液），该疫苗对多种新冠病毒变异株均能诱导产生很高滴度的中和抗体[10]。1.1.3　AS03　AS03是由葛兰素史克公司生产的一种基于角鲨烯的水包油乳液。与MF59类似，AS03可以诱导促炎细胞因子和趋化因子的生成，这种促炎反应与注射部位抗原呈递细胞的募集、激活和成熟有关[11]。但相较于MF59，AS03含有DL-α-生育酚成分。为了阐明DL-α-生育酚在AS03中的作用，有学者对抗原摄取、免疫细胞募集和细胞因子分泌水平进行测定，结果显示，与未添加α-生育酚的AS03相比，添加α-生育酚的AS03可诱导更高水平的IL-6和SCF3表达，从而产生高免疫应答和高抗体滴度[12]。上述结果表明DL-α-生育酚在AS03佐剂中起到额外的免疫增强作用。目前上市的疫苗中，流感疫苗Prepandrix、Q-PanH5N1和重组乙型肝炎疫苗Fendrix采用了AS03作为佐剂。1.1.4　Matrix-M　Novavax公司生产的Matrix-M佐剂由两个单独的皂苷组分（组分A和组分C）制备而成，使用胆固醇和磷脂作为稳定剂[13]。研究发现Matrix-M可增强患流感小鼠体内Th1和Th2型免疫反应，诱导高水平的中和抗体生成，并增强免疫细胞募集[14]。目前已有多款疫苗中使用Matrix-M，包括用于预防儿童疟疾的R21/Matrix-M和新冠病毒疫苗NVX-CoV2373。1.1.5　Advax　Vaxine公司生产的Advax佐剂是一种由德尔塔菊粉组成的微晶多糖颗粒。有研究发现德尔塔菊粉与重组疫苗混合后可以引发强烈的体液和细胞免疫反应。Advax佐剂已在多项人体试验中进行了测试，例如预防季节性流感、乙型肝炎和对昆虫毒液的过敏反应的疫苗临床研究，结果显示Advax佐剂可以增强抗原免疫原性及激活T细胞反应，安全且耐受性良好[15]。1.2　免疫增强佐剂　　Toll样受体（TLRs）属于固有免疫病原模式识别受体，能够直接或间接地检测病原体相关分子模式（pathogen-associated molecular patterns，PAMPs），激活先天免疫和适应性免疫应答，当TLRs激动剂与疫苗抗原共同给药时，它们能够利用内源性免疫信号通路来增强和调节免疫反应。　　TLR4激动剂单磷酰脂质A（monophosphoryl lipid A，MPLA）是第一个作为疫苗佐剂获批的TLR激动剂。MPLA主要通过激活TRIF转导通路，诱导产生细胞因子和干扰素，并且活化抗原特异性T细胞，从而激活抗原呈递细胞[16]。　　CpG寡核苷酸是人工合成的含有未甲基化CpG序列的DNA序列，可以通过激活Toll样受体9（toll-like receptors 9，TLR9）来刺激先天免疫系统。TLR9激动剂直接诱导树突状细胞的活化和成熟，并增强B细胞向分泌型浆细胞分化[17]。作为一种疫苗佐剂，CpG可以增强疫苗特异性细胞免疫和体液免疫。在静电作用驱动下，CpG寡核苷酸可以与铝佐剂结合，又可与疫苗抗原相互结合，因此非常适合与铝佐剂复配成基亚单位疫苗[18]。Dynavax Technologies公司开发了一种名为CpG 1018的短寡核苷酸序列，已作为乙型肝炎病毒免疫佐剂上市[19]。2新型佐剂系统基于纳米材料的疫苗递送系统是近年来疫苗开发中的一个新兴领域，通过递送系统，可以保护疫苗抗原成分，并将其靶向至APC或特定淋巴组织，从而增强疫苗的适应性免疫反应。近年来，随着生物工程技术的发展，已经开发出多种新型疫苗递送系统包括VLPs、壳聚糖及其衍生物、拱顶粒子（vault particle）、Encapsulin和脂质体等[20]。2.1　病毒样颗粒　　VLPs是通过重组技术模拟病毒衣壳自组装过程，产生与真实病毒具有相似结构和抗原特性的颗粒。VLPs与病毒的大小和形状相似，但不包含任何病毒遗传物质，因此不具有传染性[5]。目前已经证实，VLPs具有病毒蛋白重复排列的特点，可以高度活化B细胞，增加抗体水平。此外，由于VLPs自身病毒样颗粒结构和易于被抗原呈递细胞摄取的尺寸，具有佐剂特性[21]。因此，VLPs容易被抗原呈递细胞吞噬，进而活化T细胞。　　VLPs表面携带的PAMPs可以被DC细胞表面或胞内模式识别受体感知，通过DC呈递VLPs肽后可以激活CD8+或CD4+ T细胞反应，同时DC上的共刺激分子也可以激活Th细胞来发挥免疫反应[22]。在VLPs中添加更多的免疫原性结构域，可以进一步增强其免疫效力，如乙型肝炎核心抗原（hepatitis B core antigen，HBcAg）。基于HBcAg的VLPs疫苗含有更多的乙型肝炎表面抗原（hepatitis B surface antigen，HBsAg）免疫原性结构域，并刺激针对乙型肝炎病毒的广泛而特异的体液和细胞介导的反应，从而增强免疫效应[23]。2.2 壳聚糖及其衍生物　　壳聚糖是一种天然高分子聚合物，具有良好的生物相容性、低毒性、生物降解性和粘附性等优势，广泛应用于免疫刺激、药物输送和伤口愈合等众多生物医学领域，在疫苗递送系统中也备受青睐。　　带正电荷的壳聚糖及其衍生物通过与带负电荷的疫苗抗原间静电吸附作用，对疫苗抗原进行压缩，从而用于疫苗的递送。细胞内化后，通过“质子海绵作用”从溶酶体中逃逸，壳聚糖被释放到胞质中，从而诱导线粒体压力，导致活性氧和线粒体DNA释放，从而通过cGAS-STING通路激活下游信号转导，导致Ⅰ型干扰素的产生和细胞因子的分泌，如IL-12、IL-23，从而促进DC成熟，并以干扰素（interferon，IFN）受体依赖的方式增强抗原特异性辅助T细胞反应[24]。　　我国学者利用Pickering乳剂的界面稳定性和壳聚糖在酸性条件下易形成分子链的特性，成功构建了壳聚糖纳米颗粒稳定的Pickering乳剂（chitosan nanoparticle-stabilized Pickering emulsion，CSPE）。结果表明，CSPE可以有效负载抗原，促进细胞内吞和抗原交叉压积，在注射部位招募抗原提呈细胞，促进T细胞活化，增强了体液和细胞免疫应答。在预防和治疗E.G7-OVA淋巴瘤和B16-MUC1黑色素瘤模型中，CSPE显著抑制肿瘤生长，延长小鼠生存时间[25]。上述结果表明CSPE是一种很有研究价值的新型疫苗递送系统。2.3 铁笼蛋白　　铁笼蛋白是来源于铁蛋白的蛋白质组装体，是一种存在于细菌、动物和植物中的铁代谢蛋白。铁笼蛋白以自组装方式形成具有强大热稳定性和化学稳定性的纳米颗粒，因此适合携带和暴露免疫原。在正常条件下，铁笼蛋白会自行组装成一个由24个单体组成的球形颗粒，具有八面体对称性，含有一个开放的中心空腔[26，27]，铁笼蛋白纳米颗粒可能会成为亚单位疫苗新兴的递送平台。例如 CHEN YB等[28]使用杆状病毒表达系统表达铁笼蛋白，在小鼠体内研究了铁笼蛋白纳米颗粒口蹄疫疫苗的保护性免疫力。与对照组相比，铁笼蛋白纳米颗粒的重组亚单位疫苗显著增加了口蹄疫病毒特异性IgG和IgG抗体滴度，并增强了脾细胞增殖以及IL-4和IFN-γ的表达。3讨 论近年来，亚单位疫苗的研究开发飞速发展，但因其免疫原性有限，需要辅以佐剂才能发挥长期有效的保护作用，所以佐剂在亚单位疫苗中的作用越发引起关注。因此，在选择佐剂的时候需要考虑多方面，例如佐剂需具备安全性、良好的耐受性、易于生产、保质期长及良好的理化特性（如pH值、渗透压、内毒素等），并且经济负担小。材料科学与生物工程技术的快速发展为新型佐剂的开发奠定了基础。基于纳米材料的递送系统在疫苗传递效率、接种剂量、给药途径等方面都具有显著优势。但是对纳米材料的安全性、免疫原性和毒性等方面需要进一步研究。　　综上所述，传统佐剂已经被应用于多种亚单位疫苗中，但它们依旧存在一些不足，如细胞免疫效果较弱、长期保护免疫力不足等。因此，新型疫苗佐剂的研究应不断深入及改进，期望在未来病毒性疾病的流行防控中发挥更大作用，保障人类的健康安全。参考文献[1]　MASCOLA J, FAUCI A. 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Bengaluru: U.S. Health Secretary Robert F. Kennedy Jr.'s newly revamped vaccine advisory panel voted on Thursday to recommend Americans receive seasonal influenza shots that are free from the mercury-based preservative thimerosal despite decades of studies showing no related safety issues. Thimerosal is only used in multi-dose vials of flu shots in the U.S. In the 2024-25 flu season, fewer than 5% of the flu shots administered were from such vials, according to the U.S. Food and Drug Administration. Anti-vaccine groups have for decades linked thimerosal to autism and other neurodevelopmental disorders, and Kennedy wrote a book in 2014 in which he advocated for "the immediate removal of mercury" from vaccines. In recent days, Kennedy has posted on X about its alleged dangers. The FDA on its website says "there was no evidence that thimerosal in vaccines was dangerous," and that the decision to remove it previously was a precautionary measure to decrease overall exposure to mercury among young infants. Multi-dose forms of CSL's Afluria and Flucelvax as well as Sanofi's Fluzone use thimerosal as a preservative, according to the FDA's website. Sanofi said it will have sufficient supply of its flu vaccine to support customer preference for this season. CSL said it supplies a very low number of multi-dose vials of flu vaccine in response to demand. CDC staff, in a report that was briefly published and then removed from the meeting's online document site, concluded that evidence does not support an association between thimerosal-containing vaccines and autism or other neurodevelopmental disorders. Panel member Dr. Robert Malone said the directive to remove the staff report came from Kennedy's office. The panel, called the Advisory Committee on Immunization Practices, voted 5-1 in three separate votes to recommend thimerosal-free shots. The now 7-person panel was installed by Kennedy earlier this month after he fired all 17 previous ACIP outside experts. The panel advises the U.S. Centers for Disease Control and Prevention on who should take specific vaccines and related products and when they should be given after FDA approval. It typically meets three times a year and intends to conduct its next meeting in the third quarter, CDC said. "The risk from influenza is so much greater than the nonexistent - as far as we know - risk from thimerosal. So I would hate for a person not to receive the influenza vaccine because the only available preparation contains thimerosal," Dr. Cody Meissner, the only panel member who voted against the recommendation, said in explaining his vote. 'A FARCE' Lyn Redwood, formerly of the Kennedy-founded anti-vaccine group Children's Health Defense, gave the presentation on thimerosal, arguing that it was a neurotoxin. Redwood's presentation posted on the CDC's website earlier this week initially included a reference to a study that does not exist. The report she gave to the committee was significantly shorter, removing a slide that made a reference to that study and another saying she did not have any conflicts of interest. "With the vote on thimerosal this afternoon, the new committee has turned the ACIP process into a farce," said former CDC vaccine adviser Dr. Fiona Havers, who resigned last week over Kennedy's changes to vaccine policy. She said it is unprecedented to have an outside speaker present and then move immediately to a vote. Evidence is usually compiled formally by CDC and reviewed by a work group. She noted that CDC experts did not present their data publicly to refute Redwood. CBS and The New York Times have reported that the agency hired Redwood to work in its vaccine safety office. An HHS spokesman declined to comment on whether Redwood had been hired by the CDC. Earlier on Thursday, the committee voted 5-2 to recommend use of Merck's recently approved RSV antibody drug Enflonsia for infants 8 months or younger whose mothers did not receive a preventive shot during pregnancy. ACIP panel member Retsef Levi raised safety concerns about the antibody drug, which were addressed by experts at the FDA and CDC. He said he would be concerned about giving the product to one of his healthy children and was one of the two votes against the recommendation. The panel's recommendations need to be adopted by either the CDC director or the Health and Human Services Secretary before becoming final. There is currently no CDC director. President Donald Trump's nominee for the post, Susan Monarez, spoke to a Senate committee yesterday as part of the confirmation process. (Reporting by Michael Erman in New York and Julie Steenhuysen in Chicago, Christy Santhosh and Bhanvi Satija in Bengaluru, Editing by Shailesh Kuber, Frances Kerry and Bill Berkrot)