CN86103717A - 流感疫苗的制备方法 - Google Patents
流感疫苗的制备方法 Download PDFInfo
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Abstract
本发明涉及一种含有HANA抗原-MDP衍生物复合体的新流感疫苗。其制备过程是：将流感HANA抗原与至少一种MDP衍生物在适当的介质中混合，用可透析去除的一种表面活化剂处理，使混合物溶解，这种溶解过程是在有或没有胆固醇，卵磷脂和磷酸双鲸酯或它们的混合物条件下进行，然后通过透析去除其中的表面活性剂。
Description
本发明涉及一种新的流感疫苗，特别涉及一种自流感病毒获得的HANA抗原与胞壁酰二肽衍生物（以下称为MDP衍生物）人工合成囊泡样复合体颗粒组成的流感疫苗，HANA抗原为这种疫苗的活性成分，MDP衍生物为合成佐剂，这种人工合成颗粒在大小和形状上与天然发生的流感病毒颗粒相似。本发明还涉及制备这种新疫苗的方法。
由于目前使用的流感HA疫苗的接种效果受发生在流行病毒HA（血凝素）分子上的突变变异影响，因此开发较传统所用更为有效的疫苗成为紧迫的要求。
在流感疫苗开发方面的最新进展之一就是由HA和NA（神精氨酸酶）为主要成份的一种合成疫苗的出现，即流感HANA疫苗。形成的这种含有纯化HANA的疫苗在安全性和效果上被认为是一种理想的疫苗，并且在美国已被用于实践。然而，这种疫苗的效果实际上仍有不足之处。
从另一方面看，再有的进展就是佐剂的使用。这项工作已导致对胞壁酰二肽（MDP）及多种MDP衍生物的开发，适当的化学修饰使MDP衍生物作为新型佐剂材料在免疫潜能等方面得到改善。例如，Kotani等人在YAKUGAKU ZASSHI这本期刊的1983年第103卷一期第1～27页上发表了有关这些MDP衍生物的报告。它们提到将6-0-（2-四癸基六癸酰基）MDP与含有高度纯化作为主要成分的HA和NA流感疫苗（即HANA）一起注射给豚鼠，并报告说已得到了有效的佐剂效应。然而，将MDP衍生物作为佐剂简单地加入疫苗所得到的HANA疫苗并不具有足够的作用。
因此，本发明的主要目的是提供一种较传统所用具有更良好的致免疫性的新型流感疫苗。
本发明的另一目的是提供一种包括人工合成囊泡样HANA抗原-MDP衍生物复合体颗粒的新型流感疫苗，此复合颗粒与天然病毒颗粒在颗粒大小和形状上几乎相同。
本发明的这些及其它的目的通过下面的描述会更清楚。
按照本发明，提供一种包括人工合成的HANA抗原复合物的囊泡样颗粒和至少一种MDP衍生物的流感疫苗，MDP衍生物组成此颗粒的膜（相当于天然流感病毒颗粒的脂膜），HANA抗原与MDP衍生物相连出现在此膜上以形成复合体，这样，此种复合体就与简单地将一种疫苗和一种佐剂混合得到的疫苗不同了。因此，按本发明所获得的人工合成HANA抗原-MDP衍生物复合体囊泡样颗粒就具有了与天然病毒颗粒几乎相同的颗粒大小和几乎相同的形状。
图1和图2分别为本发明的1号试样疫苗和2号试样疫苗的电镜显微照片（放大150，000倍）;
图3为本发明4号试样疫苗的电镜显微照片（放大200，000倍）;
图4代表用蔗糖梯度离心法所得到的密度区带的比较，以确定本发明的此种复合物的构成。
这种新的流感疫苗可用下述专门的方法制备。
首先在某种适当的缓冲液中，例如磷酸盐缓冲液，将流感HANA抗原与MDP衍生物以重量比10/1～1/300的比值混合后，再加入有效量的表面活化剂（0.1～10重量/体积%），使形成的混合物溶解。此后，用透析方法将这种表面活化剂除去，便得到一种新的HANA抗原-MDP衍生物复合体。在此，最重要的是要使用一种可经透析去除的表面活化剂。这类表面活化剂举例包括辛基苷、胆酸钠等。参考图1～3，得到的HANA抗原-MDP衍生物复合体形成所谓病毒体，在病毒体内MDP衍生物本身使人工合成囊泡得以形成，而HANA抗原则通过它们狭窄的未端与颗粒表面结合，使得它们与存在天然病毒颗粒表面上的此抗原具有相同的方位。
根据本发明的另一方面，MDP衍生物可与（Ⅰ）胆固醇（Ⅱ）卵磷脂和磷酸双鲸酯（dicetyl phosphate）或（Ⅲ）即（Ⅰ）和（Ⅱ）的混合物等物质联合使用，这些物质具有促MDP衍生物的人工合成囊泡样颗粒形成的能力。在这种情况下，优先选用下列重量比值：
使用胆固醇：MDP衍生物/胆固醇＝1/0～1/5，更优先选用的比值为1/0.5～1/2。
使用卵磷脂：MDP衍生物/卵磷脂＝1/0～1/50，更优先选用的比值为1/1～1/20。
使用磷酸双鲸酯卵磷脂/磷酸双鲸酯＝1/0.05～1/2，更优先选用的比值为1/0.5～1/1。
此外，与本发明的这个方面一致，并不一定必须使用表面活化剂及进行透析。从这点讲，本发明比经传统的形成NDP衍生物囊泡样颗粒的声波处理（超声波法），微量注射，反相脱水等方面为优。
本发明可使用的MDP衍生物包括许多种MDP的适当化学修饰物。这些MDP衍生物在日本公开专利（KOKAI）第52-46020，52-156812，54-73729，54-130517，55-19236，55-28932，55-28933，56-18996，56-49396和60-78997号中有论述。
优先使用具有下列结构式的高级脂肪酯：
其中Q代表合成的总共具有20～60个碳原子的高级脂肪酸残基;
A代表L-丙氨酸，L-丝氨酸或甘氨酸，iso Gln代表异谷氨酰胺。
更优先使用6-0-（2-四癸基六癸酰基）MDP，即B30-MDP。这些脂肪酯的论述发表在日本公开专利（Ko KAI）54-130517号上。
具有下列结构式的MDP衍生物也可优先选用：
其中X代表一种氨基酸，如L-丙氨酸，L-丝氨酸，
L-缬氨酸及甘氨酸;
Y代表-NH-A或-
，其中R1为氢原子，短链烷基，氨甲酰基或羧基;n为1～6;A为一个带或不带有侧链的具有8～30个碳原子的饱和或不饱和脂肪族烃链残基。这种衍生物更优先选用的例子包括Nα-（N-乙酰胞壁酰-L-丙氨酰-D-异谷氨酰）-N-十八烷-L-赖氨酸，即MDP-LYS（L18）。
更进一步，优先使用Nα-（N-乙酰胞壁酰-N-甲基-L-丙氨酰-D-异谷氨酰）-Nε-十八烷-L-赖氨酸，即MDP（Me Ala）-Lys（18）。对此，日本公开专利60-78997对此有叙述。
本发明使用的HANA抗原是自流感病毒感染的胚蛋中抽尿囊液，经高速离心或化学处理等纯化流感病毒步骤，用非离子型表面活化剂溶解此纯化病毒，如去利通X-100和NP-40;或用阳离子表面活化剂，如去氧胆酸钠和胆酸钠;或用阳离子表面活化剂，如十六烷三甲铵;也可借醚类有机溶剂溶解，然后通过蔗糖密度梯度离心，亲和层析等方法，进一步纯化所得的产物。
以下非限定性实施例，将能更具体地说明本发明。
实施例1流感HANA抗原的制备
流感A/曼谷型/1/79（H3N2）病毒在鸡胚中生长，然后对生长出的病毒进行高速离心分离（23，000转/分钟，90分钟），低速离心分离（6000转/分钟，60分钟）和蔗糖密度梯度离心（30，000转/分钟，3小时）。然后将去利通X-100加到病毒悬液至终浓度1%，充分搅拌此悬液，使病毒溶解后，再通过蔗糖密度离心，便可得到纯化的HANA抗原溶液。疫苗的制备与免疫试验
利用上述得到的纯化HANA抗原溶液，按下述方法制备四种疫苗试样（它们的成分如表1所示）：
各个成分混合后，加入辛基苷至终浓度为3%（重量）。待这些成分溶解后，按传统方法放至磷酸盐缓冲液中进行透析，以此使每份样品的HANA抗原浓度调整至0.8微克当量/毫升，然后按每只小鼠0.5ml的剂量进行腹腔接种，总共接种十五只DDY小鼠（4周龄，雌鼠）接种后，将小鼠分成三个组，每组5只，分别于接种后一星期，二星期，三星期收集相应组的鼠血，按世界卫生组织的方法进行血凝抑制试验，以测定抗体形成能力。
按上述同样方法，用前述各个样品对DDY小鼠进行免疫，两周后用制备疫苗所使用的病毒株感染小鼠，再四天后摘取小鼠的肺脏。用MDCK细胞对小鼠的肺脏进行空斑形成试验，以测定肺内病毒含量。得出的结果见表1
从表1列出的结果可以明显看出，本发明的所有疫苗均比只由HANA组成的疫苗具有更良好的抗体形成能力。
借助电子显微镜观察1号，2号和3号试样的疫苗形态，可以肯定MDP衍生物人工合成囊泡样颗粒具有与天然流感病毒颗粒相同的大小和相同的形状，在其表面，HANA抗原与MDP衍生物相连，如图1～3所示，形成清晰的复合体。
为了确定上面制备的1号试样是否形成复合体，用蔗糖密度梯度离心的方法测定了HANA抗原、完整病毒和1号试样的密度。从图4中的结果明显看出，1号试样显示的区带位置与HANA抗原和完整病毒均不同，因此可以得出结论，1号试样形成了一种不同于HANA抗原和完整病毒的复合体。实施例2
除使用流感A/菲律宾型/2/82（H3N2）毒株这点不一样外，其它方法与前述实施例1的方法相同，制备HANA抗原。用表2例出的成分与这种HANA抗原混合，混合后，用装有杯状探头（范围2.5）的Heat Systems W375超声仪（Heat System-超声仪公司生产）对混合物进行8分钟的超声处理，这样得到的每份试样的抗体形成能力根据前述实施例1的同样方法测定。
表2例出了所得的结果，结果显示本发明的疫苗具有良好的抗体形成能力。
表2
试样号 成分 血凝抑制值
（经三周后）
6 HANA 1.0微克当量
B30-MDP 3.0微克 512
HANA 1.0微克当量
B30-MDP 3.0微克
7 卵磷脂 450微克 512
磷酸双鲸酯 50微克
HANA 1.0微克当量
8 B30-MDP 30微克 1024
胆固醇 50微克
HANA 1.0微克当量
MDP-LYS（L18）30微克
9 卵磷脂 450微克 1024
磷酸双鲸酯 50微克
HANA 1.0微克当量
10 MDP-LYS（L18）30微克 512
胆固醇 50 微克
对照样
11 HANA 1.0微克当量 256
从上述实施例1和2可明显看出，本发明的流感疫苗具有良好的致免疫性和改进的防流感感染性。
Claims (10)
1、一种制备流感疫苗的方法，该方法包括将流感HANA疫苗与至少一种MDP衍生物在适当的介质中混合，用可透析去除的表面活性剂使混合物溶解，溶解过程在胆固醇，卵磷脂和磷酸双鲸酯或它们的混合物存在或不存在的条件下进行；然后通过透析去除其中的表面活性剂，得到包括人工合成的流感HANA抗原和MDP衍生物复合体的囊泡样颗粒的流感疫苗。
2、根据权项1所述的方法，其中的溶解过程在胆固醇、卵磷脂及磷酸双鲸酯或它们的混合物存在的条件下进行。
3、根据权项1所述的方法，其中的溶解过程于不存在胆固醇，卵磷脂及磷酸双鲸酯或它们的混合物的条件下进行。
4、根据权项1所述的方法，其中流感HANA抗原与MDP衍生物的重量比为10/1～1/300。
5、根据权项2所述的方法，其中MDP衍生物与胆固醇的重量比为1/0～1/5。
6、根据权项2所述的方法，其中MDP衍生物与卵磷脂的重量比为1/0～1/50，卵磷脂与磷酸双鲸酯的重量比为1/0.05～1/2。
7、根据权项1所述的方法，其中的流感HANA抗原是一种经纯化流感病毒制备的抗原。
8、根据权项1所述的方法，其中MDP衍生物物具有下列结构式：
其中Q代表一种合成的总共具有20～60个碳原子的高级脂肪酸残基;A代表2-丙氨酸、2-丝氨酸或甘氨酸;iso Gln代表异谷氨酰胺。
9、根据权项1所述的方法，其中MDP衍生物具有下列结构式：
其中X为一种氨基酸;
Y代表-NH-A或-
，其中R1代表氢原子、短链烷基、氨甲酰基或羧基;n为1～6;A为带有或不带有支链的具有8～30个碳原子的饱和或不饱和脂肪族烃残基。
10、根据权项1所述的方法，其中MDP衍生物选自6-0-（2-四癸基六癸酰基）MDP，Nα-（N-乙酰胞壁酰-L-丙氨酰-D-异谷氨酰）-Nε-十八烷-L-赖氨酸和Nα-（N-乙酰胞壁酰-N-甲基-L-丙氨酸-D-异谷氨酰）-Nε-十八烷-L-赖氨酸。
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| FR2551758B1 (fr) * | 1983-08-16 | 1986-01-31 | Anvar | Derives de muramyl-peptides et de steroides ayant des proprietes d'activation des macrophages |
| IL69720A (en) * | 1983-09-14 | 1987-08-31 | Univ Ramot | Anti-tumor pharmaceutical compositions comprising liposome-bound porphyrins |
| US4663161A (en) * | 1985-04-22 | 1987-05-05 | Mannino Raphael J | Liposome methods and compositions |
-
1985
- 1985-06-06 JP JP60123341A patent/JPH0688911B2/ja not_active Expired - Lifetime
-
1986
- 1986-05-28 US US06/867,539 patent/US4826687A/en not_active Expired - Fee Related
- 1986-06-04 CA CA000510861A patent/CA1262091A/en not_active Expired
- 1986-06-05 AT AT86107631T patent/ATE76756T1/de not_active IP Right Cessation
- 1986-06-05 KR KR1019860004500A patent/KR940001373B1/ko not_active IP Right Cessation
- 1986-06-05 SU SU864027675A patent/SU1651782A3/ru active
- 1986-06-05 EP EP86107631A patent/EP0205098B1/en not_active Expired - Lifetime
- 1986-06-05 ES ES555748A patent/ES8707113A1/es not_active Expired
- 1986-06-05 AU AU58365/86A patent/AU585353B2/en not_active Ceased
- 1986-06-05 DE DE8686107631T patent/DE3685519T2/de not_active Expired - Fee Related
- 1986-06-06 CN CN86103717A patent/CN1020407C/zh not_active Expired - Fee Related
- 1986-06-06 CS CS864197A patent/CS269981B2/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0205098A2 (en) | 1986-12-17 |
| EP0205098A3 (en) | 1989-03-22 |
| AU5836586A (en) | 1986-12-18 |
| AU585353B2 (en) | 1989-06-15 |
| ES8707113A1 (es) | 1987-07-01 |
| JPS61282321A (ja) | 1986-12-12 |
| JPH0688911B2 (ja) | 1994-11-09 |
| CS419786A2 (en) | 1989-04-14 |
| CN1020407C (zh) | 1993-05-05 |
| EP0205098B1 (en) | 1992-06-03 |
| KR870000075A (ko) | 1987-02-16 |
| ATE76756T1 (de) | 1992-06-15 |
| CS269981B2 (en) | 1990-05-14 |
| CA1262091A (en) | 1989-10-03 |
| ES555748A0 (es) | 1987-07-01 |
| SU1651782A3 (ru) | 1991-05-23 |
| US4826687A (en) | 1989-05-02 |
| DE3685519D1 (de) | 1992-07-09 |
| KR940001373B1 (ko) | 1994-02-21 |
| DE3685519T2 (de) | 1993-01-21 |
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