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通讯作者:

邱晓彦(1960-),女,黑龙江肇东市人,博士生导师,主要从事肿瘤免疫学方面研究。E-mail:qiuxy@bjmu.edu.cn

中图分类号:R183.3R

文献标识码:A

文章编号:2096-8965(2021)01-0001-12

DOI:10.12287/j.issn.2096-8965.20210101

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目录contents

    摘要

    2020 年,一场突如其来的新型冠状病毒(SARS-CoV-2)的流行,让全世界的公共卫生体系经受了严峻的考验。 因此,获得有效预防和治疗 SARS-CoV-2 的疫苗是全世界共同的期待。目前,全球已经有两百多种疫苗处于临床前研究和临床试验阶段,但由于 SARS-CoV-2 首次肆虐人类,目前对其诱导免疫应答的规律及机制尚不完全清楚,且各类疫苗开发时间及临床应用数据有限, 尚不能确定哪一款 SARS-CoV-2 疫苗具有更好的保护性及安全性。本文从 SARS-CoV-2 关键结构、 免疫应答特征、现有的 SARS-CoV-2 疫苗研发技术路线及目前疫苗开发面临的挑战等方面进行综述,以期为 SARS-CoV-2 疫苗研发提供理论基础及思考。

    Abstract

    In 2020, the SARS-CoV-2 epidemic has made the world’s public system withstand extreme tests. Therefore, it is urgently expected to develop a vaccine that can effectively prevent the SARS-CoV-2 in the worldwide. At present, more than 200 vaccines are in the preclinical research or undergoing clinical trials. However, much remains to be studied because SARS-CoV-2 ravaged humans for the first time, and the mechanisms underlying its inducing immune response are not yet fully understood. Moreover, with limited time and clinical application data, it is still uncertain which SARS-CoV-2 vaccine can provide better protection and higher safety. This article reviews the key structure of SARS-CoV-2, the characteristics of immune response, the existing technical routes of SARS-CoV-2 research and the challenges faced by the current vaccine development, in order to provide a theoretical basis for the development of the SARS-CoV-2 vaccine.

  • 自新型严重急性呼吸道综合征冠状病毒2型(Severe Acute Respiratory Syndrome Coronavirus-2, SARS-CoV-2) 爆发以来,该病毒已蔓延至全球200多个国家,引发了一场大规模的流行 [1]。SARS-CoV-2主要是通过呼吸道飞沫在人与人之间快速传播,导致呼吸道感染,严重者发展为严重肺炎、多器官受累甚至死亡,目前已经造成上百万人死亡 [2]。为了应对这次SARS-CoV-2的危机,全世界科学家正在积极寻找预防及治疗方案以阻止SARS-CoV-2的肆虐。庆幸的是,得益于全基因组测序技术飞速发展,疫情爆发后科学家们迅速鉴定出病毒的全基因序列并鉴定到参与病毒入侵的关键性蛋白及其宿主体内的受体 [3],为药物和疫苗的开发奠定了重要的基础。目前,科学家们正在全力以赴地以SARS-CoV-2关键结构及入侵机制为基础研发SARS-CoV-2的疫苗。

  • 1 SARS-CoV-2感染靶器官的关键结构

  • 冠状病毒(冠状病毒科,冠状病毒亚科)是感染鸟类和哺乳动物常见的病毒。冠状病毒分为四个类型:α 冠状病毒、β 冠状病毒、γ 冠状病毒和 δ 冠状病毒 [4]。目前,7种冠状病毒已被鉴定为对人类具有传染性 [5],其中四种类型(HCoV-229E、 HCoV-OC43、HCoV-NL63和HCoV-HKU1)已被定义为人类常见的冠状病毒,并已在世界各地传播。然而,严重急性呼吸综合征冠状病毒(Severe Acute Respiratory Syndrome Coronavirus,简称SARS-CoV),中东呼吸综合征冠状病毒(Middle East Respiratory Syndrome Coronavirus,MERSCoV)[6] 及新型冠状病毒(Severe Acute Respiratory Syndrome Coronavirus-2, SARS-CoV-2)被认为是最具威胁人类健康的三种病毒。

  • SARS-CoV-2病毒有四种主要的结构蛋白:刺突蛋白(Spike Protein,S蛋白),核衣壳蛋白(Nucleocapsid,N蛋白),膜蛋白(Membrane Protein, M蛋白),包膜蛋白(Envelope Protein,E蛋白)[78]。 S蛋白是冠状病毒非常重要的表面蛋白,是病毒传染宿主的关键蛋白。S蛋白包含S1亚基和S2亚基 [9](见图1)。其中,S1亚基由N-末端结构域(NTD) 和受体结合结构域(Receptor-binding Domain, RBD)组成。受体结合结构域能与宿主细胞受体血管紧张素转换酶2(human Angiotensin-converting Enzyme2, hACE2)相互作用 [10]。S2亚基的功能是介导病毒与宿主细胞膜的融合,将病毒RNA释放到细胞质中进行复制 [11]。S蛋白棘突中隐藏的RBD可使SARS-CoV-2在逃避免疫监视的同时保持有效的进入细胞 [12]。研究表明,SARS-CoV-2其它结构蛋白的缺失均不影响S蛋白的免疫原性及其与ACE2受体的相互结合 [13]。因此,基于S蛋白制备疫苗诱导机体产生抗体,可以阻断病毒受体结合 [14, 15]。同样,N蛋白在SARS-CoV-2中含量丰富,参与基因组复制和细胞信号通路调节。N蛋白具有高度免疫原性,但针对N蛋白产生的抗体不具中和活性。S蛋白和N蛋白是SARS-CoV-2免疫检测的主要靶抗原,对SARS-CoV-2病毒的诊断和排查具有重要价值,而S蛋白是疫苗开发的重要靶点。

  • 图1 SARS-CoV-2病毒的结构[8]

  • 2 SARS-CoV-2疫苗研发的免疫学基础

  • 机体免疫系统具有多重的防御机制,SARSCoV-2侵犯机体首先要突破第一道屏障,即呼吸道黏膜屏障。由于SARS-CoV-2的受体ACE2主要表达在呼吸道上皮细胞上,故如何阻止SARS-CoV-2与其受体结合是防治的关键环节。上皮细胞不但具有完备的物理和化学屏障,同时具有强大的免疫功能,其可通过激活I型干扰素或RIG-I直接抑制病毒复制。同时,当病毒侵犯气道后上皮细胞可通过其表达的Toll样受体(Toll-like Receptors, TLR)等感知病毒并通过分泌促炎因子促进炎症反应,分泌趋化因子趋化免疫细胞到局部以清除病毒。如果上皮细胞免疫功能正常,病毒感染可止于该阶段,患者可表现为无症状感染。一旦病毒突破了上皮防线,将会启动固有免疫应答(第二道防线),激活局部巨噬细胞并趋化中性粒细胞及NK细胞等,释放促炎因子及蛋白酶等,在发挥抗病毒效应的同时导致局部组织炎症性渗出并伴有组织损伤,患者轻则可表现为“普通型”,重者可出现血气交换障碍、呼吸衰竭或细胞因子风暴,患者表现为“重症”甚至死亡。事实上,机体在启动固有免疫应答后很快又启动了适应性免疫应答(第三道防线),T细胞及B细胞在发挥抗病毒效应时具有更强的抗原识别精准性、高效性及记忆性。其中CD4+T细胞可通过分泌细胞因子等机制分别帮助B细胞产生高亲和力抗体或促进CD8+T细胞直接杀伤病毒感染的细胞发挥抗病毒效应,产生大量抗体可阻断病毒再次感染或清除已感染的病毒;或产生大量效应性杀伤病毒CD8+T细胞以清除病毒感染的细胞。重要的是,其子代细胞会成为记忆细胞,当再次遇到相同病毒感染时T/B细胞会快速增殖,发挥抗感染作用。目前,SARS-CoV-2疫苗研制的策略就是用灭活病毒或病毒感染的关键蛋白等去模拟病毒感染,促使机体产生SARS-CoV-2的S蛋白中和抗体以阻断病毒进入宿主细胞,以及促进记忆性T/B细胞产生以防御和清除感染的SARS-CoV-2。

  • 然而,不同病原体(如病毒)诱导机体免疫应答的规律及反应模式并不相同,由于SARS-CoV-2第一次入侵人类,目前尚未完全揭示其免疫应答规律及反应模式。如目前尚不确定新型冠状病毒肺炎(Corona Virus Disease2019, COVID-19)患者中和抗体滴度的高低与疾病严重程度之间的关系。尽管目前发现SARS-CoV-2感染康复人群中分离的中和抗体,对SARS-CoV-2感染动物模型及患者具有治疗作用 [16],目前开发的各种疫苗都可诱导猕猴及志愿者产生针对SARS-CoV-2病毒S蛋白的中和抗体(如IgM、IgA和IgG)及记忆性B细胞,表明SARS-CoV-2感染确实诱导了机体的免疫保护及免疫记忆,可预防机体免受SARS-CoV-2再次感染 [17-26]。研究发现,SARS-CoV-2感染后至少5-7个月内可以稳定产生中和抗体 [27]。但例外的是,总有一定比例的SARS-CoV-2感染康复人群(约20%~30%,未发表数据)检测不到具有保护作用的中和抗体,而且,一些重症患者体内往往存在高滴度的抗RBD中和抗体,甚至与病情呈现正相关 [28],提示目前尚不确定COVID-19患者中和抗体滴度的高低与疾病严重程度之间的关系。此外,中和抗体在体内持续的时间也不确定。最新的研究表明,通过6个月后的随访,相比于感染高峰期, COVID-19康复者的中和抗体水平下降了约50%左右 [29]。类似的研究,COVID-19患者从症状出现后1-4个月,中和抗体滴度平均下降了约4倍 [30],说明目前尚不清楚SARS-CoV-2诱导的体液免疫应答能否获得长期稳定的保护。所以,深入了解体液免疫应答的保护作用与潜在致病作用关系,对于指导设计针对SARS-CoV-2的疫苗和药物至关重要。

  • 事实上,免疫系统中,职业性病毒杀手是NK细胞和T细胞,NK细胞和CD8+T可直接杀伤病毒感染的细胞,阻止病毒的复制。CD4+T细胞可增强NK及CD8+T细胞的杀伤作用。目前的证据表明,在抗体血清阴性的暴露家庭成员、无症状感染者或者轻度COVID-19康复者体内均可检测到SARS-CoV-2特异性T细胞 [31]。而且,中和抗体滴度与SARS-CoV-2病毒产生的特异性T细胞的数量有很强的相关性 [16],特别是CD4+T细胞对S蛋白反应很强,且与产生的抗SARS-CoV-2的IgG和IgA滴度呈正相关 [32]。最近的研究表明,COVID-19康复期患者中分别检测出高比例的SARS-CoV-2特异性CD8+T和CD4+T细胞,并且,CD8+T和CD4+T细胞获得了记忆性T细胞表型[32, 33],相似地, COVID-19患者外周血中NK细胞的不同亚群被强烈激活 [34]。这些证据表明,T细胞及NK细胞免疫应答在COVID-19疾病中发挥了免疫防御作用。然而,不可忽视的是,SARS-CoV-2感染者突出的表现是NK总数明显减少和CD8+T细胞耗竭 [35],提示SARS-CoV-2具有很强的免疫逃逸能力。所以如何关注及开发可激活并诱导记忆性NK细胞及T细胞免疫应答的有效疫苗、抵抗SARS-CoV-2的免疫逃逸效应也是未来疫苗开发领域的重要策略。

  • 尽管髓系免疫细胞,包括巨噬细胞及中性粒细胞在病毒感染后会快速感知或吞噬病毒颗粒或病毒感染的细胞,但由于其在COVID-19患者的病理性炎症的发展过程中发挥致病作用 [36], 在疫苗开发中应避免过度激发髓系细胞。

  • 3 目前SARS-CoV-2疫苗主要设计策略及技术平台

  • 当前,全球各大制药公司以及研究机构主要SARS-CoV-2疫苗技术平台包括以下7种:灭活疫苗、减毒疫苗、重组亚单位疫苗、载体疫苗(病毒载体、细菌载体)、核酸疫苗(mRNA或DNA)、病毒样颗粒疫苗(Virus Like Particle, VLP)(见图2)[8]。截至2021年1月13日,世卫组织发布的各国正在进行的SARS-CoV-2疫苗研发管线包括236种候选疫苗 [37](见表1)。其中, 173种候选疫苗正处于临床前试验阶段,63种候选疫苗处于临床试验阶段(见图3)。目前有15种进展最快的候选疫苗正处于Ⅲ期临床试验阶段,预计很快获得批准上市。这些进展最快的候选疫苗已经启动了疫苗的大规模生产,以便在获得批准后能够快速应用 [38]

  • 图2 新型冠状病毒疫苗研发的七种平台 [8]

  • 图3 全球目前研发的疫苗进展

  • 表1 全球处于临床试验阶段的各种疫苗

  • 续表:

  • 续表:

  • 3.1 灭活疫苗、减毒疫苗

  • 采用灭活疫苗、减毒疫苗是历史上人类与各类传染病博弈积累的一种传统并且安全有效的方法,这种方法研发出的疫苗在人类疫苗的历史中已经得到长期和广泛的应用 [26]。灭活疫苗、减毒疫苗生产的步骤通常包括活病毒的培养,病毒的灭活,病毒质控等过程(见图4A)。灭活病毒可以快速生产,而且安全性很高。但是,病毒灭活和减毒过程可能导致病毒免疫原性的丧失或减弱。目前,不同疫苗开发平台生产出的疫苗安全性、免疫原性、接种程序和剂量都有区别。北京科兴生物制品有限公司报告了SARS-CoV-2疫苗临床Ⅱ 期试验(NCT04352608)。18~80岁的健康人,被分为两个年龄组(18~59岁和≥ 60岁),随机分配在第0天和第28天接受疫苗或安慰剂,剂量为2μg、4μg或8μg。在接种疫苗的第42天,所有受试者都产生了针对SARS-CoV-2的体液免疫应答(中和抗体),两种剂量的安全性都与安慰剂相当。未报告严重级不良反应 [39]。国药集团中国生物武汉生物制品所制备的灭活SARS-CoV-2疫苗(ChiCTR2000031809),完成了Ⅰ期(96例)和Ⅱ 期(224例)临床试验,第一阶段试验每隔4周注射2.5μg、5μg或10μg氢氧化铝抗原佐剂,而第二阶段试验每隔2周和3周注射5μg氢氧化铝抗原佐剂。结果表明,疫苗免疫原性好,产生约95%的中和抗体。最常见的不良反应是注射部位疼痛,其次是发热,属于轻度和自限性,未发现严重不良反应 [40]

  • 3.2 重组亚单位疫苗

  • 重组亚单位疫苗是直接应用病毒蛋白作为抗原刺激机体产生免疫应答的一种疫苗。大多数重组亚单位疫苗含有全长SARS-CoV-2病毒S蛋白或者部分,目的是诱导出高滴度的中和抗体。这些重组病毒蛋白可以用不同的体外表达系统表达,包括昆虫细胞、哺乳动物细胞和植物细胞(见图4B)。重组亚单位疫苗缺点是免疫原性低,表达具有较高的成本,而且重组蛋白可能在构象上无法模拟真正病毒蛋白分子特征,这或许导致诱导较多无效的中和抗体。诺华公司开发了纳米颗粒疫苗(NVXCoV2373),由三聚体全长SARS-CoV-2的S糖蛋白和Matrix-M1佐剂组成,其发布了临床Ⅰ期和 Ⅱ期的结果(NCT04368988)。在131名健康成人中注射NVX-CoV2373疫苗(5μg和25μg剂量,添加或不添加Matrix-M1佐剂)。大多数受试者的不良事件都是轻微的,没有严重的不良事件 [41]。 2020年6月安徽智飞龙科马生物制药有限公司与中国中科院微生物研究所联合研发的重组SARSCoV-2疫苗(CHO细胞)正式获得国家药监局颁发的药物临床试验批件,这是国内首个获批进入临床试验的重组亚单位SARS-CoV-2疫苗,也是安徽首个进入临床试验的SARS-CoV-2疫苗。2020年12月中国三叶草生物制药开发的“S-三聚体”重组亚单位SARS-CoV-2候选疫苗I期临床研究结果显示,该疫苗在与葛兰素史克和Dynavax的佐剂系统联合使用下,可在150名成年和老年受试者中诱导出强烈的免疫应答,并且显示了良好的安全性和耐受性。

  • 3.3 病毒样颗粒(Virus Like Particles,VLP)疫苗

  • 病毒样颗粒(VLP) 疫苗是一种含有关键病毒结构蛋白的自组装纳米结构疫苗(见图4C)。VLP类似于真正病毒的特征,但由于缺乏病毒致病性的遗传物质,因此不具感染性和复制性。由于VLP是由自组装形成的,当部分或全部病毒结构蛋白在细胞中以最佳方式表达时,产生的VLP基本能够完全代表天然病毒的原始形态和免疫原性特征 [42, 43]。目前,基于VLP平台研发的处在临床试验阶段的疫苗有两种:分别是处于临床Ⅰ/Ⅱ期的RBD SARS-CoV-2HBsAg VLP疫苗(印度血清研究所)和处于临床 Ⅱ/Ⅲ期的CoVLP疫苗(Medicago公司)。

  • 3.4 病毒载体疫苗

  • 腺病毒5型(Ad5)、腺病毒26型(Ad26)和水泡性口炎病毒(VSV)是该疫苗平台常用的病毒载体。通常将体外重组的靶基因序列与腺病毒载体组合成疫苗(见图4D)。病毒载体疫苗可以在不使用佐剂的情况下增强免疫原性,并诱导T细胞的免疫反应 [44]。腺病毒载体疫苗的缺点是其本身的免疫原性会影响腺病毒疫苗的免疫效果。全球最早的一款病毒载体疫苗是中国康希诺生物公司开发的Ad5载体SARS-CoV-2疫苗(NCT04341389)。目前Ⅱ期临床试验数据显示,5×1010 病毒颗粒的Ad5载体SARS-CoV-2疫苗是安全的,单次免疫后大多数受试者都能产生显著的免疫应答 [45]。Ad5载体COVID-19疫苗在接种后第28天,99.5%的受试者产生了特异性抗体,95.3%的受试者产生了中和抗体,89%的受试者产生了特异性T细胞免疫反应。两种剂量的疫苗均诱导产生显著的中和抗体反应。此外,阿斯利康与牛津大学合作开发了一款腺病毒载体的疫苗(ChAdOx1nCoV-19),它表达了全长的S蛋白。他们最近报告了临床Ⅰ期和Ⅱ 期的初步结果(NCT04324606)。1 077名参与者被分配到ChAdOx1nCoV-19(n=543)组,注射剂量为5 × 1010 病毒颗粒。没有与ChAdOx1nCoV-19相关的严重不良事件。在ChAdOx1nCoV-19组中,特异性T细胞反应在第14天达到最高值 [46]。2020年10月美国强生公司的腺病毒载体疫苗也已进入 Ⅲ期临床。

  • 3.5 DNA疫苗

  • 截止2021年1月,已经有进入临床 Ⅲ 期的基于DNA的SARS-CoV-2核酸疫苗(见图4E)。 2020年5月哈佛医学院的研究人员在Science上发表了他们的发现,研究者开发了一系列表达不同形式的SARS-CoV-2S蛋白的DNA疫苗候选物,并在35只恒河猴身上进行了评价 [47]。接种疫苗的动物产生体液和细胞免疫反应,中和抗体滴度与感染SARS-CoV-2的恢复期人类和猕猴的中和抗体滴度相当。接种后,所有动物均接受SARS-CoV-2攻击,与对照组相比,编码全长S蛋白的疫苗导致支气管肺泡灌洗液和鼻黏膜的病毒载量中位数分别减少。疫苗诱导的中和抗体滴度与保护效果相关,提示保护的免疫相关性。这些数据表明疫苗对非人灵长类动物具有保护作用。

  • 3.6 mRNA疫苗

  • SARS-CoV-2的mRNA疫苗是将S蛋白的mRNA序列通过脂质纳米颗粒(Lipid Nanoparticles, LNP)载体递送mRNA的方法携带进入细胞,并通过翻译直接产生靶蛋白(见图4F)进而激活免疫细胞,产生后续的免疫反应,如产生中和抗体及抗原特异性T细胞。基于mRNA的SARS-CoV-2疫苗的优点是生产工艺快速以及成本低。以mRNA扩增出来抗原,可以产生高浓度的中和抗体,从而提高疫苗的效率 [48]。然而,mRNA疫苗的缺陷是稳定性差、转化效率低以及细胞内传递障碍等问题 [49]。由于近期mRNA疫苗显示了很好的免疫保护性及安全性,其正在成为传统疫苗平台有力的替代者。目前有四种SARS-CoV-2候选mRNA疫苗,分别为mRNA-1273(Moderna)、BNT-162(BioNTech)、 CVnCoV(CureVac) 和LNP-nCoVsaRNA(Imperial College London) 正在进行临床试验。2020年7月, Moderna开始了其mRNA-1273疫苗的Ⅲ期临床试验。BioNTech与辉瑞公司合作,正在对BNT-162进行Ⅰ/Ⅱ临床试验。CureVac在2020年6月对其CVnCoV疫苗启动了Ⅰ/Ⅱ a期临床试验。伦敦帝国理工学院(Imperial College London)也在6月启动了自扩增RNA疫苗的I期临床试验 [50]

  • 图4 各种疫苗的制备平台

  • 4 目前SARS-CoV-2疫苗研发面临的挑战

  • 由于SARS-CoV-2的疯狂肆虐,造成全球健康的重大危机,这一紧急局面迫使尚处在临床试验阶段的多款疫苗大规模紧急接种,使疫苗研发面临多重挑战。

  • 4.1 疫苗的安全性

  • 安全性是疫苗研发的最基本要素。然而,由于临床急需,目前所有SARS-CoV-2疫苗的临床研究安全性数据是有局限性的。尽管SARS-CoV-2候选疫苗在动物模型中如人源ACE2小鼠[51, 52]、雪貂[53] 和恒河猴模型 [54] 等进行了免疫原性和安全性评估,但目前SARS-CoV-2疫苗获得批准上市前,尚未完成部分受试者的安全随访期,尚未监测到一些与疫苗相关的不良反应。事实上,目前随着mRNA1273及BNT-162在人群中接种,其安全事件不断出现。如Moderna公司近期公布开发的mRNA1273临床Ⅰ期结果(NCT04283461)中,45名健康成年人接受两次疫苗接种后,50%以上的受试者在第一次接种后出现不良事件,包括疲劳、寒战、头痛、肌痛和注射部位疼痛;在第二次接种后,系统性不良事件更为常见,尤其是最高剂量组(250μg)有21%受试者报告了一次或多次严重不良事件 [55]。因此,FDA建议SARS-CoV-2疫苗上市后,应当制定药物警戒计划。SARS-CoV-2疫苗药物警戒计划的内容将主要取决于安全性,其中包括临床安全性数据库、临床前数据和相关疫苗的可用安全性信息等,即便SARS-CoV-2疫苗上市后也要持续评估疫苗的安全性。所以,目前全球对疫苗的监管和审批也将面临巨大挑战,一方面希望尽快完成新开发疫苗上市的各种手续,另一方面也要保证新开发的疫苗符合各种规定及标准。

  • 4.2 疫苗的有效性及保护性

  • 疫苗的有效性及保护性需要临床及流行病学数据支持。SARS-CoV-2疫苗的研发旨在模拟天然条件下病毒感染人体后获得的免疫保护效应,但目前面临的挑战是天然条件下SARS-CoV-2感染人体后诱导免疫应答的规律和机制尚不完全清楚,尚不能为SARS-CoV-2疫苗的研发提供针对性策略。目前,尽管COVID-19患者恢复期血清中存在不同水平的中和抗体,具有抵抗SARS-CoV-2感染的能力,但尚有一些恢复期患者血清中检测不到中和抗体,甚至一些重症患者存在高水平中和抗体 [56],提示仅依据中和抗体产生评价疫苗的保护作用尚存在某些不确定性。况且,由于SARS-CoV-2疫苗的临床数据比较少,尚不知道SARS-CoV-2感染或疫苗是否具有诱导抗体依赖性增强(Antibody-dependent Enhancement,ADE)的风险,或出现疫苗相关增强型呼吸疾病(Vaccine Associated Enhanced Respiratory Disease,VAERD)风险。ADE产生的机制是病毒—抗体复合物与巨噬细胞或中性粒细胞表面的IgFcR结合效率增加,从而触发病毒进入,产生炎性因子导致组织严重损伤。虽然全世界正在研发的SARS-CoV-2疫苗并未发现ADE作用 [26, 57],但是ADE的产生依然是一个值得关注的风险。VAERD是接种了麻疹疫苗和呼吸道合胞病毒(RSV)的疫苗时,发生在幼儿身上的一种临床综合征 [58]。这些接种疫苗的儿童患上了非典型麻疹,并伴有高热、非典型肺炎症状 [59]。目前正在研制的SARS-CoV-2灭活疫苗 [39],尚未见到VAERD的证据。然而,全面评估SARS-CoV-2疫苗,包括ADE和VAERD的潜在的安全性风险,需要在长期随访或上市后长期监测,特别是在抗体滴度开始下降之后。

  • 此外,NK细胞及CD8+T细胞主要负责病毒免疫应答,目前对这两群细胞在SARS-CoV-2感染后的免疫防御效应及免疫应答规律尚不完全清楚,现在所有研制SARS-CoV-2疫苗的策略和关注点大都集中于诱导中和抗体上,很少关注如何激发NK细胞及CD8+T的抗病毒效应。

  • 5 总结与展望

  • 新型冠状病毒的流行给全世界带来了巨大的公共卫生和经济负担。随着各国科学家们的努力, SARS-CoV-2疫苗的快速成型给人们带来了可以战胜SARS-CoV-2病毒的强有力的武器。目前疫苗研发的关注点在于是否产生中和抗体,但是也要更多关注细胞免疫的功能,尤其是CD8+T细胞的免疫应答。如果病毒跨过由疫苗产生的中和抗体这道防线后,下一步如何激活细胞免疫的防线继续抵抗病毒也变得非常重要。所以,SARS-CoV-2疫苗有效性的关键点是提高中和抗体的滴度和激发T细胞的持久反应。根据免疫学基本原理,深入了解SARSCoV-2感染或者疫苗诱导的体液免疫反应和细胞免疫反应,确定体液免疫和细胞免疫应答的准确靶点,并且清楚的解析感染或疫苗诱导的B细胞受体和T细胞受体库,才能知道如何建立长久的保护性免疫。目前,SARS-CoV-2的疫苗开发时间已经压缩到1-2年,临床前研究、临床研究以及大规模化生产过程并行进行。由于疫苗开发进程加快,临床研究和临床前研究的一些数据几乎是同时发布的。因此,关于疫苗的安全性和有效性等关键信息或是不全面的。

  • 尽管目前主要的SARS-CoV-2候选疫苗已经以惊人的速度发展到临床试验的后期阶段,但是由于SARS-CoV-2感染后的免疫防御效应及免疫应答规律尚不清楚,且迄今缺乏可靠的大规模疫苗后期临床数据,许多不确定性仍然存在。只有通过对候选疫苗的安全性、有效性、免疫性和广泛人群中的保护等关键性评估,人类才能够生产出有效且安全的疫苗。期望人类能够尽快终止SARS-CoV-2病毒的肆虐。

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