WO2017084518A1 - 一种疫苗佐剂以及包含该佐剂的疫苗 - Google Patents

一种疫苗佐剂以及包含该佐剂的疫苗 Download PDF

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WO2017084518A1
WO2017084518A1 PCT/CN2016/105100 CN2016105100W WO2017084518A1 WO 2017084518 A1 WO2017084518 A1 WO 2017084518A1 CN 2016105100 W CN2016105100 W CN 2016105100W WO 2017084518 A1 WO2017084518 A1 WO 2017084518A1
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vaccine
vaccine adjuvant
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靳广毅
王竹林
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    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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  • the invention relates to the technical field of medicinal chemistry, in particular to a vaccine adjuvant and a vaccine comprising the same.
  • influenza viruses spread rapidly and are characterized by high morbidity and mortality. According to the difference of nuclear protein (NP) and matrix protein (M1), it can be divided into type A, type B and type C. There have been many global influenza pandemics in the last century. The most serious one was the Spanish flu that occurred between 1918 and 1919. The flu strain was the most common type A H1N1, with at least 20 million deaths. Currently, the most effective and economical means of preventing influenza viruses is vaccination against influenza. However, the effectiveness of vaccines is influenced by many factors and varies from year to year. The influenza vaccine is based primarily on a conserved region of the surface glycoprotein antigen hemagglutinin (HA).
  • HA hemagglutinin
  • the antigenic drift of HA is highly plastic, so new antigens need to be developed, and adjuvants are used to enhance the immunogenicity of the vaccine itself.
  • ordinary flu vaccine can stimulate effective antibodies against viruses, long-term repeated infections often cause severe and irreversible respiratory damage and induce breathing in young children with impaired immune systems, immunocompromised individuals, and the elderly. The system is depleted and the consequences are serious. Therefore, the development of an immunoadjuvant is of great significance.
  • the technical problem to be solved by the present invention is to provide a vaccine adjuvant in order to overcome the shortage of the vaccine adjuvant in the prior art.
  • the invention provides a vaccine adjuvant, wherein the vaccine adjuvant is a small molecule compound (named SZU-101) having the structure represented by formula (I);
  • a vaccine adjuvant comprising a compound of formula (I).
  • the vaccine adjuvant is an influenza vaccine adjuvant.
  • the vaccine adjuvant is an H1N1 influenza vaccine adjuvant.
  • the dosage form of the vaccine adjuvant is a physiologically acceptable liquid preparation, emulsion preparation or lyophilized preparation.
  • the vaccine adjuvant is an influenza vaccine adjuvant.
  • the vaccine adjuvant is an H1N1 influenza vaccine adjuvant.
  • the present invention also provides a vaccine comprising a vaccine adjuvant having the structure of formula (I).
  • the vaccine is obtained by coupling a vaccine adjuvant having the structure of the formula (I) and an antigen.
  • the vaccine is conjugated from a vaccine adjuvant having the structure of the formula (I) and an influenza vaccine.
  • the vaccine is conjugated from a vaccine adjuvant having the structure of formula (I) and an H1N1 influenza vaccine.
  • the present invention provides a novel vaccine adjuvant which can effectively enhance the immune effect of an influenza virus inactivated vaccine and is non-toxic to mice; therefore, SZU-101 can be eliminated as an influenza virus.
  • An effective adjuvant for live vaccines The results of the examples show that the SZU-101 conjugated influenza vaccine (Flu-T7) can significantly enhance the serum antibody titer, and is higher than the vaccine group alone, and promotes the mouse-specific Th1-type immune response, and the spleen index of each group is different.
  • Statistical significance P>0.05, indicating that SZU-101 has good safety and efficacy as a vaccine adjuvant.
  • Figure 1 is a graph showing the results of Flu-T7-activated T cell-induced cytokine experiments.
  • Figure 1A shows the structural formula of SZU-101 (T7);
  • Figure 1B shows the level of IL-12 cytokine produced by Flu-T7 compared to the Flu group alone;
  • Figure 1C shows the FN produced by Flu-T7 compared to the Flu group alone.
  • Figure 1D is the TNF- ⁇ cytokine level map generated by Flu-T7 compared to the Flu group alone;
  • Figure 1E is the IL-6 cytokine level map generated by Flu-T7 compared to the Flu group alone. . (P ⁇ 0.05)
  • FIG. 2 is a graph showing the results of serum antibody reaction experiments in immunized mice.
  • 2A is blood sampling in the tail vein on days 7, 21, and 35, respectively;
  • FIG. 2B shows that the antibody titer of Flu-T7 is higher than that of the Flu control group from the second immunization;
  • FIG. 2C is the subclass of IgG1. Content;
  • Figure 2D shows the content of the IgG2a subclass;
  • Figure 2E shows the ratio of Ig2a/IgG1.
  • Figure 3 is a graph of the results of the safety experiment.
  • mice in this example were SPF grade BALB/c mice, female, 4-6 weeks, purchased from Guangdong Medical Animal Experimental Center.
  • the H1N1 Influenza Virus Inactivated Vaccine (Flu) was kindly provided by Beijing Kexing Biological Products Co., Ltd.
  • the small molecule compound SZU-101 (abbreviated as T7) having the structure represented by formula (I) is synthesized and purified by the laboratory; published articles, see: Zhu J, He S, Du J, Wang Z, Li W, Chen X, Jiang W, Zheng D, Jin G. Local administration of a novel Toll-like receptor 7 agonist in combination with doxorubicin induces durable tumouricidal effects in a murine model of T cell lymphoma.J Hematol Oncol.2015 Mar 4;8(1): twenty one.
  • SZU-101 conjugated influenza vaccine (Flu-T7) was synthesized by our laboratory; see Method: Gao D, Liu Y, Li W, Zhong F, Zhang X, Diao Y, Gao N, Wang X, Jiang W, Jin G. Synthesis and immunoregulatory activities of conjugates of a Toil-like receptor 7 inert ligand. Bioorg Med Chem Lett. 2014, 24(24): 5792-5.
  • the lymphocytes in the mouse spleen are extracted by using the mouse lymphocyte separation solution, and 1*105 lymphocytes/wells are seeded in a 24-well plate, and the lymphocytes are respectively incubated at 1 ⁇ g/ml, 5 ⁇ g/ml, and 10 ⁇ g/ml. Flu or Flu-T7, cultured in a cell culture incubator for 24 hours. The supernatant was collected, and IFN- ⁇ , IL-2, IL-12, and TNF- ⁇ cytokine levels were measured using an ELISA kit.
  • mice Female 4-6 week old Balb/c mice were randomly divided into 4 groups, 8 rats in each group: 1 normal saline; 2T7 group (1 mg/ml); 3Flu (3 ⁇ g); 4Flu-T7 (3 ⁇ g). On the 0th day, the 14th day, the 28th day, the immunization was performed 3 times, each time by intraperitoneal injection, 0.1 ml/only. Dose-effect experiments were performed on day 7, 21, and 35 days, respectively, to collect mouse tail vein blood (as shown in Fig. 2A), and serum was separated to measure antibody titer.
  • IgG antibodies were detected by ELISA.
  • 100 ⁇ l of the coating solution (containing 1 ⁇ g/ml of Flu) was added to each well of a 96-well microtiter plate at 4 ° C overnight. The enzyme plate was taken out, and the coating solution in the well was discarded, and 300 ⁇ l of PBST was added to the well for 3 times. Serum samples were diluted 1:500 and incubated for 2 hours at room temperature. Alkaline phosphatase-labeled IgG, IgG1, IgG2a antibody, 100 ⁇ l/well, and incubated for 1 hour at room temperature. The p-NPP substrate solution was added to develop color, 100 ⁇ l/well, and 50 ⁇ l of 3 M NaOH was added to each well to terminate the reaction, and the OD 405 value was measured by a microplate reader.
  • FIG. 2B shows that the antibody titer of Flu-T7 was higher than that of the Flu control group from the second immunization.
  • IgG contains different subclasses depending on the results and function, and IgG1 and IgG2a are the most important IgG subclasses.
  • the ratio of IgG2a/IgG1 showed that Flu-T7 mainly belongs to the Th1 type and produces an IgG2a type antibody.
  • SZU-101 can be used as an effective adjuvant for influenza virus inactivated vaccines.

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Abstract

本发明提供了一种疫苗佐剂以及包含该佐剂的疫苗。所述的疫苗佐剂具有式(I)所示的结构。该疫苗佐剂能够增强流感病毒灭活疫苗的免疫效果，并且对小鼠无毒性。

Description

一种疫苗佐剂以及包含该佐剂的疫苗 技术领域
本发明涉及药物化学技术领域，具体涉及一种疫苗佐剂以及包含该佐剂的疫苗。
背景技术
流感病毒引起的急性呼吸系统疾病传播迅速，具有高发病率和死亡率的特点。根据核蛋白(NP)和基质蛋白(M1)的不同可分为甲型、乙型和丙型。上个世纪曾经爆发过多次全球性流感大流行，最为严重的一次是发生于1918～1919年的西班牙流感，该流感的流行毒株为最常见的甲型H1N1，至少2千万人死亡。目前，预防流感病毒最有效、最经济的手段是接种流感疫苗。然而，疫苗的有效性受多种因素影响并且每年不同。流感疫苗主要基于表面糖蛋白抗原血凝素(HA)的保守区域。HA的抗原漂移具有高塑性，因此需要开发新的抗原，利用佐剂增强疫苗自身的免疫原性。普通流感疫苗虽然能够激发有效的针对病毒的抗体，但是对于免疫系统不完善的幼儿、免疫力低下的人，及老年人，长期反复的感染常常导致严重的、不可逆转的呼吸器官损伤，诱发呼吸系统功能衰竭，后果严重。因此，开发一种免疫佐剂具有重要的意义。
发明内容
本发明所要解决的技术问题是，为了克服现有技术中疫苗佐剂的种类不足，提供一种疫苗佐剂。
本发明所要解决的上述技术问题，通过以下技术方案予以实现：
本发明提供一种疫苗佐剂，所述的疫苗佐剂为小分子化合物(命名为SZU-101)，具有式(I)所示的结构；
Figure PCTCN2016105100-appb-000001
一种疫苗佐剂，它包含式(I)所示的化合物。
优选地，所述的疫苗佐剂为流感疫苗佐剂。
更优选地，所述的疫苗佐剂为H1N1流感疫苗佐剂。
优选地，所述的疫苗佐剂的剂型为生理上可接受的液体制剂、乳液制剂或冻干制剂。
具有式(I)所示的结构的化合物(命名为SZU-101)作为疫苗佐剂的应用。
优选地，所述的疫苗佐剂为流感疫苗佐剂。
更优选地，所述的疫苗佐剂为H1N1流感疫苗佐剂。
本发明还提供一种疫苗，它包含具有式(I)所示结构的疫苗佐剂。
优选地，所述的疫苗，由具有式(I)所示结构的疫苗佐剂和抗原偶联而成。
更优选地，所述的疫苗，由具有式(I)所示结构的疫苗佐剂和流感疫苗偶联而成。
最优选地，所述的疫苗，由具有式(I)所示结构的疫苗佐剂和H1N1流感疫苗偶联而成。
以上所述的偶联是采用本领域常规手段而实现。
有益效果：本发明提供了一种新型的疫苗佐剂，该疫苗佐剂能有效地增强流感病毒灭活疫苗的免疫效果，并且对小鼠的无毒性；因此，SZU-101可以作为流感病毒灭活疫苗的一种有效的佐剂。实施例结果显示SZU-101偶联流感疫苗(Flu-T7)能显著增强血清抗体效价，且高于单独疫苗组，并且促进小鼠特异性Th1型免疫反应，各组小鼠脾脏指数差异无统计学意义(P＞0.05)，说明SZU-101作为疫苗佐剂具有良好的安全性及有效性。
附图说明
图1为Flu-T7激活T细胞诱导细胞因子实验结果图。其中图1A为SZU-101(T7)的结构式；图1B为Flu-T7对比于单独Flu组，产生的IL-12细胞因子水平图；图1C为Flu-T7对比于单独Flu组，产生的FN-γ细胞因子水平图；图1D为Flu-T7对比于单独Flu组，产生的TNF-α细胞因子水平图；图1E为Flu-T7对比于单独Flu组，产生的IL-6细胞因子水平图。(P＜0.05)
图2为免疫小鼠的血清抗体反应实验结果图。图2A为分别于第7天、21天、35天尾静脉采血；图2B为从第二次免疫开始，Flu-T7的抗体效价高于对比于Flu对照组；图2C为IgG1亚类的含量；图2D为IgG2a亚类的含量；图2E为Ig2a/IgG1的比例。
图3为安全性实验结果图。
具体实施方式
以下结合具体实施例来进一步解释本发明，但实施例对本发明不做任何形式的限定。
本实施例中的小鼠为SPF级BALB/c小鼠，雌性，4-6周，购于广东省医学动物实验中心。
H1N1流感病毒灭活疫苗(Flu)由北京科兴生物制品有限公司惠赠。
具有式(I)所示的结构小分子化合物SZU-101(简称T7)由本实验室自行合成纯化；已发表文章，参见：Zhu J，He S，Du J，Wang Z，Li W，Chen X，Jiang W，Zheng D，Jin G.Local administration of a novel Toll-like receptor 7 agonist in combination with doxorubicin induces durable tumouricidal effects in a murine model of T cell lymphoma.J Hematol Oncol.2015 Mar 4；8(1)：21.
SZU-101偶联流感疫苗(Flu-T7)由本实验室偶联合成；方法参见：Gao D，Liu Y，Li W，Zhong F，Zhang X，Diao Y，Gao N，Wang X，Jiang W，Jin G.Synthesis and immunoregulatory activities of conjugates of a Toil-like receptor 7 inert ligand.Bioorg Med Chem Lett.2014，24(24)：5792-5.
实施例1 Flu-T7激活T细胞诱导细胞因子
为了评价本发明具有式(I)所示的结构小分子化合物SZU-101(简称T7)作为流感疫苗佐剂的活性。本实施例利用小鼠淋巴细胞分离液，提取小鼠脾脏中的淋巴细胞，1*105个淋巴细胞/孔种在24孔板中，淋巴细胞分别孵育1μg/ml，5μg/ml，10μg/ml的Flu或者Flu-T7，细胞培养箱培养24小时。收集上清，利用ELISA试剂盒检测IFN-γ、IL-2、IL-12、TNF-α细胞因子水平。
结果如图1显示，Flu-T7对比于单独Flu组，产生更多的IL-12(图1B)、IFN-γ(图1C)、TNF-α(图1D)、IL-6(图1E)的表达(P＜0.05)。这些结果表明，SZU-101偶联流感疫苗(Flu-T7)促进了Th1型和Th2型免疫应答，诱导了细胞免疫和体液免疫的发生。也说明SZU-101可以作为流感病毒灭活疫苗的一种有效的佐剂。
实施例2 免疫小鼠的血清抗体反应
为了评价本发明具有式(I)所示的结构小分子化合物SZU-101(简称T7)作为流感疫苗佐剂的效果。本实施例采用如下试验：
雌性4-6周龄的Balb/c小鼠随机分为4组，每组8只：①生理盐水；②T7组(1mg/ml)；③Flu(3μg)；④Flu-T7(3μg)。分别于第0天，第14天，第28天免疫3次，每次经腹腔注射，0.1ml/只。量效实验分别在第7天，21天，35天采集小鼠尾巴静脉血(如图2A所示)，分离血清，检测抗体效价。
用ELISA法检测特异性IgG抗体。首先向96孔酶标板各孔中加入100μl包被液(含1μg/ml的Flu)，4℃过夜。取出酶标版，弃孔中包被液后，向孔中加入300μl PBST洗涤3次。血清样品1∶500稀释，室温孵育2小时。碱性磷酸酶标记的IgG，IgG1，IgG2a抗体，100μl/孔，室温孵育1小时。加入p-NPP底物溶液显色，100μl/孔，每孔加50μl 3M NaOH终止反应，酶标仪测定OD405值。
结果，图2B显示，从第二次免疫开始，Flu-T7的抗体效价高于对比于Flu对照组。IgG根据结果和功能的不同包含不同的亚类，IgG1和IgG2a为最主要的IgG亚类。IgG2a/IgG1的比例结果显示，Flu-T7主要偏属于Th1型，产生IgG2a型抗体。上述结果表明SZU-101可以作为流感病毒灭活疫苗的一种有效的佐剂。
实施例3 T7作为流感疫苗佐剂的安全性实验
免疫后第35天，对各组小鼠的脾脏和体重进行称量，计算各组小鼠脾重与体重的比值，结果比值无统计学意义(P＞0.05)，见图3。结果表明以T7为佐剂的疫苗对小鼠机体刺激性较少，对其生长并无显著影响。

Claims (10)

  1. 一种疫苗佐剂，其特征在于，所述的疫苗佐剂为小分子化合物，具有式(Ⅰ)所示的结构；
    Figure PCTCN2016105100-appb-100001
  2. 一种疫苗佐剂，其特征在于，所述的疫苗佐剂包含权利要求1中式(Ⅰ)所示的化合物。
  3. 根据权利要求1或2所述的疫苗佐剂，其特征在于，所述的疫苗佐剂为流感疫苗佐剂。
  4. 根据权利要求3所述的疫苗佐剂，其特征在于，所述的疫苗佐剂为H1N1流感疫苗佐剂。
  5. 根据权利要求1所述的疫苗佐剂，其特征在于，所述的疫苗佐剂的剂型为生理上可接受的液体制剂、乳液制剂或冻干制剂。
  6. 具有式(Ⅰ)所示的结构的化合物作为疫苗佐剂的应用。
  7. 一种疫苗，其特征在于，包含权利要求1所述的具有式(Ⅰ)所示结构的疫苗佐剂。
  8. 根据权利要求7所述的疫苗，其特征在于，由权利要求1所述的具有式(Ⅰ)所示结构的疫苗佐剂和抗原偶联而成。
  9. 根据权利要求7所述的疫苗，其特征在于，由权利要求1所述的具有式(Ⅰ)所示结构的疫苗佐剂和流感疫苗偶联而成。
  10. 根据权利要求7所述的疫苗，其特征在于，由权利要求1所述的具有式(Ⅰ)所示结构的疫苗佐剂和H1N1流感疫苗偶联而成。
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CN106267188B (zh) * 2016-08-15 2025-06-17 深圳大学 小分子免疫激动剂偶联pd-1抗体的新型抗体及其在抗肿瘤中的应用
CN107281483B (zh) * 2017-04-25 2025-10-24 深圳大学 免疫激动剂和组合物及其应用以及组合物的制备方法

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