CN103251941A - 动物病毒性疫苗脉冲释放系统、其制备方法及用途 - Google Patents
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Abstract
本发明涉及生物医药工程领域，具体涉及一种动物疫苗脉冲释放系统、其制备方法及在动物疫病防治中的应用。本发明通过制备具有不同释放特性的包含疫苗抗原的聚合物微球及其组合物构成的疫苗脉冲释放系统，通过注射途径给药，实现单剂注射完成全程免疫，从而简化免疫程序、提高免疫效果、降低劳动强度、减少漏种率。
Description
技术领域
本发明涉及生物医药工程领域，具体涉及一种动物疫苗脉冲释放系统、其制备方法及在动物疫病防治中的应用。
背景技术
疫苗免疫接种是预防、控制并消灭动物传染性疾病的最有效且最实用的方法。但是，传统的灭活疫苗以及代表未来发展方向的基因工程亚单位疫苗、合成肽疫苗、DNA疫苗等均存在不足，即免疫原性低，需要多次重复接种才能产生有效的免疫保护作用。解决这个问题的途径有两条，一是研制开发新型高效的免疫佐剂；二是研制开发可注射的疫苗抗原的控释系统，以恒定的、持续的、预定的方式将抗原递送至特定组织。
形态上类似病原体的颗粒性抗原比溶解性抗原更容易被抗原呈递细胞(APC)有效吞噬，从而引起更为强烈的细胞免疫和体液免疫。国内外正在研究用聚酯、明胶、聚丙烯淀粉、壳聚糖等作为佐剂，包裹疫苗，制成生物降解型聚合物微球，使抗原颗粒化，从而更有效地促进机体的细胞免疫和体液免疫。生物降解聚合物微球是近年疫苗佐剂的研究热点，也是研究最多也最成功的抗原载体系统。
微球的主要特征是它们能控制抗原的释放。微球可由两种或多种不同聚合物组成，所包载的抗原可以不同的速度释放。抗原长期释放相当于多次疫苗接种，从而产生高水平抗体，这将使研究开发接种一次的单剂疫苗成为可能。
现代动物生产采用集约化养殖的模式。动物疫病特别是病毒性疫病的防治是现代养殖业面临的关键问题之一。探索可单针注射的疫苗抗原的脉冲释放系统，可有效地降低免疫成本和劳动强度，减少动物应激，提高免疫效果。这在科学研究和生产实践中均具有重要价值。
发明内容
本发明公开了一种动物病毒性疫苗脉冲释放系统，通过采用聚合物制备含疫苗抗原的具有脉冲释放特性或缓释特性的疫苗微球，再将具不同释放特性的疫苗微球适当组合即构成疫苗脉冲释放系统。此种疫苗脉冲释放系统可用于动物病毒性疫病的单针免疫，取代普通疫苗的多针免疫，实现动物病毒性疫病的免疫防治。它比疫苗常规剂型使用更方便，可大大减轻劳动强度，减少动物应激，同时具有佐剂效应，使免疫效果更好。
本发明的动物病毒性疫苗脉冲释放系统的制备方法如下：
①采用复乳液中干燥法制备疫苗微球，其基本步骤包括：取初乳制成复乳，转移至烧杯中，磁力搅拌，室温下挥干溶剂，离心收集疫苗微球，用灭菌注射用水洗涤，无菌条件下真空冷冻干燥即得疫苗微球。
②采用喷雾低温萃取法制备疫苗微球，其基本步骤包括：将疫苗抗原与聚合物溶液混合制成混悬液，经喷头以雾状喷至冰冻的乙醇溶液中，再过滤除去乙醇，用灭菌注射用水洗涤，无菌条件下真空冷冻干燥即得疫苗微球。
③采用喷雾干燥法制备疫苗微球，其基本步骤包括：将疫苗抗原与聚合物溶液混合制成混悬液，经喷雾干燥器喷雾干燥即得疫苗微球。
④将疫苗微球按释放特性与抗原含量适当组合即成疫苗脉冲释放系统。
具体实施方式
实施例1
新城疫灭活疫苗抗原的制备
取新城疫弱毒La Sota株，按常规方法接种易感鸡胚，经培养，收获鸡胚液，经甲醛溶液灭活。取灭活后的新城疫病毒鸡胚液，在无菌条件下于4℃离心取上清液，上清液再经截留分子量为3万的超滤膜于4℃无菌条件下进行超滤浓缩。经超滤纯化浓缩后的上清液即为制备疫苗微球的抗原液。
实施例2
新城疫灭活疫苗微球的制备I
微球的制备：采用复乳液中干燥法制备新城疫灭活疫苗PLGA微球。将新城疫抗原液作为水相，将PLGA(50∶50)溶于二氯甲烷中制成适当浓度的溶液作为油相。将水相和油相按1∶10(V/V)比例混合，冰浴条件下超声乳化10秒得初乳。将初乳加入2％PVA溶液中，10000rpm转速下经乳化器高速搅拌30秒，得复乳。将所得复乳转移至烧杯中，在400rpm转速下磁力搅拌5小时，室温条件下挥干二氯甲烷，再在6000rpm转速下离心10分钟，收集微球，用灭菌水洗涤3次，真空冷冻干燥即得新城疫灭活疫苗PLGA微球I。
微球的质量评价：显微镜法观察微球形态并测定粒径；用紫外分光光度法或Bradford法测定微球中抗原含量，按公式计算包封率和载药量，体外法测定疫苗微球的释放曲线。
经测定，新城疫灭活疫苗微球I的体外释放呈两相模式，第一突释相在注射后半日内，第二突释相在注射后35日，两相之间为缓慢释放相。
实施例3
新城疫灭活疫苗微球的制备II
微球的制备：采用复乳液中干燥法制备新城疫灭活疫苗PLGA微球。将新城疫抗原液作为水相，将PLGA(75∶25)溶于二氯甲烷中制成适当浓度的溶液作为油相。将水相和油相按1∶10(V/V)比例混合，冰浴条件下超声乳化10秒得初乳。将初乳加入2％PVA溶液中，4000rpm转速下经乳化器高速搅拌30秒，得复乳。将所得复乳转移至烧杯中，在200rpm转速下磁力搅拌5小时，室温条件下挥干二氯甲烷，再在5000rpm转速下离心10分钟，收集微球，用灭菌水洗涤3次，真空冷冻干燥即得新城疫灭活疫苗PLGA微球II。
微球的质量评价：显微镜法观察微球形态并测定粒径；用紫外分光光度法或Bradford法测定微球中抗原含量，按公式计算包封率和载药量，体外法测定疫苗微球的释放曲线。
经测定，新城疫灭活疫苗微球II的体外释放呈两相模式，第一突释相在注射后半日内，第二突释相在注射后96日，两相之间为缓慢释放相。
实施例4
新城疫灭活疫苗微球的制备III
微球的制备：采用复乳液中干燥法制备新城疫灭活疫苗PLGA微球。将新城疫抗原液作为水相，将PLGA(85∶15)溶于二氯甲烷中制成适当浓度的溶液作为油相。将水相和油相按1∶10(V/V)比例混合，冰浴条件下超声乳化10秒得初乳。将初乳加入2％PVA溶液中，4000rpm转速下经乳化器高速搅拌30秒，得复乳。将所得复乳转移至烧杯中，在200rpm转速下磁力搅拌5小时，室温条件下挥干二氯甲烷，再在5000rpm转速下离心10分钟，收集微球，用灭菌水洗涤3次，真空冷冻干燥即得新城疫灭活疫苗PLGA微球III。
微球的质量评价：显微镜法观察微球形态并测定粒径；用紫外分光光度法或Bradford法测定微球中抗原含量，按公式计算包封率和载药量，体外法测定疫苗微球的释放曲线。
经测定，新城疫灭活疫苗微球I的体外释放呈两相模式，第一突释相在注射后半日内，第二突释相在注射后182日，两相之间为缓慢释放相。
实施例5
新城疫灭活疫苗脉冲释放系统的制备及鸡免疫试验
取新城疫灭活疫苗微球I、微球II和微球III，将三者按1∶1∶1的比例(以抗原含量计)混合，总量相当于普通新城疫灭活疫苗单次注射抗原量的1/10，无菌条件下封装于灭菌西林瓶中，4℃贮存备用，临用前用灭菌生理盐水配成0.1mL的混悬液。
取2周龄SPF鸡(经检测无新城疫抗体)，随机分组，每组10只，分为阴性对照组(灭菌生理盐水)、阳性对照组(普通新城疫灭活疫苗)和试验组(新城疫灭活疫苗脉冲释放系统)，每只鸡皮下注射0.1mL，免疫后每周每只鸡采血分离血清，按常规HI方法检测血清中新城疫抗体效价。
经检测，阴性对照组HI抗体效价的几何平均值均＜2log2，阳性对照组在免疫后2-6周内HI抗体效价的几何平均值≥4log2，之后逐渐下降至≤2log2，试验组在整个试验期(6个月)HI抗体效价的几何平均值均≥7.5log2，其中在第2、6、13、27周，血清HI效价出现峰值。
Claims (6)
1.一种动物病毒性疫苗脉冲释放系统，其特征为：①该释放系统由一种或多种包含相应抗原的具不同释放特性的聚合物微球组成；②同时包含或不包含一切药学上可接受的辅料；③同时包含或不包含一切疫苗学上可接受的免疫佐剂；④其给药方式为注射，包括皮内注射、皮下注射、肌内注射；⑤其释放方式为脉冲释放，在1-12个月时间范围内呈现2次或2次以上脉冲释放。
2.权利要求1所述的动物病毒性疫苗，包括：用于动物病毒性传染病免疫防治的灭活疫苗、基因工程亚单位疫苗、合成肽疫苗。
3.权利要求1所述的聚合物微球，其中聚合物是指一切药学上可接受的聚合物材料，其中优选具有生物相容性、可生物降解的聚合物，包括壳聚糖、胶原、明胶、白蛋白、聚氨基酸、聚酯(polyester)、聚酸酐(polyanhydride)、聚乳酸-聚乙二醇共聚物(PELA)等。
4.权利要求1所述的聚合物微球，其大小介于10nm-1000μm之间，具有脉冲释放特性或缓慢释放特性。
5.权利要求1所述的聚合物微球，其制备方法为复乳液中干燥法、喷雾低温萃取法或喷雾干燥法。
6.权利要求1所述的动物病毒性疫苗脉冲释放系统，用于动物病毒性疫病的单针免疫，代替普通疫苗的多针免疫，达到防治动物病毒性传染病的效果。
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