CN114504640A - 含有利塞膦酸锌铝的佐剂及其应用 - Google Patents
含有利塞膦酸锌铝的佐剂及其应用 Download PDFInfo
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Abstract
本申请涉及一种含有利塞膦酸锌铝的佐剂,一种包含所述佐剂和免疫原的免疫原性组合物,以及所述佐剂和免疫原性组合物的用途。
Description
技术领域
本申请涉及生物制药技术领域。具体地,本申请涉及一种含有利塞膦酸锌铝的佐剂,一种包含所述佐剂和免疫原的免疫原性组合物,以及所述佐剂和免疫原性组合物 的用途。
技术背景
佐剂是一类能与免疫原特异或者非特异性结合,并刺激诱导机体产生长期有效的特异性免疫应答的物质或混合物。佐剂的免疫生物学作用包括降低免疫原的使用量、 增强抗原的免疫原性、改变免疫应答类型等。目前被批准用于人用疫苗的佐剂有铝佐 剂、MF59、AS04、AS01B、CpG1018等,并有数种新型佐剂处于临床试验阶段,其包括: AS03、RC-529、Advax、Matrix-M等。铝佐剂是第一个被批准用于人用疫苗的佐剂, 至今已有近90年的使用历史,是公认的应用最为广泛、安全、有效的佐剂。然而,随 着疫苗研究品种的增加,发现铝佐剂刺激诱导Th2类免疫优势应答,在诱导产生Th1 类免疫应答上作用有限,这也限制了铝佐剂在治疗性疫苗中的应用,比如水痘带状疱 疹病毒疫苗、乙肝治疗性疫苗以及肿瘤疫苗等。并且,与许多新型疫苗佐剂相比,铝 佐剂活性较弱,对类病毒颗粒抗原以外的其它大多数基因工程抗原免疫增强作用不理 想,使其在非多聚化蛋白抗原疫苗中的应用受到限制。
含铝佐剂系统是指以铝佐剂为基础,与其他佐剂成分或递呈系统(如MPL、CPG、QS21和脂质体等)形成的佐剂系统,可诱导相对平衡的Th1和Th2免疫应答。目前已 有数种含铝佐剂系统批准上市或进入临床试验(NPJ Vaccines.2018,10;3:51.). 例如,由葛兰素史克公司(GlaxoSmithKline,GSK)研发的AS04,该佐剂系统是在铝 佐剂的基础上添加TLR-4(Toll like receptor 4,TLR4)激动剂:3-0-去酰基-4’- 单磷酰脂质A(Monophosphoryllipid A,MPL),因其氨基葡萄糖磷酸化,与Al3+有 很高的亲和力,被铝佐剂吸附形成复合型佐剂,其可提高抗原特异性CD4+T细胞γ- 干扰素(Interferon-γ,IFN-γ)的表达(IFN-γ为T细胞应答的重要指标之一)。 目前AS04已成功应用于乙肝疫苗(Fendrix,2005获批上市)和HPV16/18双价宫颈 癌疫苗(Cervarix,2007获批上市)中。相较于单独使用铝佐剂而言,其可明显提高 HPV16/18双价宫颈癌疫苗(Cervarix)中和抗体滴度并延长免疫保护有效期,并且该 疫苗免疫一或两次可产生类似于免疫三针次所提供的保护效果。CpG,为TLR-9的受体 激动剂,其与铝佐剂联合作为疟疾疫苗佐剂、钩虫疫苗佐剂已进入临床试验中。
铝佐剂与抗原的吸附作用是其免疫增强机制的原因之一。配体交换是佐剂和抗原间最强的一种相互作用力,由抗原中的磷酸基团与氢氧化铝或者磷酸铝中的羟基基团 发生配体交换而产生,此为发明人Zhao在2001年提出的铝佐剂白表面“亲磷性”的 概念(Analytical Biochemistry,2001,295(1):76-81)。前述的AS04,MPL通过磷 酸基团与铝佐剂吸附而形成新型的复合佐剂在临床中已得到了很好的应用。
双膦酸盐(Bisphosphonates,BPs)药物是一类以P-C-P为中心骨架的人工合成 焦磷酸类似物,为有机双膦酸,因其含有磷酸基团使得与钙、铝、锌、镁等离子具有 高度亲和力,被用于骨疾病、钙代谢性疾病的治疗,例如骨质疏松症,变形性骨炎, 恶性肿瘤骨转移引起的高钙血症和骨痛症等。同时,临床研究显示将双膦酸药物用于 多发性骨髓瘤、乳腺癌、肾癌、前列腺癌等的辅助治疗可降低患者骨相关疾病的发生 率,癌症复发率以及提高患者的存活期并改善临床结局。除此之外,双膦酸因具有免 疫正向调节作用而表现出佐剂活性,其作为免疫增强剂被用于疫苗制剂的专利发明亦 有报道(中国专利:CN103768595B;美国专利:US20170281759A1;中国专利:CN 108289902A)。双膦酸药物在临床上通常采用口服或静脉注射给药,其具有较强的粘 膜刺激作用,而在疫苗的使用中,通常以肌肉注射的方式进行免疫。然而,双膦酸具 有潜在的副作用,仍需要进一步改进。
冠状病毒(Coronavirus,CoV)是一种具有包膜的、非节段的单股正链RNA病毒, 属于巢病毒目(Nidovirales)冠状病毒科(Coronaviridae),正冠状病毒亚科(0rthocoronavirinae),被分为α、β、γ和δ四个属.截止目前为止,发现有7 种冠状病毒可感染人类,其中以季节性流行为主的冠状病毒包括:α属的229E和NL63, β属的0C43和HKU1,以及大流行冠状病毒:严重急性呼吸综合征相关冠状病毒 (SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV)和新型冠状病毒(SARS-CoV-2)。 目前已知冠状病毒可感染人、鼠、猪、猫、犬、水貂、豚鼠、地鼠、恒河猴以及禽类 等脊椎动物,同时荷兰病毒学家证实新型冠状病毒可由人类传播给水貂再传回给人类, 证实新型冠状病毒动物传人传播链。SARS-CoV、MERS-CoV以及SARS-CoV-2具有较强 的传播能力和致病性。目前新型冠状病毒的全球大流行,给人们的生命健康安全和社 会活动造成重大威胁并引起巨大的经济损失,而疫苗是控制和预防该病毒感染的最有 效手段。
冠状病毒刺突蛋白(S蛋白)是一种I型跨膜蛋白,由S1和S2蛋白亚基两部分 组成,介导与宿主细胞表面受体的结合和细胞膜的融合以进入靶细胞。多项证据表明, 针对刺突蛋白的抗体可能在新型冠状病毒性肺炎的免疫预防和治疗中发挥关键作用, 是目前新型冠状病毒重组蛋白疫苗研制和设计的关键靶点。有研究发现,急性新型冠 状病毒感染会使其长效的中和抗体反应减弱,但仍可通过病毒特异性记忆T细胞实现 免疫记忆(Cell,2020,183(1):13-15),说明T细胞应答在预防新型冠状病毒感染 的重要性。重组DNA技术表达制备的亚单位蛋白疫苗具有较好的安全性,并可实现多 针次加强免疫,但其免疫原性较弱。同时,世界卫生组织(WHO)与2020年4月份制 定了COVID-19疫苗的目标产品特性,疫苗须快速起效,在2周内可提供保护,同时1 针实现基础免疫,并不超过2剂的给药方案,同时在保护持久性上要求至少提供6个 月的保护。
因此,本领域仍然需要开发新的佐剂,以提高疫苗(例如COVID-19疫苗)的功效。
发明内容
本申请的发明人经过深入的研究,开发获得了一种包含利塞膦酸锌铝的新型佐剂, 其可作为疫苗佐剂或药物递送载体等,可用于有效提高抗原的免疫原性。
特别地,已惊讶地发现,当本申请的佐剂与免疫原(例如新型冠状病毒刺突蛋白(S蛋白)联用时,在Balb/c小鼠、水貂、豚鼠、叙利亚金黄地鼠和食蟹猴等多种动 物上,能够刺激或诱导高水平的功能性抗体与平衡的细胞和体液免疫应答。因此,本 申请的佐剂可提高疫苗(例如新型冠状病毒S蛋白疫苗)的成药性。
此外,还已发现,当本申请的佐剂与新型冠状病毒刺突蛋白(S蛋白)联用时, 能有效预防新型冠状病毒(SARS-CoV-2)的感染。例如,含有本申请的佐剂和新型冠 状病毒S蛋白的疫苗能有效阻止或降低SARS-CoV-2在动物(例如水貂)的上下呼吸道 中的复制,并防止新型冠状病毒对动物(例如水貂)的肺部的感染和损害。
佐剂
在一个方面,本申请提供了一种包含利塞膦酸锌铝的佐剂(在本文中也简称利塞膦酸锌铝佐剂),其中,锌∶利塞膦酸摩尔浓度比在1∶1至16∶1的范围内(例如,2∶1 至16∶1的范围内);并且,锌∶铝摩尔浓度比在1∶1至50∶1的范围内(例如5∶1至 50∶1的范围内)。
在某些实施方案中,利塞膦酸锌铝以颗粒形式存在。在某些实施方案中,利塞膦酸锌铝以纳米级颗粒或微米级颗粒形式存在。在某些实施方案中,所述颗粒的粒径大 小为0.01-100μm,例如0.01-60μm,0.01-50μm,0.1-60μm,0.1-30μm,0.4-30μm, 0.4-20μm。
在某些实施方案中,所述佐剂锌∶利塞膦酸摩尔浓度比在1∶1至2∶1,2∶1至4∶1, 4∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至14∶1或者14∶1至16∶1 的范围内。在某些实施方案中,所述佐剂锌∶利塞膦酸摩尔浓度比为至少1∶1,至少2∶1, 至少3∶1,至少4∶1,至少5∶1,至少6∶1,至少7∶1,至少8∶1,至少10∶1,至少12∶1, 至少14∶1,或者至少15∶1。在某些实施方案中,所述佐剂锌∶利塞膦酸摩尔浓度比为 不超过16∶1,不超过14∶1,不超过12∶1,不超过10∶1,不超过8∶1,不超过7∶1,不 超过6∶1,不超过5∶1,不超过4∶1,不超过3∶1,或者不超过2∶1。
在某些实施方案中,所述佐剂锌∶利塞膦酸摩尔浓度比为1∶1、2∶1、4∶1、4.5∶1、 6∶1、8∶1、10∶1、12∶1、14∶1或16∶1。在某些实施方案中,所述佐剂锌∶利塞膦酸摩 尔浓度比为4∶1或4.5∶1。
在某些实施方案中,所述佐剂锌∶铝摩尔浓度比在1∶1至2∶1,2∶1至3∶1,3∶1至 4∶1,4∶1至5∶1,5∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至15∶1, 15∶1至20∶1,20∶1至30∶1,30∶1至40∶1,或者40∶1至50∶1的范围内。在某些实施 方案中,所述佐剂锌∶铝摩尔浓度比为至少1∶1,至少2∶1,至少3∶1,至少4∶1,至少 5∶1,至少6∶1,至少8∶1,至少10∶1,至少12∶1,至少15∶1,至少20∶1,至少30∶1, 或者至少40∶1。在某些实施方案中,所述佐剂锌∶铝摩尔浓度比为不超过50∶1,不超 过40∶1,不超过30∶1,不超过20∶1,不超过15∶1,不超过12∶1,不超过10∶1,不超 过8∶1,不超过6∶1,不超过5∶1,不超过4∶1,不超过3∶1,或者不超过2∶1.
在某些实施方案中,所述佐剂锌∶铝摩尔浓度比为50∶1、40∶1、30∶1、20∶1、15∶1、12∶1、10∶1、8∶1、6∶1、5∶1、4∶1、3∶1、2∶1、或1∶1。在某些实施方案中,所述佐 剂锌∶铝摩尔浓度比为10∶1。
在某些实施方案中,所述佐剂中,锌∶利塞膦酸摩尔浓度比在2∶1至8∶1的范围内,例如2∶1至4∶1,4∶1至6∶1,或6∶1至8∶1,并且,锌∶铝摩尔浓度比在2∶1至50∶1 的范围内(例如5∶1至20∶1的范围内),例如2∶1至3∶1,3∶1至4∶1,4∶1至5∶1, 5∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至15∶1,或15∶1至20∶1。
在某些实施方案中,所述佐剂中,锌∶利塞膦酸摩尔浓度比为4∶1,并且,锌∶铝 摩尔浓度比为10∶1。
在某些实施方案中,所述佐剂中,锌∶利塞膦酸摩尔浓度比为4.5∶1,并且,锌∶ 铝摩尔浓度比为10∶1。
在某些实施方案中,所述佐剂的pH为5.0-8.0,例如5.0-7.0,5.0-5.5,5.5-6.0,6.0-6.5,6.5-7.0,7.0-7.5,或7.5-8.0。在某些实施方案中,所述佐剂pH为7.0-7.5。 在某些实施方案中,所述佐剂pH为5.5-6.5。在某些实施方案中,所述佐剂pH为 5.8-6.3。
在某些实施方案中,所述佐剂零电荷点为3.0-8.0,例如4.0-8.0,3.0-4.0, 4.0-5.0,5.0-6.0,6.0-7.0,或7.0-8.0。在某些实施方案中,所述佐剂零电荷点为 4.0-6.0。
本申请的佐剂对免疫原(例如蛋白)具有良好的吸附率。在某些实施方案中,本 发明的佐剂对免疫原(例如蛋白)的吸附率为至少60%,至少70%,至少75%,至少80%, 至少85%,至少90%,或至少95%。
免疫原性组合物
不受理论限制,本发明的佐剂可以与各种免疫原联用,用于增强免疫原的免疫原性。此类免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性部分等。
因此,在一个方面,本申请提供了一种免疫原性组合物,其包含免疫原和如上所述的佐剂。
在某些实施方案中,所述免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性 部分等。在某些实施方案中,所述免疫原来源于病毒、细菌、真菌等病原体。
在某些实施方案中,所述免疫原为蛋白或其免疫原性片段,例如来源于病毒、细菌、真菌等病原体的蛋白或其免疫原性片段。在某些实施方案中,所述病毒包括但不 限于,呼吸道病毒(例如,流感病毒、副流感病毒、鼻病毒、冠状病毒、呼吸道合胞 病毒),肠道病毒(例如EV71病毒,轮状病毒),水痘带状疱疹病毒(VZV)。
在某些实施方案中,所述免疫原为冠状病毒的蛋白(例如刺突蛋白)或其免疫原性片段。在某些实施方案中,所述冠状病毒选自正冠状病毒亚科α属病毒(例如229E 和NL63),正冠状病毒亚科β属病毒(例如0C43和HKU1)、严重急性呼吸综合征相 关冠状病毒(SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV),和新型冠状病毒 (SARS-CoV-2)。在某些实施方案中,所述冠状病毒选自严重急性呼吸综合征相关冠状 病毒(SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV)和新型冠状病毒 (SARS-CoV-2)。在某些实施方案中,所述冠状病毒为新型冠状病毒(SARS-CoV-2)。在 某些实施方案中,所述免疫原为新型冠状病毒的结构蛋白或其免疫原性片段,例如刺 突蛋白(S蛋白)或其免疫原性片段。
在某些实施方案中,所述免疫原是水痘带状疱疹病毒的蛋白或其免疫原性片段,例如水痘带状疱疹病毒gE蛋白或其免疫原性片段。
在某些实施方案中,所述免疫原是流感病毒的蛋白或其免疫原性片段,例如流感病毒HA蛋白或其免疫原性片段。
在某些实施方案中,所述免疫原是轮状病毒的蛋白或其免疫原性片段,例如轮状病毒VP4蛋白或其免疫原性片段。
在某些实施方案中,所述免疫原性组合物还包含药学上可接受的辅料,例如赋形剂、防腐剂、抗菌剂、缓冲剂和/或额外的免疫佐剂。在某些实施方案中,所述额外的 免疫佐剂选自铝佐剂(例如氢氧化铝)、弗氏佐剂(例如完全弗氏佐剂和不完全弗氏 佐剂)、短小棒状杆菌、脂多糖、细胞因子,或其任何组合。
在某些实施方案中,所述免疫原性组合物还包含第二免疫原。在某些实施方案中,所述第二免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性部分等。
在某些实施方案中,所述免疫原性组合物为疫苗。
佐剂制备方法
在一个方面,本申请提供了制备如上所述的佐剂的方法,其包括如下步骤:
1)提供含有锌离子、铝离子的可溶性盐溶液;
2)将步骤(1)中的可溶性盐溶液与利塞膦酸碱溶液混合,从而获得所述佐剂。
在某些实施方案中,所述方法还包括,将步骤(2)获得的佐剂进行灭菌的步骤。 在某些实施方案中,通过过滤灭菌或高温高压灭菌来对所述佐剂进行灭菌。在某些实 施方案中,通过在121℃下灭菌至少15分钟(例如至少30分钟,例如30-60分钟), 对所述佐剂进行灭菌。
在某些实施方案中,在所述可溶性盐溶液中,锌∶铝的摩尔浓度比在1∶1至50∶1 的范围内(例如5∶1至50∶1的范围内)。在某些实施方案中,在所述可溶性盐溶液中, 锌∶铝摩尔浓度比在1∶1至2∶1,2∶1至3∶1,3∶1至4∶1,4∶1至5∶1,5∶1至6∶1,6∶1 至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至15∶1,15∶1至20∶1,20∶1至30∶1,30∶1 至40∶1,或者40∶1至50∶1的范围内。在某些实施方案中,在所述可溶性盐溶液中, 锌∶铝摩尔浓度比为至少1∶1,至少2∶1,至少3∶1,至少4∶1,至少5∶1,至少6∶1, 至少8∶1,至少10∶1,至少12∶1,至少15∶1,至少20∶1,至少30∶1,或者至少40∶1。 在某些实施方案中,在所述可溶性盐溶液中,锌∶铝摩尔浓度比为不超过50∶1,不超 过40∶1,不超过30∶1,不超过20∶1,不超过15∶1,不超过12∶1,不超过10∶1,不超 过8∶1,不超过6∶1,不超过5∶1,不超过4∶1,不超过3∶1,或者不超过2∶1。
在某些实施方案中,在所述可溶性盐溶液中,锌∶铝摩尔浓度比为50∶1、40∶1、 30∶1、20∶1、15∶1、12∶1、10∶1、8∶1、6∶1、5∶1、4∶1、3∶1、2∶1、或1∶1。在某些 实施方案中,在所述可溶性盐溶液中,锌∶铝摩尔浓度比为10∶1。
在某些实施方案中,在步骤(2)中,以在1∶1至16∶1的范围内(例如2∶1至 16∶1的范围内)的锌∶利塞膦酸摩尔浓度比,将所述可溶性盐溶液与利塞膦酸碱溶液 混合。在某些实施方案中,所述锌∶利塞膦酸摩尔浓度比在1∶1至2∶1,2∶1至4∶1, 4∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至14∶1或者14∶1至16∶1 的范围内。在某些实施方案中,所述锌∶利塞膦酸摩尔浓度比为至少1∶1,至少2∶1, 至少3∶1,至少4∶1,至少5∶1,至少6∶1,至少7∶1,至少8∶1,至少10∶1,至少12∶1, 至少14∶1,或者至少15∶1。在某些实施方案中,所述锌∶利塞膦酸摩尔浓度比为不超 过16∶1,不超过14∶1,不超过12∶1,不超过10∶1,不超过8∶1,不超过7∶1,不超过 6∶1,不超过5∶1,不超过4∶1,不超过3∶1,或者不超过2∶1。
在某些实施方案中,所述锌∶利塞膦酸摩尔浓度比为1∶1、2∶1、4∶1、4.5∶1、6∶1、 8∶1、10∶1、12∶1、14∶1或16∶1。在某些实施方案中,所述锌∶利塞膦酸摩尔浓度比为 4∶1或4.5∶1。
在某些实施方案中,在步骤(2)中,以使锌离子、铝离子和利塞膦酸共同沉淀的 方式,将所述可溶性盐溶液与利塞膦酸碱溶液混合。在某些实施方案中,在步骤(2) 中,将利塞膦酸碱溶液逐滴加入所述可溶性盐溶液,使锌离子、铝离子和利塞膦酸共 同沉淀。在某些实施方案中,在步骤(2)中,在将所述可溶性盐溶液与利塞膦酸碱溶 液混合的过程中,锌离子、铝离子和利塞膦酸发生共同沉淀,产生利塞膦酸锌铝颗粒。
在某些实施方案中,所产生的利塞膦酸锌铝颗粒的粒径大小为0.01-100μm,例如0.01-60μm,0.01-50μm,0.1-60μm,0.1-30μm,0.4-30μm,0.4-20μm。
在某些实施方案中,所述利塞膦酸碱溶液选自利塞膦酸氢氧化钠,利塞膦酸磷酸盐溶液(例如利塞膦酸磷酸氢二钠溶液,利塞膦酸磷酸氢钠溶液),或其任何组合。
在某些实施方案中,所述利塞膦酸碱溶液为利塞膦酸氢氧化钠溶液或利塞膦酸磷酸氢 二钠溶液。
在某些实施方案中,步骤(1)所述可溶性盐溶液选自例如硫酸盐溶液、氯酸盐溶液、醋酸盐溶液、或其任何组合。在某些实施方案中,所述可溶性盐溶液为氯酸盐溶 液或醋酸盐溶液。
佐剂用途
在一个方面,本申请还提供了所述佐剂用于制备免疫原性组合物或用做递送免疫原的载体或用做免疫原的免疫增强剂的用途。在一个方面,本申请还提供了所述佐剂 用于增强免疫原的免疫原性的用途。在一个方面,本申请还提供了所述佐剂用于增强 受试者对免疫原的免疫应答水平的用途。在一个方面,本申请还提供了所述佐剂在制 备用于增强受试者对免疫原的免疫应答水平的制剂中的用途。易于理解,上文对于所 述佐剂和免疫原等的各种描述也同样适用于这些方面。
在某些实施方案中,所述免疫应答为细胞免疫应答和/或体液免疫应答。在某些实施方案中,所述细胞免疫应答为T细胞免疫应答。在某些实施方案中,所述T细胞免 疫应答为免疫应答Thl和/或Th2免疫应答。
免疫原性组合物制备方法/提高免疫原的免疫原性的方法
在一个方面,本申请还提供了制备免疫原性组合物的方法,其包括:将所述佐剂与免疫原进行混合的步骤。在一个方面,本申请提供了一种提高免疫原的免疫原性的 方法,其包括将免疫原与所述佐剂混合的步骤。易于理解,可以将本发明的佐剂与各 种可能的免疫原联用,以增强免疫原的免疫原性。因此,上文对于所述佐剂和免疫原 等的各种描述也同样适用于这些方面。
在某些实施方案中,所述免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性 部分等。在某些实施方案中,所述免疫原来源于病毒、细菌、真菌等病原体。
在某些实施方案中,所述免疫原为蛋白或其免疫原性片段,例如来源于病毒、细菌、真菌等病原体的蛋白或其免疫原性片段。在某些实施方案中,所述病毒包括但不 限于,呼吸道病毒(例如,流感病毒、副流感病毒、鼻病毒、冠状病毒、呼吸道合胞 病毒),肠道病毒(例如EV71病毒,轮状病毒)。水痘带状疱疹病毒(VZV)。
在某些实施方案中,所述免疫原为冠状病毒的蛋白(例如刺突蛋白)或其免疫原性片段。在某些实施方案中,所述冠状病毒选自正冠状病毒亚科α属病毒(例如229E 和NL63),正冠状病毒亚科β属病毒(例如0C43和HKU1)、严重急性呼吸综合征相 关冠状病毒(SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV),和新型冠状病毒 (SARS-CoV-2)。在某些实施方案中,所述冠状病毒选自严重急性呼吸综合征相关冠状 病毒(SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV)和新型冠状病毒 (SARS-CoV-2)。在某些实施方案中,所述冠状病毒为新型冠状病毒(SARS-CoV-2)。在 某些实施方案中,所述免疫原为新型冠状病毒的结构蛋白或其免疫原性片段,例如刺 突蛋白(S蛋白)或其免疫原性片段。
在某些实施方案中,所述免疫原是水痘带状疱疹病毒的蛋白或其免疫原性片段,例如水痘带状疱疹病毒gE蛋白或其免疫原性片段。
在某些实施方案中,所述免疫原是流感病毒的蛋白或其免疫原性片段,例如流感病毒HA蛋白或其免疫原性片段。
在某些实施方案中,所述免疫原是轮状病毒的蛋白或其免疫原性片段,例如轮状病毒VP4蛋白或其免疫原性片段。
在某些实施方案中,所述方法还包括,添加药学上可接受的辅料的步骤。在某些实施方案中,所述辅料选自例如赋形剂、防腐剂、抗菌剂、缓冲剂和/或额外的免疫佐 剂。在某些实施方案中,所述额外的免疫佐剂选自铝佐剂(例如氢氧化铝)、弗氏佐 剂(例如完全弗氏佐剂和不完全弗氏佐剂)、短小棒状杆菌、脂多糖、细胞因子,或 其任何组合。
在某些实施方案中,所述方法还包括,添加第二免疫原的步骤。在某些实施方案中,所述第二免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性部分等。
在某些实施方案中,所述免疫原性组合物为疫苗。
免疫原性组合物用途
在一个方面,本申请提供了所述的免疫原性组合物在制备用于预防和/或治疗受试 者的疾病的药物中的用途,所述疾病是能够被所述免疫原诱发的免疫应答所预防或治疗的疾病。
易于理解,上文对于所述佐剂、免疫原、免疫原性组合物等的各种描述也同样适用于本方面。还易于理解的是,免疫原性组合物中可以包含各种免疫原;相应地,所 制备的药物可用于预防或治疗各种对应的疾病。例如,当所述免疫原性组合物中含有 来源于病原体(例如病毒)的免疫原时,本申请的免疫原性组合物可用于制备用于预 防和/或治疗受试者中的病原体感染(例如病毒感染)或与病原体感染(例如病毒感染) 相关的疾病的药物。
在某些实施方案中,所述免疫原来源于冠状病毒(例如新型冠状病毒),并且, 所述疾病为冠状病毒(例如新型冠状病毒)感染或与冠状病毒(例如新型冠状病毒) 感染相关的疾病。在某些实施方案中,所述免疫原为冠状病毒(例如新型冠状病毒) 的蛋白(例如刺突蛋白)或其免疫原性片段,并且,所述疾病为冠状病毒(例如新型 冠状病毒)感染或与冠状病毒(例如新型冠状病毒)感染相关的疾病。
在某些实施方案中,所述免疫原为新型冠状病毒的结构蛋白(例如刺突蛋白(S 蛋白))或其免疫原性片段;并且,所述疾病为新型冠状病毒感染或与新型冠状病毒 感染相关的疾病(例如,新型冠状病毒性肺炎(COVID-19))。
在某些实施方案中,所述免疫原来源于水痘带状疱疹病毒,并且,所述疾病为水痘带状疱疹病毒感染或与水痘带状疱疹病毒感染相关的疾病。
在某些实施方案中,所述免疫原为水痘带状疱疹病毒的蛋白(例如gE蛋白)或其免疫原性片段,并且,所述疾病为水痘带状疱疹病毒感染或与水痘带状疱疹病毒感染 相关的疾病。
在某些实施方案中,所述免疫原来源于流感病毒,并且,所述疾病为流感病毒感染或与流感病毒感染相关的疾病。
在某些实施方案中,所述免疫原为流感病毒的蛋白(例如HA蛋白)或其免疫原性片段,并且,所述疾病为流感病毒感染或与流感病毒感染相关的疾病。
在某些实施方案中,所述免疫原来源于轮状病毒,并且,所述疾病为轮状病毒感染或与轮状病毒感染相关的疾病。
在某些实施方案中,所述免疫原为轮状病毒的蛋白(例如VP4蛋白)或其免疫原 性片段,并且,所述疾病为轮状病毒感染或与轮状病毒感染相关的疾病。
在某些实施方案中,所述受试者是动物,例如禽类动物或哺乳动物。在某些实施方案中,所述受试者是啮齿类动物、猪科动物、猫科动物、犬科动物、马科动物、灵 长类动物或禽类动物。在某些实施方案中,所述受试者是非人受试者。在某些实施方 案中,所述受试者是小鼠、水貂、豚鼠、叙利亚金黄地鼠或食蟹猴。在某些实施方案 中,所述受试者是人。
刺激/增强免疫应答的方法
在一个方面,本申请提供了一种刺激或增强受试者对免疫原的免疫应答的方法,其包括给予受试者有效量的含有所述免疫原和本发明佐剂的免疫原性组合物的步骤。 易于理解,上文对于所述佐剂、免疫原、免疫原性组合物、受试者等的各种描述也同 样适用于本方面。
在某些实施方案中,所述免疫应答为细胞免疫应答和/或体液免疫应答。在某些实施方案中,所述细胞免疫应答为T细胞免疫应答。在某些实施方案中,所述T细胞免 疫应答为免疫应答Th1和/或Th2免疫应答。
在某些实施方案中,所述免疫原性组合物是通过选自下列的途径进行给药的:肌内注射、皮下注射、皮内、鼻内、口服、透皮或静脉注射。在某些实施方案中,所述 免疫原性组合物通过肌内注射给药。
疾病治疗/预防方法
在一个方面,本申请提供了一种预防或治疗疾病的方法,其包括给予受试者有效量的免疫原性组合物的步骤,其中,所述疾病是能够被所述免疫原诱发的免疫应答所 预防或治疗的疾病。
易于理解,上文对于所述佐剂、免疫原、免疫原性组合物、受试者等的各种描述 也同样适用于本方面。还易于理解的是,免疫原性组合物中可以包含各种免疫原;相 应地,免疫原性组合物可用于预防或治疗各种对应的疾病。例如,当所述免疫原性组 合物中含有来源于病原体(例如病毒)的免疫原时,本申请的免疫原性组合物可用于 预防和/或治疗受试者中的病原体感染(例如病毒感染)或与病原体感染(例如病毒感 染)相关的疾病。
在某些实施方案中,所述疾病为冠状病毒(例如新型冠状病毒)感染或与冠状病毒(例如新型冠状病毒)感染相关的疾病。相应地,在此类实施方案中,所述免疫原 来源于冠状病毒(例如新型冠状病毒)。在某些实施方案中,所述免疫原为冠状病毒(例如新型冠状病毒)的蛋白(例如刺突蛋白)或其免疫原性片段。
在某些实施方案中,所述疾病为新型冠状病毒感染或与新型冠状病毒感染相关的疾病,例如新型冠状病毒性肺炎(COVID-19)。相应地,在此类实施方案中,所述免 疫原来源于新型冠状病毒。在某些实施方案中,所述免疫原为新型冠状病毒的结构蛋 白(例如刺突蛋白(S蛋白))或其免疫原性片段。
在某些实施方案中,所述疾病为水痘带状疱疹病毒感染或与水痘带状疱疹病毒感染相关的疾病。相应地,在此类实施方案中,所述免疫原来源于水痘带状疱疹病毒。 在某些实施方案中,所述免疫原为水痘带状疱疹病毒的蛋白(例如gE蛋白)或其免疫 原性片段。
在某些实施方案中,所述疾病为流感病毒感染或与流感病毒感染相关的疾病。相应地,在此类实施方案中,所述免疫原来源于流感病毒。在某些实施方案中,所述免 疫原为流感病毒的蛋白(例如HA蛋白)或其免疫原性片段。
在某些实施方案中,所述疾病为轮状病毒感染或与轮状病毒感染相关的疾病。相应地,在此类实施方案中,所述免疫原来源于轮状病毒。在某些实施方案中,所述免 疫原为轮状病毒的蛋白(例如VP4蛋白)或其免疫原性片段。
在某些实施方案中,所述受试者是动物,例如禽类动物或哺乳动物。在某些实施方案中,所述受试者是啮齿类动物、猪科动物、猫科动物、犬科动物、马科动物、灵 长类动物或禽类动物。在某些实施方案中,所述受试者是非人受试者。在某些实施方 案中,所述受试者是小鼠、水貂、豚鼠、叙利亚金黄地鼠或食蟹猴。在某些实施方案 中,所述受试者是人。
本申请中相关术语的说明及解释
在本申请中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。
根据本发明,术语“S蛋白”是指新型冠状病毒刺突蛋白,其属于I型跨膜蛋白, 由S1和S2蛋白亚基两部分组成,介导与宿主细胞表面受体的结合和细胞膜的融合以 进入靶细胞。野生型S蛋白的氨基酸序列是本领域技术人员所公知的,其典型氨基酸 序列可参见Genbank:QHD43416.1。在某些实施方案中,所述野生型S蛋白的氨基酸 序列如SEQ ID NO:1所示。
易于理解,本领域技术人员可对野生型S蛋白进行改造,例如,去除弗林酶切位点,增加蛋白多聚化结构域(例如增加T4噬菌体fibritin蛋白质的三聚化结构域), 和/或,增加标签以获得期望的性能。在某些实施方案中,所述经改造的S蛋白的氨基 酸序列如SBQID NO:4所示。
除非本文另外指明或根据上下文明显矛盾,否则,术语“S蛋白”应被解释成覆 盖野生型S蛋白以及经改造的S蛋白。
根据本发明,“gE蛋白”为水痘带状疱疹病毒(varicella-zoster virus,VZV) 的一种囊膜糖蛋白。野生型gE蛋白的氨基酸序列是本领域技术人员所公知的,其典型 氨基酸序列可参见Cenbank:DQ008355.1。在某些实施方案中,所述gE蛋白的氨基酸 序列如SEQ IDNO:2所示。
根据本发明,术语“HA蛋白”是指流感病毒血凝素(hemagglutinin,HA),其 为介导病毒入侵宿主细胞的关键蛋白,也是抗流感病毒中和抗体的主要靶点。各亚型 流感病毒HA蛋白的氨基酸序列是本领域技术人员所公知的,例如,乙型Victoria系 流感病毒的一个典型氨基酸序列可参见Genbank:AIU46088。在某些实施方案中,所 述HA蛋白的氨基酸序列如SBQ ID NO:3所示。
根据本发明,“VP4蛋白”为轮状病毒的外层衣壳蛋白。VP4蛋白是一种重要的中 和抗原,能够刺激机体产生中和抗体。野生型VP4蛋白的氨基酸序列是本领域技术人 员所公知的,其典型氨基酸序列可参见Genbank:KP752474或GenBank:MG729832。
除非本文另外指明或根据上下文明显矛盾,否则,本文所述gE蛋白、HA蛋白和 VP4蛋白应被解释成覆盖其相应的野生型蛋白以及其相应的经改造的蛋白。
根据本发明,术语“佐剂”是指非特异性免疫增强剂,当其与抗原一起或预先递 送入机体时,其可增强机体对抗原的免疫应答或改变免疫应答类型。佐剂有很多种, 包括但不限于铝佐剂(例如氢氧化铝)、弗氏佐剂(例如完全弗氏佐剂和不完全弗氏 佐剂)、短小棒状杆菌、脂多糖、细胞因子等。弗氏佐剂是目前动物试验中最常用的 佐剂。氢氧化铝佐剂则在临床实验中使用较多。
根据本发明,术语“药学上可接受的辅料”可以是例如惰性稀释剂,例如水或其 他溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄 酯、丙二醇、1,3-丁二醇、油(具体而言为棉籽油、花生油、玉米油、胚芽油、橄榄 油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇、脱水山梨糖醇的脂肪酸酯,以及 它们的混合物;除了惰性稀释剂之外,口服组合物还可包含佐剂如湿润剂、乳化剂和 悬浮剂、甜味剂、矫味剂、着色剂、香味剂和防腐剂;混悬剂制剂还可含有悬浮剂, 例如乙氧基化异十八醇、聚氧乙烯山梨醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化 铝、膨润土、琼脂和黄蓍胶以及它们的混合物;这些组合物还可含有辅剂如湿润剂、 乳化剂和分散剂。还可能需要在组合物中包含等渗剂,如糖类、氯化钠等。另外,可 通过掺入能延迟吸收的物质如单硬脂酸铝和明胶,实现可注射药物形式的延长吸收。
如本文中使用的,术语“免疫原性”是指,能够刺激机体形成特异抗体或致敏淋 巴细胞的能力。其既指,抗原能刺激特定的免疫细胞,使免疫细胞活化、增殖、分化, 最终产生免疫效应物质如抗体和致敏淋巴细胞的特性,也指抗原刺激机体后,机体免 疫系统能形成抗体或致敏T淋巴细胞的特异性免疫应答。免疫原性是抗原最重要的性 质,一种抗原能否成功地诱导宿主产生免疫应答取决于三方面的因素:抗原的性质、 宿主的反应性和免疫方式。
根据本发明,术语“免疫原性片段”是指这样的多肽片段,其至少部分地保留了 所源自的蛋白的免疫原性。例如,冠状病毒刺突蛋白(S蛋白)的免疫原性片段是指, 冠状病毒刺突蛋白的至少部分地保留了免疫原性的片段。
根据本发明,术语“额外的免疫佐剂”包括但不限于稳定剂;乳化剂;pH调节剂, 如氢氧化钠、盐酸等;脂质体;iscom佐剂;合成的糖肽,如胞壁酰二肽;增量剂, 如右旋糖苷;聚羧乙烯;细菌细胞壁,如分枝杆菌细胞壁提取物;它们的衍生物,如 短小棒状杆菌(Corynebacterium parvum);痤疮丙酸杆菌(Propionibacterium acne); 牛分支杆菌(Mycobacterium bovis),例如卡介菌(Bovine Calmette Guerin,BCG); 牛痘或动物痘病毒蛋白;亚病毒颗粒佐剂,如环状病毒;霍乱毒素;N,N-双十八烷基 -N′,N′-双(2-羟乙基)-丙二胺(吡啶);单磷酰脂质A;二甲基双十八烷基溴化铵; 它们的合成物和混合物。合适的稳定剂的例子包括但不限于蔗糖、明胶、蛋白胨、消 化的蛋白质提取物如NZ-胺或NZ-胺AS。乳化剂的例子包括但不限于矿物油、植物油、 花生油和其他可用于注射剂或鼻内疫苗组合物的标准、可代谢、无毒的油。
如本文中所使用的,术语“受试者”可以是任何动物,例如禽类动物或哺乳动物。在某些实施方案中,所述受试者是啮齿类动物、猪科动物、猫科动物、犬科动物、马 科动物、灵长类动物或禽类动物。在某些实施方案中,所述受试者是非人受试者。在 某些实施方案中,所述受试者是小鼠、水貂、豚鼠、叙利亚金黄地鼠或食蟹猴。在某 些实施方案中,所述受试者是人。
如本文中所使用的,术语“新型冠状病毒肺炎”和“COVID-19”是指,因 SARS-CoV-2感染而导致的肺炎,二者具有相同的含义。
根据本发明,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如COVID-19)有效量是指,足以预防,阻止,或延迟疾病(例如COVID-19) 的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾 病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如, 对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体 状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其 他治疗等等。
发明的有益效果
与现有技术相比,本发明提供了一种包含利塞膦酸锌铝的佐剂,其可作为疫苗佐剂或药物递送载体等,可用于有效提高抗原的免疫原性,其效果优于Al佐剂的效果。
特别地,当本申请的佐剂与免疫原(例如新型冠状病毒刺突蛋白(S蛋白))联 用时,在Balb/c小鼠、水貂、豚鼠、叙利亚金黄地鼠和食蟹猴等多种动物上,能够刺 激或诱导高水平的功能性抗体与平衡的细胞和体液免疫应答。因此,本申请的佐剂可 提高疫苗(例如新型冠状病毒S蛋白疫苗)的成药性。
附图说明
图1为铝佐剂(A1001)(图1A)与利塞膦酸锌铝佐剂(FH002C)(图1B)悬浊 液外观以及在光学显微镜和电镜下的颗粒形态图。
图2为A1001(图2A)与FH002C(图2B)的颗粒粒径测量结果。n=3,mean±SD
图3为A1001与FH002C在不同pH值下Zeta电位的测量结果。n=3,mean±SEM
图4A至图4F为不同锌、铝、利塞膦酸比例的FH002C佐剂的悬浊液外观以及在电 镜下的颗粒形态图。
图5为未吸附佐剂的新型冠状病毒S重组蛋白与经解离的疫苗制剂(FH002C联合 S重组蛋白)的抗原性检测结果,图中显示的是不同蛋白浓度下基于ACE2受体特异性 结合的ELISA检测结果。
图6为用不同免疫原组分(S重组蛋白1μg,S重组蛋白10μg,S重组蛋白 +A1001 1μg,S重组蛋白+A1001 10μg,S重组蛋白+FH002C 1μg,和S重组蛋白 +FH002C 10μg)分别免疫小鼠后,小鼠血清中抗体结合滴度及中和滴度的检测结果。 *p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=5,mean±SEM。
图7为不同锌、铝、利塞膦酸比例的FH002C佐剂联合新型冠状病毒S重组蛋白免 疫Balb/C小鼠后的特异性抗体结合滴度,*p<0.05;**p<0.01;***p<0.001;n=5, mean±SEM。注:横坐标表示锌∶铝∶利塞膦酸的摩尔浓度比例。
图8为FH002C或A1001联合新型冠状病毒S重组蛋白免疫叙利亚金黄地鼠后的特异性抗体结合滴度,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=22 或16,Geometric mean±Geometric mean SD。
图9为FH002C或A1001联合新型冠状病毒S重组蛋白免疫食蟹猴后的特异性抗体结合滴度,n=2,Geometric mean±Geometric mean SD。
图10为FH002C或A1001联合新型冠状病毒S重组蛋白免疫叙利亚金黄地鼠后血 清的中和抗体滴度,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=22 或16,Geometric mean±Geometric mean SD。
图11为FH002C或A1001联合新型冠状病毒S重组蛋白免疫食蟹猴的中和抗体滴度,n=2,Geometric mean±Geometric mean SD。
图12为FH002C或A1001联合新型冠状病毒S重组蛋白免疫叙利亚金黄地鼠后的 血清阻断滴度,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=22或16, Ceometricmean±Geometric mean SD。
图13为FH002C或A1001联合新型冠状病毒S重组蛋白免疫食蟹猴的血清阻断滴度,n=2,Geometric mean±Geometric mean SD。
图14为FH002C或A1001联合新型冠状病毒S重组蛋白免疫Balb/c小鼠后的血清 抗体亲合力,n=4或5,mean±SEM。
图15为FH002C或A1001联合新型冠状病毒S重组蛋白免疫叙利亚金黄地鼠后的 血清抗体亲合力,n=16,mean±SEM。
图16为FH002C或A1001联合新型冠状病毒S重组蛋白免疫Balb/c小鼠后的血清 抗体亚型,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=4或5,mean±SEM。
图17为酶联免疫斑点法测定FH002C或A1001联合新型冠状病毒S重组蛋白免疫Balb/c小鼠后的T细胞应答的结果,图17(左)为捕获的图像,图17(右)为对捕 获图像的计数结果,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=8, mean±SD。
图18为FH002C或A1001联合水痘带状疱疹病毒gE蛋白免疫Balb/C小鼠后的特 异性抗体结合滴度,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=5, mean±SBM。
图19为FH002C或弗氏佐剂联合流感病毒HA蛋白免疫Balb/C小鼠后的特异性抗 体结合滴度,*p<0.05;**p<0.01;***p<0.001;****p<0.0001;n=10,mean±SBM。 注:“Victoria/WT”表示未经去糖基化酶(Pngase)处理的Victoria野生型HA蛋白, “Victoria/Pngase”表示经Pngase处理的Victoria野生型HA蛋白。
图20为FH002C或A1001联合轮状病毒VP4蛋白免疫Balb/C小鼠的中和抗体滴度, n=5,mean±SEM。
图21为FH002C或A1001联合轮状病毒VP4蛋白免疫豚鼠的中和抗体滴度,n=5,mean±SBM。
序列信息
本申请涉及的序列的描述提供于下表中。
表1序列信息
具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明,但是本领域技术人员将理解,下列附图和实施例仅用于说明本发明,而不是对本发明的范 围的限定。根据附图和优选实施方案的下列详细描述,本发明的各种目的和有利方面 对于本领域技术人员来说将变得显然。
制备例所用试剂如下:
利塞膦酸钠(C7H10NNaO7P2),购自湖南华腾制药有限公司;
无水氯化锌(ZnCl2),购自西陇化工;
六水合氯化铝(AICl3·6H2O),购自西陇化工;
十二水合磷酸氢二钠(Na2HPO4·12H2O),购自西陇化工;
氢氧化钠(NaOH),购自西陇化工
制备例1:利塞膦酸锌铝佐剂(FH002C)的制备
(1)溶液配制:
按照1∶0.1∶0.22的Zn/Al/利塞膦酸摩尔浓度比,配制0.5L(47mM氯化锌+4.7 mM氯化铝)溶液,定义为A溶液;配制0.5L(10.3mM利塞膦酸+55mM氢氧化钠+63 mM磷酸氢二钠)溶液,定义为B液,A溶液和B溶液用0.22μm滤膜过滤备用。
(2)利塞膦酸锌铝佐剂FH002C悬浊液的制备:
将A和B溶液按照1∶1体积配比,以共同沉淀的方式来制备利塞膦酸锌铝佐剂, 即将配制好的B溶液,按照体积比1∶1的方式逐滴直至全部加入A溶液形成的悬浊液。 对混合后获得悬浊液进行一次121℃,60min灭菌,测定灭菌之后的pH、粒径及颗 粒形态等理化性质。
制备例2:不同锌、铝、利塞膦酸比例的利塞膦酸锌铝佐剂(FH002C)的制备
(1)溶液配制:
以Zn的摩尔浓度为1,设计了Zn/Al/利塞膦酸摩尔浓度比为1∶0.02∶0.1、 1∶0.02∶0.15、1∶0.02∶0.22、1∶0.02∶0.33、1∶0.02∶0.5、1∶0.02∶1以及1∶0.05∶0.1、 1∶0.05∶0.15、1∶0.05∶0.22、1∶0.05∶0.33、1∶0.05∶0.5、1∶0.05∶1以及1∶0.1∶0.1、1∶0.1∶0.15、1∶0.1∶0.22、1∶0.1∶0.33、1∶0.1∶0.5、1∶0.1∶1以及1∶0.15∶0.1、 1∶0.15∶0.15、1∶0.15∶0.22、1∶0.15∶0.33、1∶0.15∶0.5、1∶0.15∶1以及1∶0.25∶0.1、 1∶0.25∶0.15、1∶0.25∶0.22、1∶0.25∶0.33、1∶0.25∶0.5、1∶0.25∶1以及1∶0.5∶0.1、 1∶0.5∶0.15、1∶0.5∶0.22、1∶0.5∶0.33、1∶0.5∶0.5、1∶0.5∶1,分别配制0.5L(47mM 氯化锌+0.94、2.35、4.7、7.05、11.75、23.5mM氯化铝)溶液,定义为A溶液;配 制0.5L(4.7、7.05、10.3、15.51、23.5、47mM利塞膦酸+35-250mM氢氧化钠+63 mM磷酸氢二钠)溶液,定义为B液,A溶液和B溶液用0.22μm滤膜过滤备用。
2)悬浊液的制备:
将A和B溶液按照1∶1体积配比,以共同沉淀的方式来制备利塞膦酸锌铝佐剂, 即将配制好的B溶液,按照体积比1∶1的方式逐滴直至全部加入A溶液形成的悬浊液。 对混合后获得悬浊液进行一次121℃,60min灭菌。
制备例3:铝佐剂A1001的制备
按照0.15∶1的磷酸根/Al摩尔浓度配比,配制0.5L 124mM的氯化铝溶液,定 义为A溶液;配制0.5L 18.6mM浓度的磷酸氢二钠溶液,定义为B液,B溶液中含 有140mM氢氧化钠,0.22μm滤膜过滤备用。
铝佐剂A1001悬浊液的制备过程可参考FH002C悬浊液的制备。
实施例1:利塞膦酸锌铝(FH002C)以及铝佐剂(A1001)的理化性质测定
对混合后获得的FH002C悬浊液(制备例1)以及A1001悬浊液(制备例3)进行 一次121℃,60min灭菌,测定灭菌之后的pH、粒径及颗粒形态、零电荷点等理化 性质。
(1)佐剂外观以颗粒形态观察
将利塞膦酸锌铝佐剂FH002C用100mM NaAc缓冲溶液稀释1倍以及铝佐剂A1001 用生理盐水稀释1倍后,用中国华为mate30 5G手机摄像机进行拍摄,记录其佐剂的 外观;同时将利用中国Motic的AE31E倒置生物显微镜进行颗粒形态的观察与拍摄, 目镜和物镜的放大倍数为10x。
将铝佐剂A1001和利塞膦酸锌铝佐剂FH002C用去离子水稀释分别稀释50和100 倍后,利用日本Electronics的JEM-2100透射电子显微镜(Transmission ElectronMicroscopy,TEM)进行观察。具体的步骤如下:将佐剂样品滴于铜网上,令其吸附 10min,用滤纸擦去残液,送入透射电镜的样品室里,观察样品形态,拍照。
实验结果:如图1所示,利塞膦酸锌铝佐剂FH002C以及铝佐剂A1001均为乳白色 悬浊物;光学显微镜下两者均为无定型的团簇状形态;在电镜下FH002C为无规则的片 状结构,而A1001佐剂可以清晰看到丝状结构。
(2)pH测定
取供试品,放置室温平衡至少30分钟,利用Sartorius酸度计进行测量。
选择标准缓冲液(pH 7.00)、标准缓冲液(pH 4.01)、标准缓冲液(pH 10.01) 按照使用说明书要求校正仪器。
按“Mode”(转换)键可以在pH和mV模式之间进行切换。通常测定溶液pH值将 模式至于pH状态。
按“SETUP”键,显示屏显示Clear buffer,按“ENTER”键确认,清除以前的校 准数据。
按“SETUP”键直至显示屏显示缓冲溶液组“4.01,7.00,10.01”,按“ENTER” 键确认。
将电极小心从电极储存液中取出,用去离子水充分冲洗电极,冲洗干净后用滤纸吸干表面水(注意不要擦拭电极)。
将电极浸入第一种缓冲溶液(pH 7.00),等到数值稳定并出现“S”时,按“STANDARDIZE”键,等待仪器自动校准。校准成功后,将显示“7.00”和电极斜率。
将电极从第一种缓冲溶液中取出,用去离子水充分淋洗电极,将电极依次浸入第二种缓冲溶液(pH 4.01),等到数值稳定并出现“S-时,按“STANDARDIZE”键,等 待仪器自动校准。校准成功后,将显示“4.01 7.00-和信息“Slope”。Slope显示 测量的电极斜率值,该测量值在90-105%范围内可以接受。
如果与理论值有很大偏差,将显示错误信息(Err),电极应清洗,并重复上述步 骤校准。
重复以上操作完成第三点(pH 10.01)校准。
校准完成后,用去离子水充分淋洗电极,然后滤纸轻轻吸干。摇匀供试品溶液, 将玻璃电极浸入供试品溶液中,至pH值的读数在1分钟内改变不超过±0.05时进行 读数。
摇匀供试品溶液,重新测量,两次pH值的度数相差应不超过0.1。取两次读数的 平均值作为供试品pH值。
实验结果:A1001佐剂灭菌前pH为8.00-8.40,灭菌后6.50-6.90;FH002C佐剂 灭菌前pH为7.00-7.50,灭菌后5.80-6.30。
(3)粒径大小的测定
打开Beckman LS 13320激光粒径测试仪,预热15min。
打开仪器控制软件和样品池封闭舱,将样品池从样品槽中取出并加入12mL纯化水。
将样品池置于样品槽上,关闭舱门。
打开LS13320软件后,点击弹窗中“OK”进行仪器自检。点击菜单栏“run”,选 择“Use Optical Module”,打开检测模块。点击菜单栏“control”,选择“stirrer on”启动样品池内置的自动搅拌器。点击“start cycle”,依次选择“Measure Offsets”、“Align”、“Measure Background”,最后点击“start”,在弹出的对 话框中点击“OK”开始校正空白背景。
取出样品池,加入一定质量的标准样品(仪器自带),点击“start cycle”,依 次选择“Measure Loading”、“Enter Sample Info”、“Enter run setting”、 “start runs”,最后点击“start”,在弹出的对话框中输入标准样品名称,待软件 中“Obscuration”参数为8%-12%时点击“OK”,进行标准样品的测试。
为保证实验数据的准确性和可靠性,每次开机测量之前均需校正空白背景和测试标准样品的大小。
打开样品池封闭舱,取出样品池。
将样品池内含有标准样品的水溶液倒弃,倒入去离子水清洗样品池3遍。
清洗完毕后加入12mL去离子水,将样品池置于样品槽上,关闭舱门。
点击“start cycle”,依次选择“Measure Offsets”、“Align”、“MeasureBackground”,最后点击“start”,在弹出的对话框中点击“OK”开始校正空白背景。
取出样品池,加入一定体积的检测样品,打开样品测试舱门,将
样品池置于样品槽上,关闭舱门。
点击“start cycle”,选择“Enter Sample Info”、“Enter run setting”、 “startruns”,最后点击“start”,在弹出的对话框中输入样品名称,待软件中 “Obscuration”参数为8%-12%时点击“OK”,记录样品测得的粒径大小;对铝佐 剂A1001和利塞膦酸锌铝FH002C分别进行三次重复测量。
实验结果:如图2所示,A1001的颗粒分布为单峰,大小在0.4-60μm之间, 主要分布在15-16μm(图2A);利塞膦酸锌铝佐剂FH002C颗粒分布为双峰,大小 在0.4-25μm之间,主峰的颗粒大小为5.0μm左右(图2B)。
(4)PZC(零电荷点)检测
仪器检测:Nanobrook Omni(Brookhaven)
实验操作:打开电源,将多角度粒度及高灵敏Zeta电位仪预热30min。
使用36%-38%盐酸和10M NaOH将A1001佐剂调节pH至6.5、7.0、7.5、8.0、8.5 以及FH002C佐剂调节至3.0、4.0、5.0、6.0、7.0。
钝化电极:向样品管中加入3-4mL佐剂,电极插入后,SOP中将cycle设置为: 50,运行仪器,使得电极钝化。
样品检测:电极取出后,去离子水冲洗下端,加入相应样品,SOP中点击“instrument parameters”,在“cell type”中选择“square polystyrene cell”, 在“electrode assembly”中选择“BI-SREL(1250μL)”后,点击“advanced settings”,设置“equilibration time”为120seconds,“inter-cycle delay” 为1seconds,在“timedependent”中选择“measurements”为3,“time interval” 为0,点击“liquid”,pH设置为各样品对应的pH,点击“Data Analysis”中的 “model“,选择“smoluchowski”,最后点击“save”,点击“OK”,完成参数设置。
运行仪器:将不同pH的佐剂充分摇匀后,依次吸取2mL于塑料样品池中,插入 电极,放入样品槽中,将仪器与样品槽的数据连接起来,点击“start”开始测量,再 进行下一次样品检测。
数据处理:得到不同pH值下对应的Zeta电位,运行仪器自带软件,得到PZC值, 再采用GraphPad Prism 8.0.2(厂商:GraphPad Software,LLC)进行绘图。
实验结果:如图3所示,铝佐剂A1001的PZC为7.52;利塞锌铝佐剂FH002C的 PZC为4.75。
(5)FH002C中Zn/Al/利塞膦酸的沉淀率
实验方法:游离上清中锌、铝含量采用原子吸收光谱仪(岛津,AA6300C(P/N 206-52430))进行检测,利塞膦酸采用紫外分光光度仪(贝克曼,DU800)进行检测,具 体如下:
采用原子吸收光谱仪的火焰法进行锌元素含量测定:
标准曲线的配制:将锌单元素标准溶液(北京有色金属研究总院,CSB 04-1761-2004)用0.2%硝酸稀释成0,500,1000,1500,2000ng/mL的锌标准溶液。
供试品溶液的准备:用0.2%硝酸溶液将样品进行梯度稀释直至浓度在标准曲线范 围内(Abs读值在0.2-0.8之间),每步稀释之前需用涡旋混和仪震动混匀。
登录WizAArd:双击WizzAArd图表打开软件,在“操作”一栏中点击“测定”图 标,在“Login ID”一栏中输入“Admin”,无需密码点击<OK>即可。
Wizard选择:选择“元素选择”,点击<OK>。
选择元素:在“元素选择”页面中选择“选择元素”选项,在“装载参数”页面 中选择“Zn”,选择[火焰连续]测定方法,“使用ASC”选项无需打钩,选择[普通灯], 点击<确定>。“校准曲线设置”和“编辑参数”页面无需特殊设定,点击<确定>。“未 连接仪器/发送参数”页面,点击<连接/发送参数>。
在“仪器初始化”页面中,有关石墨炉法的ASC检查、GFA检查选项无需检查; 出现“检查燃气”对话框,选择<否>;出现“现在可以检查安全装置,希望检查助燃 器压力监控器?”对话框,选择<是>;出现“请供应空气,在供应空气后点击确定键, 空气排放”对话框,选择<确定>;出现“检查N02”对话框,选择<否>;出现“不能使 用N02-C2H2”对话框,选择<确定>;出现“把废液探头提到液面之上”,按照提示操作 并向废液罐中加入足够多的超纯水,直至水从废液管流出,防止回火;出现“移动废 液探头到液面之下”,按照提示操作并旋紧废液罐瓶口,所有项目检查完成后,点击< 确定>。
在“火焰分析的仪器检查目录”中逐项检查并打钩,点击<OK>。
在“光学参数”页面中设定波长[213.86nm],狭缝宽[0.7],点灯方式[发射],[灯位设置]保证Zn空心阴极灯的实际位置与设定位置相同,选择[点灯],待屏幕下方显 示“就绪”,点击<确定>。
“谱线搜索”页面:当“谱线搜索”及“光束平衡”均显示[OK]时,点击[关闭], 回到“光学参数”页面,点击<下一步>。在“原子化器/气体流量设置”页面中,无需 更改,点击<完成>。
燃烧器原点位置调节:依次选择[仪器]→[维护保养]→[燃烧器原点位置调节],调节前后位置旋钮及燃烧器上的扳手,控制燃烧器的位置,用AA-6300C标准卡片观察 发射光的位置,利用卡片上的刻度,使通过整个燃烧器缝上的光处于同一水平线上, 调好后,等待Abs值稳定;通过计算机调节燃烧器的垂直高度,<向上移动>或<向下移 动>,先粗调后细调,使Abs值为最大示数的一半(保证有1/2最大光强通过燃烧器), 选择<原点记忆>并关闭当前页面,在燃烧器上方罩上安全罩。
在菜单栏中选择[参数]→[编辑参数]→将点灯方式改为<BGC-D2>。重新进行“谱线搜索”当“谱线搜索”及“光束平衡”均显示[OK]时,点击<关闭>。
点火:确保C2H2打开且压力达到要求后,同时按下主机上的PURGE和IGNITE键, 直至点火。
自动调零:正式检测样品前,选择[自动调零],除去燃烧器中残余的杂质。
在MRT工作单上设置空白组(BLK)、标准品(STD)、待测样品(UNK),输入标 准品的理论浓度以及样品名称,通过雾化器延伸出来的上样管进行手动上样,每次上 样量最少1mL,选择[开始]进行检测。
数据处理:根据标准品的Abs和其浓度在Excel中制作散点图,添加趋势线,显 示公式和相关系数R2,R2≥99%证明相关性良好,可用于计算样品浓度。
采用原子吸收光谱仪的石墨法进行铝元素含量测定:
标准曲线的配制:将铝单元素标准溶液(国家有色金属及电子材料分析测试中心,GNM-SAl-002-2013),用2%硝酸稀释成0,20,50,100,150,200ng/mL的铝标准 溶液。
供试品溶液的准备:将样品用0.2%进行稀释直至浓度在标准曲线范围内(Abs读值在0.2-0.8之间)。
登录WizAArd:双击WizzAArd图表打开软件,在“操作”一栏中点击“测定”图 标,在”Login ID”一栏中输入“Admin”,无需密码点击<OK>即可。Wizard选择: 选择“元素选择”,点击<OK>。
选择元素:在“元素选择”页面中选择“选择元素”选项,在“装载参数”页面 中选择“Al”,“使用ASC”选项打钩,选择[普通灯],点击<下一步>。“校准曲线 设置”和“编辑参数”页面无需特殊设定,点击<确定>。打开GFA-EX7i的电源开关扳 手(HEAT),在“连接主机/发送参数”页面,点击<连接/发送参数>。出现“未连接仪 器,希望连接?”对话框,点击<是>。
在“仪器初始化”页面中,有关火焰法的C2H2阀、助燃器、燃气、火焰监控器、 燃烧器、废液探头选项无需检查,点击<NO>,所有项目检查完成后,点击<确定>。绕 过火焰分析:出现“将要进行火焰分析?”对话框,点击<否>。
“光学参数”标签页中,设定波长[396.2nm],狭缝宽[0.7nm],点灯方式[发 射],[灯位设置]保证铝灯处于设定位置,在[点灯]选项处打钩待屏幕右下角显示[就 绪],点击<确定>。
“谱线搜索”页面:当“谱线搜索”及“光束平衡”均显示[OK]时,点击<关闭>, 回到“光学参数”页面,点击<下一步>。
在“石墨炉程序”页面中,“最大阶段号”选择[7],“采样阶段号”选择[6], “石墨管类型”选择[未知],点击<完成>。
石墨炉原子化器原点位置调节:依次选择[仪器],[维护保养],[石墨炉原点位置调节],待原子化器位置示数稳定后,使用手动前后位置旋钮移动石墨炉原子化器直至 Abs示数达到最大,利用WizAArd软件调节原子化器上下位置,先[快速]调节后改用[慢 速]调节直至示数达到最大,点击<原点记忆>。
检查ASC管口位置:从菜单栏中依次选择[仪器]→[石墨炉管口位置],根据计算机提示,使吸样管口先移向ASC转盘,而后移向石墨炉原子化器,根据WizAArd软件 提示,先放松臂引导螺丝,点击<向下移动>使吸样管口下移,接近石墨炉注入孔时, 调节ASC工作台的注入位置调节旋钮,前后左右水平调节吸样管口的位置,直至位于 注入孔的正中央。利用<向上移动>和<向下移动>调节上样位置,先粗调后细调,用ASC 配备的观察镜观察吸样管口在注入孔内的位置,吸样管口处距离注入孔底端1/3时为 最佳位置。点击<确定>保存当前位置并关闭当前页面。
重复检查ASC管口位置:旋紧旋钮,从菜单栏中依次选择[仪器]→[石墨炉管口位置],当吸样管口移向原子化器后,选择[移向管],若吸样管口位于注入孔正中央则无 需调节,若吸样管口位置偏移则重新调至注入孔正中央,并选择<取消>,直至吸样管 口位于注射孔正中央。
在菜单栏中选择[参数]→[编辑参数]→将点灯方式改为<BGC-D2>。重新进行“谱线搜索”当“谱线搜索”及“光束平衡”均显示[OK]时,点击<关闭>。清洁:正式检 测样品前,选择<清洁>,除去石墨管中残余的杂质。
在MRT工作单上依次设置空白组(BLK)、标准品(STD)、待测样品(UNK)的位 置及上样量(10μL),输入标准品的理论浓度以及待测样品的样品名称,选择<开始> 进行检测。
结果处理:根据标准品的Abs值和理论浓度在excel中制作散点图,添加趋势线,显示公式和相关系数R2,R2≥99%证明相关性良好,可用于计算样品浓度。
紫外分光光度仪对FH002C上清的利塞膦酸含量进行测定:
开机预热:打开仪器右后侧的总电源开关,一般预热10-20分钟。
根据要求进行选项测定:在屏幕左上角第一行可选栏中选择Fixed Wavelength(固 定波长测定)进行测定。
Fixed Wavelength(固定波长测定):点击Edit Method图标出现波长设定界面,Number of wavelengths栏中选择262nm波长,设定完毕点击OK。将空白管的样本装 上干净的比色皿中,放入比色架,点击BLK图标,扣除空白,再分别加入样品,点击 Read即可。
实验结果:根据得出的标准曲线,分别计算FH002C上清中的锌离子、铝离子以及利塞膦酸,根据公式:(各成分总含量-上清中各成分的含量)/各成分总浓度*100%, 即为各成分的沉淀率,通过计算得出利塞膦酸锌铝佐剂FH002C中的锌的沉淀率大于 99.0%、铝和利塞膦酸的沉淀率大于99.9%(表2)。
表2 FH002C中锌离子、铝离子以及利塞膦酸的沉淀率
(6)吸附率测定
如下设计和制备新型冠状病毒S重组蛋白。简言之,通过在SARS-CoV-2的野生型 S蛋白(SEQ ID NO:1)全长胞外段的C末端融合T4噬菌体fibritin蛋白质的三聚 化结构域,去除其中的弗林酶切位点,并在C端融合6*His标签设计重组新型冠状病 毒S蛋白(S重组蛋白,SEQ ID NO:4)。利用中国仓鼠卵巢癌细胞(Chinese hamster ovarian cancer cells,CHO)表达系统(购自Thermo Scientific,A29133)表达S 重组蛋白,并通过镍-琼脂糖凝胶柱(Cytiva,17-5318-03)进行纯化,从而获得纯度 大于95%的S重组蛋白。通过BCA方法(PierceBCA Protein Assay Kit,Thermo Scientific,23227)对经纯化的S重组蛋白进行定量。将S重组蛋白稀释至400μg/mL, 与FH002C佐剂混合,S重组蛋白∶佐剂=1∶1(体积比),将混合后的样品制剂摇匀后4℃ 静置吸附,在各个时间点分别进行取样。取样前充分摇匀,500μL/次;取出的样品 按13000rpm/min离心5min后取上清,再根据预实验结果将样品上清稀释相应倍数, 待用。
绘制标准曲线:将S重组蛋白原液作为标准品进行梯度稀释,样稀液SD-1为稀释缓冲液,将标准品稀释至EP管中规定的浓度梯度:50ng/mL、25ng/mL、12.5ng/mL、 6.25ng/mL、3.12ng/mL、1.56ng/mL,待用。
实验过程:
(1)包板:用1x CB9.6包被缓冲液将36H6单克隆抗体(实验室自制,36H6单 克隆抗体为识别新冠S蛋白上RBD表位的抗体,采用杂交瘤技术制备,方法参考Li,et al.EmergingMicrobes Infection.2020)稀释至1μg/mL,100μL/孔加至聚苯 乙烯96孔板中,4℃包被过夜。
(2)封闭:弃去孔内包被液,PBST洗液洗板1次,甩干,加封闭液-1,200μL/ 孔,25℃封闭4h。
(3)弃去孔内封闭液,PBST洗板1次,甩干,将稀释好的标准品和样品上清加 入相应的96孔板内,25℃孵育反应1h。
(4)加酶标抗体(85F7-HRP)(实验室自制):弃去孔内液体,PBST洗板5次, 甩干,加酶标抗体(85F7-HRP,按1∶5000(V∶V)稀释,ED-11作为酶稀液)100μL/ 孔,25℃孵育反应1h。
(5)显色:弃去孔内酶标抗体,PBST洗板5次,甩干,以100μL/孔加入A、 B等体积混匀的显色液,25℃反应10min。
(6)终止:50μL/孔,2M硫酸终止液,终止反应。
(7)读板:在酶标仪上设置检测双波长为450nm和630nm,测各反应孔的0D 值。
FH002C佐剂吸附率计算:将稀释后的样品孔OD读值带入标准曲线内,求得该样 品孔相应的蛋白浓度,再乘以相应的稀释倍数,即为原样品上清中蛋白浓度。佐剂吸 附率=(原样品中蛋白总浓度-上清中蛋白浓度)/原样品中蛋白总浓度*100%。
实验结果如表3所示:根据吸附率计算公式计算,FH002C配伍S重组蛋白的疫苗制剂 在吸附30h时,佐剂吸附率可到达95%以上,4℃放置70天,该疫苗制剂中的蛋白吸 附率均在95%以上(96.5%-99.9%)。
表3.FH002C佐剂对新冠S重组蛋白的吸附率
实施例2:不同锌、铝、利塞膦酸比例的利塞膦酸锌铝佐剂(FH002C)的理化性 质测定
对混合后获得的FH002C悬浊液(制备例2)以及A1001悬浊液(制备例3)进行 一次121℃,60min灭菌,测定灭菌之后的pH、吸附率、金属沉淀率、外观与颗粒 形态等理化性质。
(1)pH测定
pH测定方法同实施例1中的pH测定过程。
实验结果:不同锌、铝、利塞膦酸比例的FH002C佐剂灭菌前pH为7.20-7.90, 灭菌后6.00-6.60。
(2)吸附率测定
BSA标准品绘制标准曲线:100mM NaAc为稀释缓冲液,将BSA标准品(2mg/mL) 进行系列稀释,用紫外分光光度计检测其在280nm处的吸光值,绘制标曲。
BSA配制:100mM NaAc为稀释缓冲液,称取一定量BSA样品,稀释至EP管中, 最终浓度为1mg/mL。
BSA与佐剂混合:将佐剂摇匀后,按照1mg/mL BSA∶佐剂=1∶1(体积比)进行 混合,室温吸附1h,期间摇晃5次,离心(13000rpm/min,3min),取上清,待 用。
吸附率测定:采用紫外分光光度计直接测定上清在280nm处的吸光值,使读值在0.2-0.8之间。吸附率计算:将稀释后的样品孔OD读值带入标准曲线内,求得该样品 孔相应的蛋白浓度,再乘以相应的稀释倍数,即为原样品上清中蛋白浓度。佐剂吸附 率=(原样品中蛋白总浓度-上清中蛋白浓度)/原样品中蛋白总浓度*100%。
实验结果如表4所示:根据吸附率计算公式计算,不同锌、铝、利塞膦酸比例的FH002C佐剂吸附率在39%-96%之间。以75%为标准,选取吸附率大于75%以上的佐剂 进行金属沉降率观察。
表4.不同锌、铝、利塞膦酸比例的FH002C佐剂对0.5mg/mL BSA的吸附率结果
注:以Zn的摩尔浓度为1对铝以及利塞膦酸摩尔浓度比例的换算
(3)金属沉降率检测
混合金属元素标准溶液制备:取12mL离心管,用5%硝酸稀释四种金属单元素标准溶液至标曲最高浓度点STD7。再将其用1%硝酸逐级对倍稀释(6mL盐酸加6mL上 一级标准工作液),依次得到STD6-STD1溶液,最终每份混合标曲溶液体积为6mL, 以确保进样完全。
表5.混合金属标准曲线
注:表中单位“ppm”等同于“μg/mL”。
供试品溶液制备(至少4mL):取供试品平衡至室温,用旋涡混合仪充分混匀, 精密量取供试品用5%硝酸溶液稀释至合适倍数,混匀后静置1小时,即为供试品溶液 (测定钙、镁和锌的含量建议稀释倍数200倍,测定铝含量建议稀释50倍)。
空白对照溶液制备:取5%硝酸溶液作为空白对照
测定:打开氩气瓶(调节气压为0.6MPa左右);吹气平衡:打开ICP-OES仪器 设备及软件,在软件界面中的“Dashboard”选择“Purge Gas Flow”,点击选择下拉 选项中“Normal”模式。在该状态下至少平衡仪器1个小时。平衡时观察软件界面 “Torchcompartment”、“Plasma Gas Pressure”、“Purge Gas Pressure”、“Drain Flow”、“ExhaustFlow”和“Optics Temperature”应变为绿色状态。打卡水箱, 等待约2分钟,待仪器状态栏“Detector Water Flow”和“Detector Temperature” 状态变绿。连接仪器管路并清洗:将导管进样口放在超纯水中,正确连接导管至蠕动 泵上,选择界面中“Pump Speed”改为50,点击“Apply”,观察导管出口是否能正 常流出液体。待1-2分钟清洗后,可进行点火。点火:选择软件界面中的“Dashboard”, 单击操作界面上方中间蓝色图标“Get Ready”,弹出窗口,点击“OK”,大约等2-5 分钟,点火成功。若第一次点火未识别为正常情况,待仪器自清洗完全后,再次进行 点火操作。在日志查看Carbon line中x值与y值。两者的绝对值分别均应小于10。 建立LabBook:点击右侧菜单栏“LabBooks”,在“Name”栏输入待做实验名称(实 验日期+实验内容+操作人),选择“Create a new LabBook from an exsiting LabBook”, 打开“Risedronate Sodium-Zinc-Aluminum adjuvant Method Template”,点击界 面下方“Create LabBook”,即成功在利塞膦酸锌铝佐剂模板中新建当次实验LabBook; 参数选择:进入新创建的模板界面,在右侧“Analytes”栏检查待测元素及其检测波 长Zn(213.856nm)、Al(396.152nm)、Ca(396.847nm)、Mg(279.553nm)。在 “Measure Modes”栏检查观测方向是否为Radial。建立样品进样序列:在右侧栏选 择“Sample list”将样品信息及进样位置输入序列中并保存,点击左上角绿色三角形 图标“Start”,再点击左下角绿色三角形图标即可开始运行序列。每个样品测样时将 导管放入离心管中,每一针测完后系统提示放入wash中清洗前,需用无尘纸(或滤纸) 擦去导管上残留液滴。将导管从wash中放回下一个样品中时同样需擦去导管上液滴。 结果计算:以混合标准溶液的浓度为横坐标,以相应的峰面积为纵坐标绘制4条标准 曲线,拟定直线回归方程。将稀释后的供试品溶液对应的各单元素峰面积代入回归方 程,乘以稀释倍数,求出供试品溶液的金属元素浓度(ppm)。
实验结果:如表6、7、8所示,Zn基本存在于沉淀中,Mg和Ca有部分存在沉淀, 部分存在于上清中。根据Mg和Ca的沉淀率结果选择标灰的部分进行佐剂外观和颗粒 形态观察。
表6.不同锌、铝、利塞膦酸比例的FH002C佐剂中锌的沉淀率
注:以Zn的摩尔浓度为1,换算铝和利塞膦酸的摩尔浓度比例。“/”表示未测量
表7.不同锌、铝、利塞膦酸比例的FH002C佐剂中镁的沉淀率
注:以Zn的摩尔浓度为1,换算铝和利塞膦酸的摩尔浓度摩尔浓度比例。“/”表示未测量
表8.不同锌、铝、利塞膦酸比例的FH002C佐剂中钙的沉淀率
注:以Zn的摩尔浓度为1,换算铝和利塞膦酸的摩尔浓度比例。“/”表示未测量
(4)佐剂外观以颗粒形态观察
佐剂外观以颗粒形态观察可参考实施例1中的检测过程。
实验结果:如图4A-图4F所示,不同锌、铝、利塞膦酸比例的利塞膦酸锌铝佐剂 均为乳白色悬浊物,混浊度不一;在电镜下大部分为无规则的片状结构,个别为丝状 结构。
实施例3:含FH002C的新型冠状病毒S重组蛋白制剂抗原活性的测定(基于ACE2 受体结合)
将FH002C(如制备例1所制备的)与新型冠状病毒S重组蛋白通过体积比为1:1 混合形成疫苗制剂,4℃放置1周后(吸附完全),以检测其抗原性。以未吸附的新型 冠状病毒S重组蛋白原液作对照,对佐剂吸附抗原并解离后的抗原性进行比较。
基于ACE2受体结合的体外相对效力实验检测蛋白的抗原性:
(1)抗体包被液:1X CB 9.6缓冲液(15mM Na2CO3;35mM NaHCO3)。
(2)洗涤液:PBST,INNOVAX公司ELISA试剂盒
(3)封闭液:封闭液-1,INNOVAX公司ELISA试剂盒。
(4)显色液A:INNOVAX公司ELISA试剂盒。
(5)显色液B:INNOVAX公司ELISA试剂盒。
(6)终止液:INNOVAX公司ELISA试剂盒。
实验过程:
(1)包板:用1x CB9.6包被缓冲液将新型冠状病毒S蛋白抗体45C3(实验室自 制)稀释至1μg/mL。100μL/孔加至聚苯乙烯96孔板中,4℃包被过夜。
(2)封闭:弃去孔内包被液,PBST洗液洗板1次,甩干,加封闭液200μL/孔, 室温封闭4h。
(3)样品准备:S重组蛋白抗原原液(吸附前),S重组蛋白疫苗制剂(制剂中 S重组蛋白抗原浓度为100μg/mL,佐剂为FH002C)经解离后的抗原。首孔抗原浓度 均为4μg/mL。弃去孔内封闭液,PBST洗板1次,甩干,首孔加待检血清200μL/ 孔,后面的每孔加入100μL样品稀释液,2倍梯度稀释,25℃孵育反应1h。
(4)加ACE2-hFc(购自SinoBiological,货号:10108-H02H):弃去孔内液体, PBST洗板5次,甩干,加ACE2-hFc,1μg/mL,100μL/孔,25℃孵育反应1h.
(5)加酶标抗体(MAH-HRP)(购自SouthernBiotech,货号:9042-05):弃去 孔内液体,PBST洗板5次,甩干,加酶标抗体(MAH-HRP,V∶V=1∶5000)100μL/ 孔,25℃孵育反应1h。
(5)显色:弃去孔内酶标抗体,PBST洗板5次,甩干,以100μL/孔加入A、 B等体积混匀的显色液,25℃反应10min。
(6)终止:50μL/孔加2M硫酸终止液,终止反应。
(7)读板:在酶标仪上设置检测双波长为450nm和630nm,测各反应孔的0D 值。
实验结果如图5所示:利用基于ACE2受体结合的抗原性检测结果表明,FH002C 联合新型冠状病毒S重组蛋白疫苗制剂经解离液解离后,其抗原性与S重组蛋白原液 抗原性相当(rEC50=EC50,原液/EC50,解离后=0.9),说明含FH002C的新型冠状病毒S 重组蛋白疫苗制剂具有良好的稳定性。
实施例4:含利塞膦酸锌铝佐剂的新型冠状病毒S重组蛋白量效关系研究
将按制备例1制备好的FH002C佐剂和按制备例3制备好的A1001佐剂作为佐剂分别与新型冠状病毒重组S重组蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射小 鼠,测定血清中特异性抗体结合滴度和中和滴度。具体方法如下:
实验动物:Balb/C小鼠(购自上海斯莱克实验动物有限责任公司,货号:2017000502480),6-8周,5只/组,雌性。
实验分组:(1)S重组蛋白水溶液低剂量组(1μg);(2)S重组蛋白水溶液 高剂量组(10μg);(3)S重组蛋白+A1001低剂量组(1μg);(4)S重组蛋白 +A1001高剂量组(10μg);(5)S重组蛋白+FH002C低剂量组(1μg);(6)S 重组蛋白+FH002C高剂量组(10μg)。
免疫方案:S重组蛋白1μg/只或10μg/只,佐剂与S重组蛋白通过体积比为 1∶1混合形成疫苗,而后肌肉注射小鼠,每只100μL,小鼠每条后腿各50μL.0, 3周免疫,即动物按照免疫分组首次免疫后3周,眼眶采血,测定血清中特异性抗体 滴度。第3周加强免疫,其后每周进行眼眶取血,采用ELISA法测定血清中特异性抗 体结合滴度。
酶联免疫吸附法(ELISA)检测抗体结合滴度:
(1)抗体包被液:1X CB 9.6缓冲液(15mM Na2CO3;35mM NaHCO3)。
(2)洗涤液:PBST,INNOVAX公司ELISA试剂盒
(3)封闭液:封闭液-1,INNOVAX公司ELISA试剂盒。
(4)显色液A:INNOVAX公司ELISA试剂盒。
(5)显色液B:INNOVAX公司ELISA试剂盒。
(6)终止液:INNOVAX公司ELISA试剂盒。
实验过程:
(1)包板:用CB9.6包被缓冲液将抗原S重组蛋白稀释至一定浓度。100μL/ 孔加至聚苯乙烯96孔板中,4℃包被过夜。
(2)封闭:弃去孔内包被液,PBST洗液洗板1次,甩干,加封闭液200μL/孔, 室温封闭4h。
(3)加一定稀释度的血清:弃去孔内封闭液,PBST洗板1次,甩干,首孔加待 检血清200μL/孔,后面的每孔加入100μL样品稀释液,2倍梯度稀释,25℃孵 育反应1h。
(4)加酶标抗体(GAM-HRP)(购自Bio-Rad Laboratories Inc.,货号:1706516):弃去孔内血清稀释液,PBST洗板5次,甩干,加酶标抗体(GAM-HRP,V∶V=1∶5000) 100μL/孔,25℃孵育反应1h。
(5)显色:弃去孔内酶标抗体,PBST洗板5次,甩干,以100μL/孔加入A、B 等体积混匀的显色液,25℃反应10min。
(6)终止:50μL/孔加2M硫酸终止液,终止反应。
(7)读板:在酶标仪上设置检测双波长为450nm和630nm,测各反应孔的0D 值。
血清中特异性抗体中和滴度检测方法参见H.L.xiong et al.,Robustneutralization assay based on SARS-CoV-2 S-protein-bearing vesicularstomatitis virus(VSV)pseudovirus and ACE2-overexpressing BHK21 cells.EmergMicrobes Infect,1-38(2020).
实验结果如图6所示:
小鼠免疫一针后3周,相同免疫剂量下,FH002C佐剂组小鼠抗体滴度高于水溶液组和A1001佐剂组,高于铝佐剂组1-1.5个数量级,具有起效快的特点。免疫两针后, 其体液免疫增强优势依然明显。4周时,低剂量组中,FH002C佐剂组抗体滴度高于铝 佐剂组1.5个数量级,高于水溶液组3个数量级。高剂量组中,FH002C佐剂组与A1001 组抗体水平相当,均高于水溶液组2个数量级。第5、6周时,在高低剂量组中,FH002C 佐剂组抗体滴度仍然明显优于A1001组(0.5-1个数量级)和水溶液组(2.5-3个数量 级)。
免疫一针后,第三周仅有FH002C佐剂组小鼠产生中和抗体,水溶液组及A1001佐剂组小鼠均未产生。第二针加免后,第4,5,6周中,无论在高剂量组还是低剂量组, FH002C佐剂组小鼠中和滴度均高于A1001佐剂组(高于0.5-1.5个数量级)和水溶液 组(高于1.5-2.5个数量级)。
实施例5:不同锌、铝、利塞膦酸比例的FH002C佐剂联合新型冠状病毒S重组蛋 白产生的特异性抗体结合滴度
将制备好的FH002C(制备方法参见制备例2)作为佐剂分别与新型冠状病毒S重 组蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射Balb/C小鼠,测定产生的特异 性抗体滴度。具体方法如下:
实验动物:Balb/C小鼠,6-7周,雌性,每组5只
免疫方案:抗原1μg/只,每只100μL(左右腿各半)。0,3周免疫二针,0-6 周每周经眼眶采血后进行血清中的抗体滴度检测。
酶联免疫吸附法(ELISA)检测抗体结合滴度,具体如下:
ELISA所用试剂可参考实施例4。
实验过程:
(1)包板与封闭:将S重组蛋白使用CB9.6稀释至1μg/mL按照100μL/孔加 入到96孔酶标板中,放置于37℃下孵育2h后用PBST缓冲液(即PBS中含0.05% Tween-20)洗板1次,向每孔中添加200μL含20%NBS的PBS,再放置于37℃下 孵育2h进行封闭。除去多余的液体并甩干备用。
(2)血清稀释:向首孔中添加100μL稀释300倍的后血清,3倍稀释10个梯 度,在37℃下孵育1h。
(3)加酶标抗体:用PBST缓冲液将板洗涤5次后,添加100μL稀释一定倍数 的羊抗鼠-辣根过氧化物酶酶标抗体GAM-HRP(实验室自制),在37℃下孵育0.5h。
(4)显色、终止、读值。
实验结果:如图7所示,不同锌、铝、利塞膦酸比例的FH002C佐剂联合新型冠状 病毒S重组蛋白均能产生特异性结合抗体。
实施例6:利塞膦酸锌铝佐剂联合新型冠状病毒S重组蛋白产生的特异性抗体结合滴度
将制备好的A1001(制备例3)和FH002C(制备例1)作为佐剂分别与新型冠状病 毒S重组蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射叙利亚金黄地鼠(本文 也称“叙利亚仓鼠”)以及食蟹猴,测定产生的特异性抗体滴度。具体方法如下:
实验动物:叙利亚金黄地鼠(购自上海斯莱克实验动物有限责任公司),6-7周,FH002C组22只/组,A1001组16只/组,雌雄各半。成年食蟹猴(购自广西雄森灵长 类实验动物养殖开发有限公司),2只/组,雌雄各半。
实验分组:(1)S重组蛋白+A1001;(2)S重组蛋白+FH002C
叙利亚金黄地鼠免疫方案:抗原10μg/只,佐剂与新型冠状病毒S重组蛋白通 过体积比为1∶1混合形成疫苗,而后肌肉注射叙利亚金黄地鼠,每只200μL。0,2, 6周免疫三针,0-7周每周经眼眶采血后进行血清中的抗体滴度检测。
食蟹猴免疫方案:抗原20μg/只,佐剂与新型冠状病毒S重组蛋白通过体积比 为1∶1混合形成疫苗,而后肌肉注射食蟹猴,每只500μL。0,2周免疫2针,0-6 周每周进行采血进行抗体结合滴度检测。
酶联免疫吸附法(ELISA)检测抗体结合滴度,具体如下:
ELISA所用试剂可参考实施例4。
实验过程:
(1)包板与封闭:将S重组蛋白使用CB9.6稀释至2μg/mL按照100μL/孔加 入到96孔酶标板中,放置于37℃下孵育2h后用PBST缓冲液(即PBS中含0.05% Tween-20)洗板1次,向每孔中添加200μL含20%NBS的PBS,再放置于37℃下 孵育2h进行封闭。除去多余的液体并甩干备用。
(2)血清稀释:向各孔中添加100μL稀释50或100倍的后血清,在37℃下 孵育1h。
(3)加酶标抗体:用PBST缓冲液将板洗涤5次后,添加100μL稀释一定倍数 的HRP偶联的山羊抗人IgG(H+L)(BEYOTIME,A0201)或山羊叙利亚金黄地鼠IgG H&L(Abcam,ab6892),在37℃下孵育0.5h。
(4)显色、终止、读值。
实验结果:如图8所示,叙利亚金黄地鼠免疫一针后2周,FH002C组的抗体滴度 高于A1001组,即为铝佐剂组15倍,具有起效快的特点。免疫两针后,其体液免疫增 强优势依然明显,第4周时,FH002C组的抗体滴度是铝佐剂组的8倍。免疫三针后, 第7周时,FH002C组的抗体滴度是对照组的11倍。
食蟹猴免疫一针后2周,FH002C组的抗体滴度高于A1001组,即为铝佐剂组6倍, 具有起效快的特点。免疫两针后,第4周时,FH002C组的抗体滴度与铝佐剂组相当(图 9)。
实施例7:利塞膦酸锌铝佐剂联合新型冠状病毒S重组蛋白后产生的中和抗体滴度
采用实施例6所述的实验流程,将A1001(制备例3)与FH002C(制备例1)佐剂 分别配伍新型冠状病毒S重组蛋白通过肌肉注射来免疫叙利亚金黄地鼠和食蟹猴,检 测血清中和抗体滴度。叙利亚金黄地鼠以及食蟹猴免疫程序同实施例6。
通过假病毒中和法(Pseudovirus neutralization)检测抗体中和滴度(H.L.Xiong et al.,Robust neutralization assay based on SARS-CoV-2 S-protein-bearing vesicular stomatitis virus(VSV)pseudovirus and ACE2-overexpresslngBHK21 cells.Emerg Microbes Infect,1-38(2020)),具体 如下:
通过重组质粒pCAG-nCoVSde118和VSVdG-EGFP-G病毒(Addgene,31842)将承载 了SARS-CoV-2 S蛋白(Wuhan-Hu-1株,基因库:QHD43416.1)的水疱性口炎病毒(VSV) 假病毒(rVSV-SARS-CoV-2)进行了包装。提前24h将hACE2表达的BHK21(BHK21-hACE2) 细胞铺到96孔板中,接着用含10%FBS(GIBCO,10099141)和青霉素-链霉素(GIBCO, 15140122)的高糖DMEM培养基(Sigma-Aldrich,D6429)将血清稀释50倍,然后进 行3倍梯度稀释。将稀释了的rVSV-SARS-CoV-2病毒(MOI=0.05)与稀释后的血清 混合,并在37℃下孵育1h。紧接着,将混合物转入铺了BHK21-hACE2细胞的板中, 随后在含5%C02,37℃的培养箱孵育12h。通过Opera Phenix或Operetta CLS高 含量分析系统(PerkinElmer)捕获荧光图像数据,再用Columbus系统(PerkinElmer) 分析每个孔的GFP阳性细胞的计数。每个板包含8个无血清的孔作为病毒对照。血清 中和滴度定义为与阳性孔相比,CFP阳性细胞数量减少了50%时对应的血清稀释倍数 (ID50)。
实验结果:如图10所示,叙利亚金黄地鼠免疫一针后2周,FH002C组的抗体滴 度高于A1001组,即为铝佐剂组1.8倍,具有起效快的特点。免疫两针后,其体液免 疫增强优势依然明显,第4周时,FH002C组的抗体滴度是铝佐剂组的2.6倍。免疫三 针后,第7周时,FH002C组的抗体滴度是对照组的6.5倍。
食蟹猴免疫一针后2周,FH002C组的抗体滴度高于A1001组,即为铝佐剂组2.6 倍,具有起效快的特点。免疫两针后,第4周时,FH002C组的抗体滴度为铝佐剂组的 3.5倍(图11)。
实施例8:利塞膦酸锌铝佐剂联合新型冠状病毒S重组蛋白免疫血清基于细胞的Spike阻断实验
采用实施例6所述免疫程序,将A1001(制备例3)与FH002C(制备例1)佐剂分 别配伍新型冠状病毒S重组蛋白通过肌肉注射来免疫叙利亚金黄地鼠和食蟹猴,用基 于细胞的Spike血清阻断实验(Y.Zhang et al.,Virus-free and live-cell visualizing SARS-CoV-2 cell entry for studies of neutralizing antibodies and compoundinhibitors.bioRxiv,(2020)),具体如下:
将表达hACE2-mRuby3 293T(293T-ACE2iRb3)的细胞以2×104个/孔提前24h铺 在用聚-D-赖氨酸预处理的96孔板上。用含10%FBS的DMEM培养基以2倍梯度稀释 的方式稀释叙利亚金黄地鼠及食蟹猴血清。将11μL芽孢杆菌与SARS-CoV-2 S(STG) 融合的探针与44μL稀释的血清混合,使得探针终浓度为2.5nM。将铺有 293T-ACE2iRb3细胞孔除去一半的培养基后,吸取50μL混合物到细胞中,并在37℃, 5%CO2的条件下孵育1h。随后,通过OperaPhenix高内涵分析系统以共聚焦模式捕 获细胞图像。
数据分析:采用Columbus System进行图像数据定量分析。首先,根据 293T-ACE2iRb3细胞都表达定位在细胞核中的融合H2B的iRFP670的原理,通过近红 外通道(Ex:640/Em:670)找到所有已经接种的细胞.又根据融合了mRuby3的hACE2 会位于膜上的原理,通过红色通道(Ex:561/Em:590)定义细胞边界。接着通过计算 细胞质区域(cMFI,外边界:20%,内边界:45%)中STG探针通道(Ex:488/Em:525) 的MFI,可得到其抑制比:[(cMFIpc-cMFItst)/(cMFIpc-cMFIb1k)]×100%.cMFItst 是指测试孔的cMFI值,cMFIpc和cMFIblk分别是仅探针(阳性对照)孔和仅细胞孔 的cFMI值。血清阻断水平用ID50进行表示。
实验结果:如图12所示,在叙利亚金黄地鼠FH002C组的血清阻断率均高于A1001组;如图13所示,在食蟹猴中,两个佐剂组的血清阻断率相当。
实施例9:利塞膦酸锌铝佐剂联合新型冠状病毒S重组蛋白对抗体亲合力的影响
采用实施例6所述的实验流程,将A1001(制备例3)与FH002C(制备例1)佐剂 分别配伍新型冠状病毒S重组蛋白通过肌肉注射来免疫小鼠与叙利亚金黄地鼠,检测 血清抗体亲合力。叙利亚金黄地鼠免疫程序同实施例6,但FH002C和A1001每组各16 只,雌雄各半。小鼠的免疫程序具体如下:
实验动物:Balb/C小鼠(购自上海斯莱克实验动物有限公司),6-8周,4或5 只/组,雌性
实验分组:(1)S重组蛋白+A1001;(2)S重组蛋白+FH002C
小鼠免疫方案:抗原1μg/只,佐剂与新型冠状病毒S重组蛋白过体积比为1∶1 混合形成疫苗,而后肌肉注射Balb/C小鼠,每只150μL。0,2,4周免疫三针,0-6 周每周经眼眶采血后进行血清中的抗体亲合力检测。
酶联免疫吸附法(ELISA)检测抗体亲合力,具体如下:
ELISA所用试剂可参考实施例4。
实验过程:
包板与封闭:将纯化的S重组蛋白使用CB9.6稀释至2μg/mL后进行包被,按 照100μL/孔加入到ELISA板中,放置于37℃下孵育2h后用PBST缓冲液(即PBS 中含0.05%Twenn-20)洗板1次,向每孔中添加200μL含20%NBS的PBS,再放置 于37℃下孵育2h进行封闭。除去多余的液体并甩干。
血清抗体亲合力检测:向各孔中添加100μL血清,每份样品进行双孔重复,在 37℃下孵育1h。用PBST缓冲液将板洗涤1次后,向双孔重复的其中一孔添加100μL PBS,另一孔添加100μL 4M尿素(用PBS配制),放于37℃20min后用PBST缓冲 液将板洗涤4次。接着加入稀释一定倍数的HRP偶联的山羊抗小鼠IgG(H+L) (Proteintech,SA00001-1)或者山羊抗叙利亚仓鼠IgG H&L(Abeam,ab6892),在 37℃下孵育0.5h。用洗涤缓冲液洗涤板5次。向每孔添加100μL显色底物混合液, 并使用PHOMO Microplate读取器读取在450nm处的吸光度。抗体亲合力可用抗体比 例表示,即尿素处理组的EC50与未处理组的EC50的比值。
实验结果:如图14和15所示,不管在小鼠模型还是叙利亚金黄地鼠模型上,FH002C组比A1001组能产生具有更高比例的高亲合力抗体。
实施例10:利塞膦酸锌铝佐剂联合新型冠状病毒S重组蛋白免疫小鼠产生特异性抗体亚型
将制备好的A1001(制备例3)与FH002C(制备例1)作为佐剂分别与新型冠状病 毒S重组蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射小鼠,免疫程序如实施 例9。
酶联免疫吸附法(ELISA)检测抗体亚型水平,具体如下:
ELISA所用试剂可参考实施例4。
实验过程:
包板与封闭:将纯化的S重组蛋白使用碳酸盐缓冲液稀释至2μg/mL后进行包 被,按照100μL/孔加入到ELISA板中,放置于37℃下孵育2h后用PBST缓冲液(即 PBS中含0.05%Tween-20)洗板1次,向每孔中添加200μL含20%NBS的PBS,再 放置于37℃下孵育2h进行封闭。除去多余的液体并甩干。
血清抗体亚型水平检测:向各孔中添加100μL血清,在37℃下孵育1h,在 37℃下孵育1h。用PBST缓冲液将板洗涤5次后,添加100μL稀释一定倍数的HRP 偶联的山羊抗鼠IgG1(AbD Serotec,STAR132P)或者山羊抗鼠IgG2a(AbD Serotec, STAR133P)或者山羊抗鼠IgG2b(AbD Serotec,STAR134P),在37℃下孵育0.5h。 用洗涤缓冲液洗涤板5次。向每孔添加100μL稀释3倍后的显色底物混合液,并使 用PHOMO Microplate读取器读取在450nm处的吸光度。每块板中包含5孔阴性血清 作为阴性对照。
实验结果:如图16所示,与铝佐剂组相比,FH002C佐剂组能激起更高水平的IgG2a和IgG2b亚型抗体,且IgG1与IgG2a和IgG2b的比例较铝佐剂组更低,表明起在Th1 免疫途径具有一定的刺激作用。
实施例11:利塞膦酸锌铝佐剂配伍新型冠状病毒S重组蛋白对T细胞应答的影响
将制备好的A1001(制备例3)与FH002C(制备例1)作为佐剂分别与新型冠状病 毒S重组蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射小鼠,测定产生的T细 胞应答。具体方法如下:
实验动物:C57BL/6,6-8周,8只/组,雌性。
实验分组:(1)空白组;(2)S重组蛋白+A1001;(3)S重组蛋白+FH002C
C57BL/6小鼠免疫方案:抗原10μg/只,佐剂与新型冠状病毒S重组蛋白通过体 积比为1∶1混合形成疫苗,而后肌肉注射,每只150μL。0,3周免疫两针,第4周 处死后分离脾脏与淋巴结进行T细胞免疫应答实验。
酶联免疫斑点法(Enzyme-linked immunospot assay,ELISPOT)检测T细胞应答
取小鼠脾脏和淋巴结,制备成单细胞悬液,按照每孔106个细胞(脾)或每孔4×105个细胞(淋巴结)铺到小鼠IFN-γ包被的ELISPOT板(DAKEWEI,2210005)中。然后, 用PBS或者具有11个氨基酸重叠的15个单元的SARS-CoV-2 S肽库刺激(Genscript, RP30020)培养20h。随后,根据试剂盒说明书进行检测。使用CTL-S5 (Cellular TechnologyLimited)进行图像捕获和点计数。将刺突肽库刺激的孔中减 去PBS刺激的孔来计算分泌IFN-γ的细胞的点数。
实验结果:如图17所示,FH002C和A1001组分泌IFN-γ的细胞数量在脾脏中分 别增加了28.9倍和5.8倍,在淋巴结中分别增加了14.0倍和2.3倍,与A1001相比, FH002C组可以诱导较高水平的T细胞应答。
实施例12:铝佐剂(A1001)、FH002C佐剂配伍水痘带状疱疹病毒gE蛋白(VZV gE)产生的特异性抗体结合滴度
将制备好的A1001(制备例3)、FH002C(制备例1)作为佐剂分别与水痘带状疱 疹病毒gE蛋白(VZV gE,SEQ ID NO:2)通过体积比为1∶1混合形成疫苗,而后肌肉 注射Balb/C小鼠,测定产生的特异性抗体滴度。其中,所述gE蛋白为利用大肠杆菌 表达系统(购自上海唯地生物技术有限公司,EC1060)表达所得。
具体方法如下:
实验动物:Balb/C小鼠,6-7周,每组5只,雌性。
实验分组:(1)VZV gE+A1001;(2)VZV gE+FH002C
Balb/C小鼠免疫方案:抗原5μg/只,佐剂与水痘带状疱疹病毒gE蛋白(VZV gE) 通过体积比为1:1混合形成疫苗,而后肌肉注射Balb/C小鼠,每只100μL。0,2, 4周免疫二针,0-4周每周经眼眶采血后进行血清中的抗体滴度检测。
酶联免疫吸附法(ELISA)检测抗体结合滴度,具体如下:
ELISA所用试剂可参考实施例4。
实验过程:
(1)包板与封闭:将VZV gE使用PB7.4+NaCl稀释至1μg/mL按照100μL/ 孔加入到96孔酶标板中,放置于4℃下孵育过夜后用PBST缓冲液(即PBS中含0.05% Tween-20)洗板1次,向每孔中添加200μL含20%NBS的PBS,再放置于37℃下 孵育2h进行封闭。除去多余的液体并甩干备用。
(2)血清稀释:向各孔中添加100μL稀释50或100倍的后血清,在25℃下 孵育1h。
(3)加酶标抗体:用PBST缓冲液将板洗涤5次后,添加100μL稀释一定倍数 的酶标抗体(GAM-HRP)(购自Bio-Rad Laboratories Inc.,货号:1706516),25℃ 孵育反应1h。
(4)显色、终止、读值。
实验结果:如图18所示,免疫两针后FH002C佐剂组的结合滴度明显高于A1001 组,大约10倍左右。
实施例13:弗式佐剂、FH002C佐剂配伍流感病毒HA蛋白产生的特异性抗体结合 滴度
将商品化的弗氏佐剂(购自SIGMA-ALDRICH,货号:F5881)、FH002C佐剂(制备 例1)分别与经去糖基化酶处理或未经去糖基化酶处理的流感病毒HA蛋白(SEQ ID NO: 3)通过体积比为1∶1混合形成疫苗,而后皮下注射Balb/C小鼠,测定产生的特异性 抗体滴度。其中,所述流感病毒HA蛋白为利用杆状病毒表达系统(购自美国Invitrogen, 10359016)表达所得。所述去糖基化酶购自NEB,货号P0705S;所述去糖基化酶处理 过程参照所述去糖基化酶的说明书进行。
具体方法如下:
实验动物:Balb/C小鼠(购自上海斯莱克实验动物有限责任公司),6-7周,FH002C组10只/组,弗氏佐剂组10只/组。
实验分组:(1)HA+弗氏佐剂;(2)HA+FH002C
免疫方案:(1)抗原30μg/只,弗氏佐剂与流感病毒HA蛋白通过体积比为1∶1 混合形成疫苗,而后皮下注射Balb/C小鼠,每只300μL;(2)抗原30μg/只,FH002C 与流感病毒HA蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射Balb/C小鼠,每 只200μL。免疫后14天经眼眶采血后进行血清中的抗体滴度检测。
酶联免疫吸附法(ELISA)检测抗体结合滴度,具体如下:
ELISA所用试剂可参考实施例4。
(1)包板与封闭:将重组HA蛋白或流感超离病毒使用CB9.6稀释至2μg/mL 或者按照100μL/孔加入到96孔酶标板中,放置于37℃下孵育2h后用PBST缓冲 液(即PBS中含0.05%Tween-20)洗板1次,向每孔中添加200μL商品化封闭液,再 放置于37℃下孵育2h进行封闭。除去多余的液体并甩干备用。
(2)血清稀释:向各孔中添加100μL稀释不同倍数的血清,在37℃下孵育1 h。
(3)加酶标抗体:用PBST缓冲液将板洗涤5次后,添加100μL稀释5000倍 的酶标羊抗鼠抗体GAM-HRP(实验室自制),在37℃下孵育0.5h。
(4)显色、终止、读值。
实验结果:如图19所示,Balb/C小鼠免疫一针后2周,针对经去糖基化酶处理 和未经去糖基化酶处理的流感病毒HA蛋白,FH002C佐剂组的抗体滴度均高于弗式佐 剂组,具有起效快的特点。
实施例14:铝佐剂(A1001)、FH002C佐剂配伍轮状病毒VP4蛋白产生的中和抗 体结合滴度
将制备好的A1001(制备例3)与FH002C(制备例1)作为佐剂分别与轮状病毒VP4 蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射Balb/C小鼠和豚鼠,测定产生的 中和抗体滴度。其中,所述VP4蛋白由大肠杆菌表达系统(购自上海唯地生物技术有 限公司,EC1060)表达。
具体方法如下:
实验动物:Balb/C小鼠,购自上海斯莱克实验动物有限责任公司,6-8周,豚鼠,450-500g,购自上海松联实验动物场。
小鼠组:FH002C组5只/组,A1001组5只/组,均为雌性。
豚鼠组:FH002C组5只/组,A1001组5只/组,均为雌性。
实验分组:(1)VP4+A1001;(2)VP4+FH002C
免疫方案:小鼠免疫抗原10μg/只,豚鼠免疫抗原10μg/只,佐剂与轮状病毒 VP4蛋白通过体积比为1∶1混合形成疫苗,而后肌肉注射小鼠,豚鼠体内,小鼠豚鼠 均每只200μL,第一针免疫前以及第三针免疫后2周采血,分离血清检测中和抗体 滴度。
酶联免疫斑点实验(ELISPOT)检测中和抗体滴度,具体如下:
(1)MA104细胞铺96孔细胞板:将细胞用胰酶消化液消化后,然后用含10%FBS的细胞培养基将细胞吹悬起来,然后利用细胞计数板计数之后,添加培养基稀释至25000 个/mL,然后均匀的添加到96孔板中,100μL/孔,37℃培养20h,CO2浓度为5%。
(2)病毒酶切处理:往1mL轮状病毒溶液中加入4μL的2.5μg/μL的胰酶,混 匀后置于,处理结束后用无血清的含1μg/mL胰酶的DMEM培养基稀释病毒至一定滴 度。
(3)血清补体灭活处理:取10μL血清样本于1.5mL的EP管中,然后56℃热处 理30min。处理结束后用含1μg/ml胰酶的DMEM稀释血清样品,双孔重复检测。
(4)血清与病毒反应:将(2)中的病毒和(3)中的血清各取100μL混合,37℃ 中和反应1h。
(5)更换细胞培养基:将(1)中的细胞上清移去,用无血清的含1μg/mL胰酶的 DMEM培养基漂洗(1)中的MA104细胞5min,重复漂洗三次。
(6)感染:最后一次漂洗结束后,移去漂洗的培养基,并将(4)中的中和反应混合液加入细胞中,在37℃培养14h后,CO2浓度为5%。
(7)细胞固定:将(6)中的细胞上清甩干,注意轻缓,避免细胞受损,然后用含0.1%戊二醛的PBS溶液固定细胞,100μL/孔,室温固定1h,注意在避光条件下固 定,避免戊二醛见光分解影响固定效果。
(8)细胞通透:移去(7)中戊二醛固定液,并加入100μL含0.3%Triton X-100 的PBS溶液,室温通透处理30min。
(9)氧化:移去(8)中的TritonX-100通透液,然后加入100μL含3%的H2O2的 PBS溶液,室温处理15min。
(10)洗涤:移去氧化液,并用PBST洗液漂洗细胞5次,每次漂洗5min。
(11)酶标抗体反应:将漂洗液甩干,然后将事先配好的酶标抗体反应液(酶稀释液, ED-13)稀释标记HRP的VP6抗体(实验室自制,该单克隆抗体为识别VP6的抗体,采 用杂交瘤技术制备,方法参考Li,et al.Emerging Microbes Infection.2020,1: 5000稀释)加入到细胞上,37℃反应1h。
(12)洗涤:移去酶标抗体反应液,并用PBST洗液漂洗细胞5次,每次漂洗5min。
(13)显色:将漂洗液甩干,然后现配的TMB显色液,100μL/孔,室温反应15min, 注意避光,避免显色液见光反应,影响实验结果。
(14)读板:甩干显色反应液,利用ELISPOT读板仪对上述96孔板进行读板和计数。
实验结果:如图20和21所示,小鼠和豚鼠免疫三针后均可产生中和抗体,且FH002C组的中和抗体滴度高于A1001组。其中,在小鼠中,FH002C佐剂组血清中和滴度约为 A1001佐剂组的16倍(图20);而在豚鼠中,FH002C佐剂组血清中和滴度约为A1001 组的4倍(图21)。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据 已经公布的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部分为由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 厦门大学;厦门万泰沧海生物技术有限公司
<120> 含有利塞膦酸锌铝的佐剂及其应用
<130> IDC210403
<150> CN202011278492.2
<151> 2020-11-16
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 1273
<212> PRT
<213> Artificial Sequence
<220>
<223> 野生型S蛋白氨基酸序列
<400> 1
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 2
<211> 623
<212> PRT
<213> Artificial Sequence
<220>
<223> gE蛋白氨基酸序列
<400> 2
Met Gly Thr Val Asn Lys Pro Val Val Gly Val Leu Met Gly Phe Gly
1 5 10 15
Ile Ile Thr Gly Thr Leu Arg Ile Thr Asn Pro Val Arg Ala Ser Val
20 25 30
Leu Arg Tyr Asp Asp Phe His Ile Asp Glu Asp Lys Leu Asp Thr Asn
35 40 45
Ser Val Tyr Glu Pro Tyr Tyr His Ser Asp His Ala Glu Ser Ser Trp
50 55 60
Val Asn Arg Gly Glu Ser Ser Arg Lys Ala Tyr Asp His Asn Ser Pro
65 70 75 80
Tyr Ile Trp Pro Arg Asn Asp Tyr Asp Gly Phe Leu Glu Asn Ala His
85 90 95
Glu His His Gly Val Tyr Asn Gln Gly Arg Gly Ile Asp Ser Gly Glu
100 105 110
Arg Leu Met Gln Pro Thr Gln Met Ser Ala Gln Glu Asp Leu Gly Asp
115 120 125
Asp Thr Gly Ile His Val Ile Pro Thr Leu Asn Gly Asp Asp Arg His
130 135 140
Lys Ile Val Asn Val Asp Gln Arg Gln Tyr Gly Asp Val Phe Lys Gly
145 150 155 160
Asp Leu Asn Pro Lys Pro Gln Gly Gln Arg Leu Ile Glu Val Ser Val
165 170 175
Glu Glu Asn His Pro Phe Thr Leu Arg Ala Pro Ile Gln Arg Ile Tyr
180 185 190
Gly Val Arg Tyr Thr Glu Thr Trp Ser Phe Leu Pro Ser Leu Thr Cys
195 200 205
Thr Gly Asp Ala Ala Pro Ala Ile Gln His Ile Cys Leu Lys His Thr
210 215 220
Thr Cys Phe Gln Asp Val Val Val Asp Val Asp Cys Ala Glu Asn Thr
225 230 235 240
Lys Glu Asp Gln Leu Ala Glu Ile Ser Tyr Arg Phe Gln Gly Lys Lys
245 250 255
Glu Ala Asp Gln Pro Trp Ile Val Val Asn Thr Ser Thr Leu Phe Asp
260 265 270
Glu Leu Glu Leu Asp Pro Pro Glu Ile Glu Pro Gly Val Leu Lys Val
275 280 285
Leu Arg Thr Glu Lys Gln Tyr Leu Gly Val Tyr Ile Trp Asn Met Arg
290 295 300
Gly Ser Asp Gly Thr Ser Thr Tyr Ala Thr Phe Leu Val Thr Trp Lys
305 310 315 320
Gly Asp Glu Lys Thr Arg Asn Pro Thr Pro Ala Val Thr Pro Gln Pro
325 330 335
Arg Gly Ala Glu Phe His Met Trp Asn Tyr His Ser His Val Phe Ser
340 345 350
Val Gly Asp Thr Phe Ser Leu Ala Met His Leu Gln Tyr Lys Ile His
355 360 365
Glu Ala Pro Phe Asp Leu Leu Leu Glu Trp Leu Tyr Val Pro Ile Asp
370 375 380
Pro Thr Cys Gln Pro Met Arg Leu Tyr Ser Thr Cys Leu Tyr His Pro
385 390 395 400
Asn Ala Pro Gln Cys Leu Ser His Met Asn Ser Gly Cys Thr Phe Thr
405 410 415
Ser Pro His Leu Ala Gln Arg Val Ala Ser Thr Val Tyr Gln Asn Cys
420 425 430
Glu His Ala Asp Asn Tyr Thr Ala Tyr Cys Leu Gly Ile Ser His Met
435 440 445
Glu Pro Ser Phe Gly Leu Ile Leu His Asp Gly Gly Thr Thr Leu Lys
450 455 460
Phe Val Asp Thr Pro Glu Ser Leu Ser Gly Leu Tyr Val Phe Val Val
465 470 475 480
Tyr Phe Asn Gly His Val Glu Ala Val Ala Tyr Thr Val Val Ser Thr
485 490 495
Val Asp His Phe Val Asn Ala Ile Glu Glu Arg Gly Phe Pro Pro Thr
500 505 510
Ala Gly Gln Pro Pro Ala Thr Thr Lys Pro Lys Glu Ile Thr Pro Val
515 520 525
Asn Pro Gly Thr Ser Pro Leu Leu Arg Tyr Ala Ala Trp Thr Gly Gly
530 535 540
Leu Ala Ala Val Val Leu Leu Cys Leu Val Ile Phe Leu Ile Cys Thr
545 550 555 560
Ala Lys Arg Met Arg Val Lys Ala Tyr Arg Val Asp Lys Ser Pro Tyr
565 570 575
Asn Gln Ser Met Tyr Tyr Ala Gly Leu Pro Val Asp Asp Phe Glu Asp
580 585 590
Ser Glu Ser Thr Asp Thr Glu Glu Glu Phe Gly Asn Ala Ile Gly Gly
595 600 605
Ser His Gly Gly Ser Ser Tyr Thr Val Tyr Ile Asp Lys Thr Arg
610 615 620
<210> 3
<211> 566
<212> PRT
<213> Artificial Sequence
<220>
<223> HA蛋白氨基酸序列
<400> 3
Met Lys Thr Ile Ile Ala Leu Ser His Ile Leu Cys Leu Val Phe Ala
1 5 10 15
Gln Lys Leu Pro Gly Asn Asp Asn Ser Thr Ala Thr Leu Cys Leu Gly
20 25 30
His His Ala Val Pro Asn Gly Thr Ile Val Lys Thr Ile Thr Asn Asp
35 40 45
Gln Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Asn Ser Ser Ile
50 55 60
Gly Glu Ile Cys Asp Ser Pro His Gln Ile Leu Asp Gly Glu Asn Cys
65 70 75 80
Thr Leu Ile Asp Ala Leu Leu Gly Asp Pro Gln Cys Asp Gly Phe Gln
85 90 95
Asn Lys Lys Trp Asp Leu Phe Val Glu Arg Ser Lys Ala Tyr Ser Asn
100 105 110
Cys Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu Arg Ser Leu Val
115 120 125
Ala Ser Ser Gly Thr Leu Glu Phe Asn Asn Glu Ser Phe Asn Trp Thr
130 135 140
Gly Val Thr Gln Asn Gly Thr Ser Ser Ala Cys Ile Arg Arg Ser Asn
145 150 155 160
Asn Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr His Leu Asn Phe Lys
165 170 175
Tyr Pro Ala Leu Asn Val Thr Met Pro Asn Asn Glu Gln Phe Asp Lys
180 185 190
Leu Tyr Ile Trp Gly Val His His Pro Gly Thr Asp Lys Asp Gln Ile
195 200 205
Phe Leu Tyr Ala Gln Ser Ser Gly Arg Ile Thr Val Ser Thr Lys Arg
210 215 220
Ser Gln Gln Ala Val Ile Pro Asn Ile Gly Ser Arg Pro Arg Ile Arg
225 230 235 240
Asn Ile Pro Ser Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro Gly
245 250 255
Asp Ile Leu Leu Ile Asn Ser Thr Gly Asn Leu Ile Ala Pro Arg Gly
260 265 270
Tyr Phe Lys Ile Arg Ser Gly Lys Ser Ser Ile Met Arg Ser Asp Ala
275 280 285
Pro Ile Gly Lys Cys Asn Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile
290 295 300
Pro Asn Asp Lys Pro Phe Gln Asn Val Asn Arg Ile Thr Tyr Gly Ala
305 310 315 320
Cys Pro Arg Tyr Val Lys Gln Ser Thr Leu Lys Leu Ala Thr Gly Met
325 330 335
Arg Asn Val Pro Glu Lys Gln Thr Arg Gly Ile Phe Gly Ala Ile Ala
340 345 350
Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly
355 360 365
Phe Arg His Gln Asn Ser Glu Gly Arg Gly Gln Ala Ala Asp Leu Lys
370 375 380
Ser Thr Gln Ala Ala Ile Asp Gln Ile Asn Gly Lys Leu Asn Arg Leu
385 390 395 400
Ile Gly Lys Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser
405 410 415
Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp Thr
420 425 430
Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu
435 440 445
Asn Gln His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe
450 455 460
Glu Lys Thr Lys Lys Gln Leu Arg Glu Asn Ala Glu Asp Met Gly Asn
465 470 475 480
Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Gly Ser
485 490 495
Ile Arg Asn Gly Thr Tyr Asp His Asp Val Tyr Arg Asp Glu Ala Leu
500 505 510
Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys
515 520 525
Asp Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Leu Cys
530 535 540
Val Ala Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn Ile
545 550 555 560
Arg Cys Asn Ile Cys Ile
565
<210> 4
<211> 1249
<212> PRT
<213> Artificial Sequence
<220>
<223> S重组蛋白氨基酸序列
<400> 4
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Gly Ser Ala Ser Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Gly Ser Gly Tyr Ile Pro Glu Ala Pro Arg
1205 1210 1215
Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu
1220 1225 1230
Ser Thr Phe Leu Gly Ser Leu Glu His His His His His His His
1235 1240 1245
His
Claims (9)
1.一种包含利塞膦酸锌铝的佐剂,其中,锌∶利塞膦酸摩尔浓度比在1∶1至16∶1的范围内(例如,2∶1至16∶1的范围内);并且,锌∶铝摩尔浓度比在1∶1至50∶1的范围内(例如5∶1至50∶1的范围内);
优选地,所述佐剂以颗粒形式存在;优选地,所述颗粒的粒径大小为0.01-100μm,例如0.01-60μm,0.01-50μm,0.1-60μm,0.1-30μm,0.4-30μm,0.4-20μm;
优选地,所述佐剂锌∶利塞膦酸摩尔浓度比在1∶1至2∶1,2∶1至4∶1,4∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至14∶1,或者14∶1至16∶1的范围内;优选地,所述佐剂锌∶利塞膦酸摩尔浓度比为4∶1或4.5∶1;
优选地,所述佐剂锌∶铝摩尔浓度比在1∶1至2∶1,2∶1至3∶1,3∶1至4∶1,4∶1至5∶1,5∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至15∶1,15∶1至20∶1,20∶1至30∶1,30∶1至40∶1,或者40∶1至50∶1的范围内;优选地,所述佐剂锌∶铝摩尔浓度比为10∶1;
优选地,所述佐剂锌∶利塞膦酸摩尔浓度比在2∶1至8∶1的范围内,例如2∶1至4∶1,4∶1至6∶1,或6∶1至8∶1,并且,锌∶铝摩尔浓度比在2∶1至50∶1的范围内(例如5∶1至20∶1的范围内),例如2∶1至3∶1,3∶1至4∶1,4∶1至5∶1,5∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至15∶1,或15∶1至20∶1;
优选地,所述佐剂锌∶利塞膦酸摩尔浓度比为4∶1,并且,锌∶铝摩尔浓度比为10∶1;
优选地,所述佐剂锌∶利塞膦酸摩尔浓度比为4.5∶1,并且,锌∶铝摩尔浓度比为10∶1;
优选地,所述佐剂pH为5.0-8.0,例如5.0-7.0,5.0-5.5,5.5-6.0,6.0-6.5,6.5-7.0,7.0-7.5,或7.5-8.0;
优选地,所述佐剂零电荷点为3.0-8.0,例如4.0-8.0,3.0-4.0,4.0-5.0,5.0-6.0,6.0-7.0,或7.0-8.0;
优选地,所述佐剂对免疫原(例如蛋白)的吸附率为至少60%,至少70%,至少75%,至少80%,至少85%,至少90%,或至少95%。
2.制备权利要求1所述的佐剂的方法,其包括如下步骤:
1)提供含有锌离子、铝离子的可溶性盐溶液;
2)将步骤(1)中的可溶性盐溶液与利塞膦酸碱溶液混合,从而获得所述佐剂;
优选地,所述方法还包括,将步骤(2)获得的佐剂进行灭菌的步骤;优选地,通过过滤灭菌或高温高压灭菌来对所述佐剂进行灭菌,例如通过在121℃下灭菌至少15分钟(例如至少30分钟,例如30-60分钟),对所述佐剂进行灭菌;
优选地,在所述可溶性盐溶液中,锌∶铝的摩尔浓度比在1∶1至50∶1的范围内(例如5∶1至50∶1的范围内);优选地,在所述可溶性盐溶液中,锌∶铝摩尔浓度比在1∶1至2∶1,2∶1至3∶1,3∶1至4∶1,4∶1至5∶1,5∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至15∶1,15∶1至20∶1,20∶1至30∶1,30∶1至40∶1,或者40∶1至50∶1的范围内;
优选地,在步骤(2)中,以在1∶1至16∶1的范围内(例如2∶1至16∶1的范围内)的锌∶利塞膦酸摩尔浓度比,将所述可溶性盐溶液与利塞膦酸碱溶液混合;优选地,所述锌∶利塞膦酸摩尔浓度比在1∶1至2∶1,2∶1至4∶1,4∶1至6∶1,6∶1至8∶1,8∶1至10∶1,10∶1至12∶1,12∶1至14∶1或者14∶1至16∶1的范围内;
优选地,在步骤(2)中,以使锌离子、铝离子和利塞膦酸共同沉淀的方式,将所述可溶性盐溶液与利塞膦酸碱溶液混合;
所述方法为以共同沉淀的方式使锌离子、铝离子和利塞膦酸产生沉淀,从而获得利塞膦酸锌铝颗粒;
优选地,在步骤(2)中,将利塞膦酸碱溶液逐滴加入所述可溶性盐溶液,使锌离子、铝离子和利塞膦酸共同沉淀;
优选地,所述利塞膦酸碱溶液选自利塞膦酸氢氧化钠,利塞膦酸磷酸盐溶液(例如利塞膦酸磷酸氢二钠溶液,利塞膦酸磷酸氢钠溶液),或其任何组合;
优选地,步骤(1)所述可溶性盐溶液选自例如硫酸盐溶液、氯酸盐溶液、醋酸盐溶液、或其任何组合,优选氯酸盐溶液或醋酸盐溶液。
3.一种免疫原性组合物,其包含免疫原和权利要求1所述的佐剂;
优选地,所述免疫原选自蛋白,核酸,多糖,或其免疫原性部分;
优选地,所述免疫原来源于病毒、细菌、真菌等病原体;
优选地,所述免疫原是蛋白或其免疫原性片段;优选地,所述免疫原是来源于病毒、细菌、真菌等病原体的蛋白或其免疫原性片段;优选地,所述病毒选自,呼吸道病毒(例如,流感病毒、副流感病毒、鼻病毒、冠状病毒、呼吸道合胞病毒),肠道病毒(例如BV71病毒,轮状病毒),水痘带状疱疹病毒(VZV);优选地,所述免疫原是冠状病毒的蛋白或其免疫原性片段,例如冠状病毒刺突蛋白(S蛋白)或其免疫原性片段;
优选地,所述冠状病毒选自正冠状病毒亚科α属病毒(例如229E和NL63),正冠状病毒亚科β属病毒(例如OC43和HKU1)、严重急性呼吸综合征相关冠状病毒(SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV),和新型冠状病毒(SARS-CoV-2);优选地,所述冠状病毒选自严重急性呼吸综合征相关冠状病毒(SARS-CoV)、中东呼吸综合征相关冠状病毒(MERS-CoV)和新型冠状病毒(SARS-CoV-2),优选为新型冠状病毒(SARS-CoV-2);
优选地,所述免疫原为新型冠状病毒刺突蛋白(S蛋白)或其免疫原性片段,水痘带状疱疹病毒gE蛋白或其免疫原性片段,流感病毒HA蛋白或其免疫原性片段,或者,轮状病毒VP4蛋白或其免疫原性片段;
优选地,所述免疫原性组合物还包含药学上可接受的辅料,例如赋形剂、防腐剂、抗菌剂、缓冲剂和/或额外的免疫佐剂;优选地,所述额外的免疫佐剂为选自铝佐剂(例如氢氧化铝)、弗氏佐剂(例如完全弗氏佐剂和不完全弗氏佐剂)、短小棒状杆菌、脂多糖、细胞因子,或其任何组合;
优选地,所述免疫原性组合物还包含第二免疫原;优选地,所述第二免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性部分;
优选地,所述免疫原性组合物为疫苗。
4.权利要求1所述的佐剂的用途,其用于制备免疫原性组合物,用做递送免疫原的载体,用做免疫原的免疫增强剂,用于增强免疫原的免疫原性,用于增强受试者对免疫原的免疫应答水平,或用于制备用于增强受试者对免疫原的免疫应答水平的制剂;
优选地,所述免疫原如权利要求3所定义;
优选地,所述免疫应答为细胞免疫应答和/或体液免疫应答;优选地,所述细胞免疫应答为T细胞免疫应答;优选地,所述T细胞免疫应答为免疫应答Th1和/或Th2免疫应答。
5.一种制备免疫原性组合物的方法,其包括:将权利要求1所述的佐剂与免疫原进行混合的步骤;
优选地,所述免疫原如权利要求3所定义;
优选地,所述方法还包括,添加药学上可接受的辅料的步骤;
优选地,所述辅料是例如赋形剂、防腐剂、抗菌剂、缓冲剂和/或额外的免疫佐剂;优选地,所述额外的免疫佐剂为选自铝佐剂(例如氢氧化铝)、弗氏佐剂(例如完全弗氏佐剂和不完全弗氏佐剂)、短小棒状杆菌、脂多糖、细胞因子,或其任何组合;
优选地,所述方法还包含添加第二免疫原的步骤;优选地,所述第二免疫原包括但不限于蛋白,核酸,多糖,或其免疫原性部分等;
优选地,所述免疫原性组合物为疫苗。
6.权利要求3所述的免疫原性组合物在制备用于预防和/或治疗受试者的疾病的药物中的用途,所述疾病是能够被所述免疫原诱发的免疫应答所预防或治疗的疾病;
优选地,所述免疫原来源于冠状病毒(例如新型冠状病毒),并且,所述疾病为冠状病毒(例如新型冠状病毒)感染或与冠状病毒(例如新型冠状病毒)感染相关的疾病;
优选地,所述免疫原为冠状病毒(例如新型冠状病毒)的蛋白(例如刺突蛋白)或其免疫原性片段,并且,所述疾病为冠状病毒(例如新型冠状病毒)感染或与冠状病毒(例如新型冠状病毒)感染相关的疾病;
优选地,所述免疫原为新型冠状病毒的结构蛋白(例如刺突蛋白(S蛋白))或其免疫原性片段;并且,所述疾病为新型冠状病毒感染或与新型冠状病毒感染相关的疾病(例如,新型冠状病毒性肺炎(COVID-19));
优选地,所述免疫原来源于水痘带状疱疹病毒,并且,所述疾病为水痘带状疱疹病毒感染或与水痘带状疱疹病毒感染相关的疾病;
优选地,所述免疫原为水痘带状疱疹病毒的蛋白(例如gE蛋白)或其免疫原性片段,并且,所述疾病为水痘带状疱疹病毒感染或与水痘带状疱疹病毒感染相关的疾病;
优选地,所述免疫原来源于流感病毒,并且,所述疾病为流感病毒感染或与流感病毒感染相关的疾病;
优选地,所述免疫原为流感病毒的蛋白(例如HA蛋白)或其免疫原性片段,并且,所述疾病为流感病毒感染或与流感病毒感染相关的疾病;
优选地,所述免疫原来源于轮状病毒,并且,所述疾病为轮状病毒感染或与轮状病毒感染相关的疾病;
优选地,所述免疫原为轮状病毒的蛋白(例如VP4蛋白)或其免疫原性片段,并且,所述疾病为轮状病毒感染或与轮状病毒感染相关的疾病;
优选地,所述受试者是动物,例如禽类动物或哺乳动物;
优选地,所述受试者是啮齿类动物、猪科动物、猫科动物、犬科动物、马科动物、灵长类动物或禽类动物;
优选地,所述受试者是小鼠、水貂、豚鼠、叙利亚金黄地鼠或食蟹猴;
优选地,所述受试者是人。
7.一种提高免疫原的免疫原性的方法,其包括将免疫原与权利要求1所述的佐剂混合的步骤;优选地,所述免疫原如权利要求3所定义。
8.一种刺激或增强受试者对免疫原的免疫应答的方法,其包括给予受试者有效量的含有所述免疫原和权利要求1所述的佐剂的免疫原性组合物的步骤;
优选地,所述免疫原如权利要求3所定义;
优选地,所述受试者是动物,例如禽类动物或哺乳动物;优选地,所述受试者是啮齿类动物、猪科动物、猫科动物、犬科动物、马科动物、灵长类动物或禽类动物;优选地,所述受试者是小鼠、水貂、豚鼠、叙利亚金黄地鼠或食蟹猴;优选地,所述受试者是人;
优选地,所述免疫应答为细胞免疫应答和/或体液免疫应答;优选地,所述细胞免疫应答为T细胞免疫应答;优选地,所述T细胞免疫应答为免疫应答Th1和/或Th2免疫应答;
优选地,所述免疫原性组合物是通过选自下列的途径进行给药的:肌内注射、皮下注射、皮内、鼻内、口服、透皮或静脉注射;
优选地,所述免疫原性组合物通过肌内注射给药。
9.一种预防或治疗疾病的方法,其包括给予受试者有效量的权利要求3所述的免疫原性组合物的步骤,所述疾病是能够被所述免疫原诱发的免疫应答所预防或治疗的疾病;
优选地,所述疾病为冠状病毒(例如新型冠状病毒)感染或与冠状病毒(例如新型冠状病毒)感染相关的疾病,并且,所述免疫原来源于冠状病毒(例如新型冠状病毒);例如,所述免疫原为冠状病毒(例如新型冠状病毒)的蛋白(例如刺突蛋白)或其免疫原性片段;
优选地,所述疾病为新型冠状病毒感染或与新型冠状病毒感染相关的疾病,例如新型冠状病毒性肺炎(COVID-19),并且,所述免疫原来源于新型冠状病毒;例如,所述免疫原为新型冠状病毒的结构蛋白(例如刺突蛋白(S蛋白))或其免疫原性片段;
优选地,所述疾病为水痘带状疱疹病毒感染或与水痘带状疱疹病毒感染相关的疾病,并且,所述免疫原来源于水痘带状疱疹病毒;例如,所述免疫原为水痘带状疱疹病毒的蛋白(例如gE蛋白)或其免疫原性片段;
优选地,所述疾病为流感病毒感染或与流感病毒感染相关的疾病,并且,所述免疫原来源于流感病毒;例如,所述免疫原为流感病毒的蛋白(例如HA蛋白)或其免疫原性片段;
优选地,所述疾病为轮状病毒感染或与轮状病毒感染相关的疾病,并且,所述免疫原来源于轮状病毒;例如,所述免疫原为轮状病毒的蛋白(例如VP4蛋白)或其免疫原性片段;
优选地,所述受试者是动物,例如禽类动物或哺乳动物;优选地,所述受试者是啮齿类动物、猪科动物、猫科动物、犬科动物、马科动物、灵长类动物或禽类动物;优选地,所述受试者是小鼠、水貂、豚鼠、叙利亚金黄地鼠或食蟹猴;优选地,所述受试者是人。
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