CN1207048A - 抗耳炎的预防免疫牛奶制剂 - Google Patents
抗耳炎的预防免疫牛奶制剂 Download PDFInfo
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- CN1207048A CN1207048A CN96199507A CN96199507A CN1207048A CN 1207048 A CN1207048 A CN 1207048A CN 96199507 A CN96199507 A CN 96199507A CN 96199507 A CN96199507 A CN 96199507A CN 1207048 A CN1207048 A CN 1207048A
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- A61J7/0092—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine for holding medicines in, or fixing medicines on, a tooth, e.g. holder containing medicines fixed on a tooth
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- C—CHEMISTRY; METALLURGY
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Abstract
一种用于抗耳炎的预防用途的来源于用诸如流感嗜血菌(非乙型)、肺炎链球菌和布兰汉氏球菌(莫拉氏菌)的细菌免疫的母牛的免疫牛奶制剂。该制剂含有抗引起耳炎的细菌的IgG。可以补充引起龋的细菌(如变异链球菌,表兄链球菌)的特异抗体来预防龋。可以用一种橡皮奶头样的装置来进行该制剂的给药。
Description
本发明涉及一种用于防治儿童中耳感染(中耳炎)免疫牛奶制剂。该制剂含有所生产的抗引起中耳感染的细菌的抗体，并且，如果需要，还含有龋牙抑制剂。
通过接种怀孕的母牛以抗某些病原菌，由此母牛机体形成对这些疾病的抗体，该抗体被转移到初乳中，就能够产生所谓的免疫牛奶。长期以来已经了解了免疫牛奶的治疗作用。从本世纪初就已在对各种细菌和病毒性疾病的治疗中试验免疫的羊或母牛的奶。新近的最重要的研究是集中在基于胃肠道的微生物的疾病上，这些疾病尤其是类风湿性关节炎，龋牙，龈炎，腹泻，痢疾，胃炎和隐孢子虫病。已知一种免疫母牛奶的龋齿抑制产品，其含有杀死的变异链球菌细胞的特异性抗体(美国专利4,324,782)。在美国常见的免疫牛奶是通过以激发剂来维持抗体水平来生产的。抗体的量相当少，并且效果是以每天给药为基础。在台湾免疫牛奶是作为健康饮料出售的。在澳大利亚，已将含轮状病毒抗体的粉末混合到特别是婴儿配方食品中(Murtomaa-Niskala，1994)。全奶制品还含有可能对微生物菌群有效的非特异性抗菌因子(Takahashi等人，1992)。
在芬兰已制成了抗特别是幽门螺杆菌(Helicobacter pylori)感染的免疫牛奶(Dona等人，1994)，在Turku大学的牙科系已研究了获自免疫牛的初乳的抗变异链球菌和表兄链球菌(Streptococcus sobrinus)的抗体(Loimaranta等人，1996)(Jorma Tenoruo教授，未发表资料)。这种免疫牛奶已在Jokioninen的农业研究中心生产。
已证明一种由免疫初乳分离的抗变异链球菌抗体制剂抑制牙齿表面被变异链球菌感染并且在加到限菌鼠的生龋饮食中时保护牙齿不生龋齿(Michalek等人，1987)。与对照组相比较，使用用于早晚漱口一分钟的溶于水的冻干的基于同样技术的免疫乳清粉末两星期显著减少了年轻成人的牙斑(dental plaque)中变异链球菌的比例(Filler等人，1991)。但是漱口对于小的儿童来说并不是一种合适的给药方法，而他们则可能从增加的免疫保护获益最多(Aaltonen等人，1987)。
Suhonen(1992)曾提出在用于预防龋齿的预防方法中使用一种缓慢释放氟化物，木糖醇，单克隆龋抗体或乳酸过氧化物酶系统的成份至口腔中的安慰器样(pacifier)的给药装置的理论基础。已确立作为氟化钠，木糖醇和山梨糖醇从片剂释放的释放装置的投药安慰器的体外可操作性，并建议通过安慰器给药抗引起口腔疾病的微生物的被动疫苗(passive vaccines)(Suhonen等人，1994)。在本发明人的在Lohja地区保健中心对16个月大的儿童的区域实验中用于投药氟化钠，木糖醇和山梨糖醇的安慰器试制型式已证明是一种对于治疗哺乳期儿童的口腔和喉部疾病的研究有潜力的有效工具。在本发明人随后的研究中，显然，与由于一些原因或其它原因而未使用试验的安慰器的对照组相比，儿童接受试验的安慰器良好的一组表现出在18个月大之前中耳感染的频率明显要低(48％比78％)(Suhonen J.，Aaltonen A.S.，Jenovuo J.，“受龋牙危险因素影响的婴儿的睡熟安慰器”(Fall-asleep pacifierin toddlers subject to cariologic risk factors)，Poster，“国际儿科牙医学会第十五次大会”(The 15th Congress of International Association of PediatricDentistry，Gothenburg 1995)。
从理论上说，可能是由于在儿童睡熟时从安慰器缓释并留下来在口腔中长时间地起作用的木糖醇已阻止肺炎链球菌(Streptococcus pneumoniae)(肺炎球菌属)在儿童喉部生长，接受试验的安慰器的儿童才有如此少的中耳感染(Sipponen，1995，Kontiokari等人，1995)。两岁以下儿童中一半以上的源于细菌的中耳感染(中耳炎)是由肺炎球菌所造成的。中耳感染中另一种相当普通的病原菌是非典型的(非乙型)细菌种流感嗜血菌，再一种更常见的是粘膜炎布兰汉氏球菌。在以日托儿童的两个月实验中，每天5次咀嚼木糖醇口香糖5分钟比使用相应的加糖的口香糖的对照组减少中耳感染50％(Uhari等人，1996)。一种解释这一作用的可能方式是木糖醇可能已减少肺炎链球菌还有流感嗜血菌在粘膜细胞上的粘着并且因此阻止了这些耳病原菌通过听音管上升到中耳(助教Matti Uhari，未发表资料，8，11，1996；Andersson等人，1986)。
在本发明人的研究中，已在12-14个月龄时每晚吮吸一瓶牛奶或牛奶麦片粥的那些儿童比吮吸汁或水的那些儿童的中耳感染显然要更频繁些。可能与木糖醇有联系的这一观察和以前的观察表明所给药的药剂的作用可能通过安慰器扩散到鼻咽菌群并由此上升到中耳。本发明人的一些结果表明，虽然认为这些细菌的主要位置是鼻咽部，但是儿童会经由通过口的唾液接触而获得引起中耳感染的细菌。因而在抗目的在于中耳的细菌中，口腔可能是首要保护区。因此，如果将上述预防龋齿的Suhonen方法拓宽到用于鼻咽区的病原微生物群，以由该方法已知的给药装置或由其改进的装置，还可将针对中耳感染病原菌起作用的药剂长期给药以预防儿童中耳感染。
为治疗儿童急性中耳炎，现在主要使用抗生素，并且使用耳鼓穿刺和滴耳剂来立即去痛。大量使用抗生素被担心会促进抗性菌株的流行(Bacuero和loza，1994)和对口腔微生物菌群的选择，以致以牺牲其它种类为代价，产生蛋白酶降解免疫球蛋白A(IgA)的种类会变得更为常见(φstergaard，1983)。反复经受呼吸道感染的儿童比健康对照唾液中含IgA显著要少(Lenhtonen等人，1987)。由于该疾病的高发病率以及与治疗相关的困难，正在研制不经肠的有效增加血清特异性IgG免疫应答的抗该疾病的疫苗。将来也可使用以鼻喷雾剂形式提供有效的病毒疫苗，其刺激粘膜上的分泌的IgA应答，从而减少患中耳炎的危险。就本发明人所知，以前还未公开这一构思，即儿童中耳炎可能以一种尤其可通过吮吸装置来在延长的时间给药的被动的人体外产生的疫苗来预防。经鼻给药的针对乙型流感嗜血杆菌荚膜多糖的IgG型抗体曾抑制这种病原菌在鼠婴中的鼻咽部繁殖(Kauppi等人，1993)。
为本发明的目的的预防用的免疫牛奶产品，即牛初乳的抗耳炎的免疫球蛋白产物，会补充被动免疫防御，其在本质上大致相当于从母乳获得的免疫防御，但不同的是，人乳主要含IgA型抗体，牛乳含IgG型抗体。欧洲专利申请0479 579中公开了人或牛乳的免疫球蛋白可用于如中耳炎的治疗，但该申请特别地涉及IgA。大多数引起中耳炎的细菌的特征是其产生降解IgA的蛋白酶，因而需要其本身在喉部微生物群中具有生态存活优势。所述蛋白酶不降解IgG型抗体。急性中耳炎的发病高峰恰好是在儿童的生命的第一年的后半年中最渴望用安慰器时。在对抗通过口感染并且酶解IgA的耳病原菌中，通过口服装置或其他经口传送的被动IgG型疫苗可能是一种有效的治疗。
属于牛奶乳清蛋白的抗体的化学和生物学特性是相当熟知的。一升初乳含40-100g抗体，但相同量的乳只含0.5-1g。借助于现代乳品技术方法，可将抗体浓缩，分离纯化并且还可以干燥而不在任何显著程度上改变其活性。抗体全部是可溶于水的，无臭无味的蛋白。含有抗体的浓缩物或粉末可以加到不同的乳制品，特殊食品或临床营养制剂中(Korhonen，1992)。虽然牛奶以及其中因此还有的天然或免疫产生的抗体是一种普通的营养物，但其在婴儿体内的用途与一些缺点相联系，其在婴儿配方食品中被减少且在免疫乳制品中可达到更大程度的减少，其必定需要的仅仅是牛奶成份的乳清蛋白抗体。抗体或者换句话说为牛奶的免疫球蛋白相对较少地引起儿童的变应化作用。大约20％的芬兰儿童通常在生命的第一年发生牛奶变态反应，并且其最经常的原因是已从乳清产物除去的牛奶的酪蛋白成份。
在头三个月中终止人乳哺育或少量人乳哺育以及变应性素因似乎使儿童易患经常性的耳炎。在已从免疫乳制品除去大部分变应化因子时，从紧接着终止人乳哺育的相当小的年龄或将婴儿配方食品用作补充哺育时，可将其供应给儿童。在睡熟的情况下，抑制耳病原菌生长的预防安慰器要优于如此使易患耳炎的奶瓶。在本发明人的研究中，那些使用试验的安慰器的儿童比其他儿童更要减少夜晚使用奶瓶(Suhonen等人，1995)。
要测试产免疫牛奶的母牛的健康状况并且必须对其给予特殊的照料。干燥的免疫牛奶粉末也具有营养价值，因为其含有乳清蛋白，并且通常还含有一定量的用于稳定蛋白和增加口味的乳糖。通过水解可将乳糖再分解成半乳糖和葡萄糖，即更易被肠吸收并且增加产品甜味的糖。通过维持嗜酸性双歧杆菌菌群，乳糖增加婴儿的肠道健康(Korpela，1992)。但是更长时间使用时，牛奶的糖类会造成龋齿。
儿童易患龋齿取决于光滑的表面上的小孔底部或正在长出的牙的咬合的缝隙是否被生龋或非生龋微生物菌群所覆盖(Sranberg和Loesche，1997)。如果在菌群中建立起由糖产生酸和长链多糖的变异链球菌(MS)，就会形成生龋牙斑。MS阳性儿童的龋齿损伤的发生是一个多原因的过程，但被认为主要是与在口腔中长时间暴露给蔗糖有关(Gustafsson等人，1953，Aaltonen，1991，Grindefjord等人，1995a，b)。在长时间人乳哺育中乳钙和缓冲的磷酸盐类已减少时，还有诸如乳糖的其他糖类增加了龋齿的危险(Matee等人，1992)。由于宿主的抗性以及病原菌的毒力可能随着环境因素改变或与环境因素无关(Aaltonen，1989，1991，1992，Aaltonen和Tenoruo，1994)，在个体水平上不能预先知道一个幼小的婴儿是否是MS携带者，以及因此在长出乳牙时是否是龋齿患者。因此，根据本发明要从免疫乳制品除去生龋的糖类。另外一个工艺技术好的替代方案是要向产品中加入足够的防护剂以抑制变异链球菌的粘着，牙斑的增加，酸和其他毒力因子的产生。第三个变通方法是要转向重矿化剂(remineralizing agent)，其抑制龋齿病的损伤症状，牙的去矿质化。在这些药剂中，对氟化物的效果的了解已有半个多世纪了。
在本发明人的平行专利申请(PCT/FI 96/00...)中，本发明人提出了在一种用于抑制儿童中耳炎的预防方法中的一种新的用于递送如本发明的免疫乳制品的给药装置模型。不过也可将不同形式的此发明的产品加至给幼儿的不同食品中，以此获得还可以以其他不同于通过上述给药装置的方式经口向儿童给药的生物活性产物。在此上下文中，生物活性产物是指含对人体有益的有生物学效果的活性剂的产物。
对用于生产抗体的抗原的选择
通过一种将有效抗体缓慢释放到口中的给药装置，以小剂量达到了比较持久的对口腔和喉部微生物菌群的效果。因而重要的是所用抗体不干扰对口腔健康有重要性的正常菌群的发育。在口腔部区域，例如非生龋血链球菌和生龋的变异链球菌在牙齿表面集群中竞争，这是毫无疑问的，但是并不知道相关的肺炎链球菌(肺炎球菌属)的抗原结构会与类似每一种，由此为抑制耳病原链球菌的交叉反应抗体也会影响上述与龋齿有关的竞争情况。在使用产物前必须在体外检查交叉反应，并且虽然认为由几种抗原得到的组合产物对于临床应用是诱人的，应该选择一次仅针对一种病原菌种的抗体产物(可能有不同菌株)以利于以后的研究。只有在已研究了其效果时，才能将分类扩大。
由于在化学上已知免疫牛奶的安全性和容易生产，如果需要，可将免疫原全部组成成份更快地扩大并调整到例如针对已变得抗抗生素的细菌菌株。在这些医疗情况下，治疗以诊断为基础，待用的抗体应尽可能地专一，优选是单克隆地生产的。
在选择用于大规模的预防用途的抗原时，必须注意到与其他治疗方法相比可由新的治疗方法得到的益处。至于耳病原性肺炎球菌，预计一种已在芬兰试验的八价的缀合在蛋白质载体上的多糖抗原疫苗会在大的程度上消除由肺炎球菌引起的中耳炎的问题(Giebink，1994)。还有流感嗜血菌(非乙型)和粘膜炎布兰汉氏球菌，其更难治疗并且没有针对其的已知疫苗。其中，前者由于其生活习性而更了解。长期以来就已证明其也生活在口部区域，是5岁以下儿童经常发生的中耳炎的一个相当常见的原因。在那些易经常患中耳炎的儿童的喉部，即使在健康的时候显然也比在其他儿童的喉部更经常发现流感嗜血菌(Faden等人，1991)。由于关于耳病原体，文件最能证明流感嗜血菌的咽部载体与人乳中抗体之间的联系，将其作为免疫牛奶预防的头一个目标似乎是有道理的，因为未确切了解流感嗜血菌的免疫原性结构，预计最可靠的结果是通过使用杀死的全细胞疫苗。由于与中耳炎有关的非典型且通常无被膜的形式(非乙型)有相当大的变异，在免疫母牛时同时使用几种获得的菌株是值得的。目前在芬兰流行的纯培养菌株可从Oulu的国家公共卫生研究所获得，那里收集了在Tampere进行的以研究婴儿喉部是否携带了耳病原体的一类研究的样品材料(Docent Aino K.Takala，未发表资料)。
除针对流感嗜血菌的免疫之外，还值得用相应的抗粘膜炎布兰汉氏球菌的疫苗免疫奶牛。当然对耳最具致病性的肺炎链球菌菌株(尤其是6，14，19，23)至少在对比研究的意义上也是有实际意义的，尽管期望有一种有效的抗它们的不经肠疫苗。这种或其他已知的在蛋白质载体上缀合的多价疫苗对在母牛体内生产的免疫牛奶也可能是非常有效的。多糖-蛋白质缀合物中的长链碱性化合物是一种免疫佐剂。一种通过给药装置给药的预防使用的抗体可能是意想不到地有效，因为其会已在细菌细胞的浮游生物期在粘膜最外的表面的早期生物膜中起作用，在这里不经肠产生的血清抗体的作用不会达到任何显著的程度。疫苗的制备和使用
通过用已知的微生物学方法，生长所选择的用于制备疫苗(参照上文)的纯细菌菌株到培养物足够大。培养物被如通过于适宜的温度下温育直至该培养物被灭菌而杀死。几小时后从样品证实无菌。将杀死的细菌细胞洗涤，离心并冻干以贮存。
也可用甲醛水溶液来灭活。在这一过程中要考虑到上述细菌细胞壁薄度并用已知的实验技术来试图将菌毛等可能的抗原结构尽可能地保持完整。称取同样量的获自鼻咽部最常见的流感嗜血菌菌株(或粘膜炎布兰氏球菌)的干细胞粉末并混合以得到多价抗原。然后将干细胞混合到生理盐溶液中以形成浓缩的储备悬液。由此进行稀释直至达到某一与适于用于疫苗的细胞数目相当的光密度。将储备悬液分批冰冻保存。根据预先测定的稀释系数作最后的稀释，同时检验其无菌性。在免疫中用一些接受的佐剂(如氢氧化铝和磷酸盐，脂质体)来辅助。接种技术在兽医学中是已知的。在干燥季节于分娩前通过肌内注射适量抗原悬液来接种母牛数次。免疫后从血清取样。母牛对所用抗原的免疫可通过用例如ELISA方法并比较用安慰剂接种的母牛的结果测血清的特异抗体来确定。大量主要为IgG型的抗体被从血清输送到初乳中。免疫牛奶的收集和加工
在分娩后2-2天内收集头3-5次挤奶的初乳。从一头母牛最多获得50升初乳。一头牛犊一次饮大约3升，但其可饮用其他冰冻的初乳。用已经使用的乳品技术从初乳分离含免疫球蛋白的基于乳清的浓缩物。可将免疫牛奶消毒但会失去大约30％的抗体活性。通过借助于膜滤器(0.2μm)纯化免疫乳清并通过以微生物学实验证实母牛是健康的来保存抗体并达到足够高的卫生水平。乳清产品可被冻干成粉末。或者，如果采用低温，也可以采用喷雾干燥，由此也能保存抗体活性。可以用与从血清测定的相同方法来检测乳清粉末中含有的疫苗中所用抗原的抗体。与由安慰剂疫苗制备的相比，可以证明如本发明作用的免疫乳清产物中有水平显著升高的抗流感嗜血菌(非乙型)特异结构抗原和/或全细胞抗原，或者分别是抗粘膜炎布兰汉氏球菌全细胞抗原(如果已将其用作母牛的疫苗)的IgG抗体。流感嗜血菌的已知结构抗原特别是蛋白质“e”(FI专利申请914241)和蛋白质P6(Harabuchi等人，1994)。肺炎链球菌的被膜多糖抗原是已知的，例如为对肺炎链球菌专一的蛋白酶的肺炎球菌溶血素也可被用作识别抗原。免疫乳清粉末含有稳定蛋白质并有助于将粉末压成片剂形式的乳糖。可以除去乳糖并至少部分地用木糖醇代替乳糖。抗龋齿的保护作用
在本发明人的产品中可使用例如在下面详细研究的以下药剂或药剂组来抗龋齿：1.木糖醇(C5H12O6)
在自然界中几乎在所有水果中都发现有少量木糖醇，其为人类代谢的正常中间体(Touster，1960，Makinen，1978)。木糖醇不能产生细菌酸产物，因而其为一种止龋剂(Muhlemann等人，1970，Scheinin和Makinen，1975)。除已提及的止龋作用外，木糖醇在长时间且经常给药时还有十分明显的抑龋特性(Isokangas，1994)。已发现木糖醇特别是增加牙斑中的碱性氨基酸，精氨酸和赖氨酸的量。这使得口腔中引起龋齿的赖酸的和产酸的变异链球菌的繁盛更加困难(Makinen和Isokangas，1988，Soderling和Scheinin，1991)。木糖醇抑制生龋的变异链球菌的生长，削弱其他口腔微生物产酸的能力，并阻止胞外多糖和脂磷壁酸(lipoteichoic acid)的生物合成，属于生龋牙斑特征的形成。
通过使用一种缓释活性药剂的给药装置，可在睡着的儿童的口中正在长出的牙周围几小时内营造一种口腔液体环境，根据本发明人的研究，这种环境显然有止龋特性。在使用这一方法时，预计以相当小的剂量会最大限度增加木糖醇的有益特性而无轻泻的副作用。特别是对于幼儿来说，木糖醇和其他多羟基化合物的缺点是其从肠道吸收缓慢，由此的大剂量会导致渗透腹泻。2.氟化物
通常认为F离子不会影响变异链球菌(MS)在通常的环境条件下的繁殖(Kiltan等人，1979，Van Houte等人，1978，Zickert和Emilson，1982)。但是根据一种理论，氟化物至少在较高浓度时会通过减少附着的静电力来阻力细菌在牙齿表面附着(Rolla，1977a)。氟化物在牙齿上的止龋作用通常是和氟离子坚固牙齿和促进补充矿质作用相联系的。另外，氟化物离子破坏变异链球菌的碳水化合物代谢并因而减少牙斑中的酸的产生。(Hamilton，1997，Harper和Loseche，1986)。氟化物在免疫乳制品中作为龋齿保护剂的用途受到其过量的危险限制。根本就不将其推荐给那些年龄小于6个月的人，用于那些年龄为6-24个月的人的最大剂量为1片/天(也就是0.25mgF/天)，对于那些年龄为2-7岁的人是2片。现在幼儿中使用含氟牙膏已是常见的了，而儿童可能吞下相当大量的氟，以另一种产品形式给药额外的氟可能是禁忌的。在从夜晚维持的给药装置给药时，即使本发明含氟片剂的氟剂量的一部分也能和通过装置在正长出的牙的表面达到的长时间局部效果一样有效，该表面在未成熟时期易被MS繁殖脱矿质。3.单克隆龋齿抗体
以所知的杂交瘤和基因操作技术，原理上在被鉴定后可以产生MS的任何毒力因子的极专一的抗体，也许因此最有前途的抗龋抗体制剂是抗MS细胞壁的粘着蛋白抗原SAI/II的单克隆IgG1型抗体(Ma等人，1990)。通过用这种抗体治疗牙齿已成功地阻成人牙斑中MS的复发(Ma和Lehner，1990)。在芬兰西南部的牙齿还没有变异链球菌的幼儿血清样中的是相当大量的抗SA I/II抗原的IgG型抗体(Aaltonen，1989，Tenovuo等人，1990)。显然这些天然抗体能通过正在长出的牙齿表面的由牙龈渗出的血清液影响来限制免疫儿童感染MS。但是足够有效的天然免疫是罕见的。如果在半岁到两岁半时脱落的牙长出时通过上述给药装置将如本发明的产品中的所研究的特异抗体送入儿童口中，理论上这种被动疫苗即使在后来的时期当脱落的牙齿将被无变异的非生龋微生物群覆盖时也能抑制龋齿，其可能会被运输到永久牙齿上，在竞争中有优势，抑制由给药装置给药的MS的生物活性的特异性和非特异性蛋白质的甚至是后来的扩散，而该给药装置可能成为在正长出的牙齿的表面的上形成的且其组成对病原菌的繁殖有重要意义的糖蛋白表膜的结构部分(Gibbons，1984)。4.免疫牛奶的抗龋抗体
在本发明人的在Jokioinen农业研究中心初步研究中已生产出抗生龋的MS种变异链球菌(S，mutans)和表兄链球菌(S.sobinus)的免疫牛奶(初乳)(Loimaranta等人，1996)。在Turku大学的牙科系已体外检验免疫乳清产品抗-MS的效果(J.Tenovuo，未发表资料)。这以前已在动物和成人实验中证明相应的抗变异链球菌的效果(Michalek等人，1987，Filler等人，1991)。如果Turku的研究证实以往在国外获得的结果，那么用同样的芬兰人的方法获得的抗体作用用于如本发明的抗肺炎链球菌，抗流感嗜血菌和抗布兰汉氏球菌产品或其组合的止龋剂将是极合适的。但是，由于可期望的相加的抗龋和抗耳炎作用以及对蛋白质的稳定作用，向本发明人的组合产物加入木糖醇也会是合适的。非环状木糖醇通过与水分子竞争蛋白质的初级水化层来稳定蛋白质结构，并由此阻止变性。给药装置
本发明人已研制出一种新型的用于最优化给药如本发明的抗耳炎免疫乳制品的给药装置。这种装置已详细描述于本发明人的平行申请PCT/FI96/00...中。附图的简要描述：
图1示已免疫的抗流感嗜血菌(非乙型)的母牛初乳的抗体滴度(ELISA)。
图2示已免疫的抗肺炎链球菌的母牛初乳的抗体滴度(ELISA)牛免疫初乳制品
在Jokioinen农业研究中心，已用以甲醛水溶液杀死的被膜肺炎链球菌和无被膜(非乙型)流感嗜血菌全细胞抗原免疫怀孕母牛。在国家公共卫生研究所(Helena Kayhty)制备疫苗。母牛被相当充分地免疫(从血清样测定抗体)，在初乳中产生抗体，这由所发现的升高的抗体滴度证实。图1示以ELISA实验测定的用流感嗜血菌(非典型的：IH 57501，IH57522，IH57596，IH57602，IH57608)免疫的母牛(Hapero，Astma，Hunnari)初乳抗全细胞抗原的抗体滴度，图2分别示用肺炎链球菌(血清型4，IH31890，IH32026菌株)免疫的母牛(Esitys，Harmikki)初乳抗血清型特异性多糖抗原(ELISA)的抗体滴度。用作为对照的母牛(Iretta)仅接受氢氧化铝佐剂。
可从获得的初乳分离抗体，如通过由Loimaranta等人描述的方法(1996)。得到的抗体粉末可用作如本发明的产品的活性成份。
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Claims (9)
1.一种用于预防儿童中耳感染的免疫牛奶制剂，其特征在于该制剂含有引起中耳感染的一种或几种细菌的特异IgG型抗体。
2.如权利要求1的制剂，其特征在于该抗体已从免疫了的抗一种引起中耳感染的细菌的健康母牛的初乳中通过分离含免疫球蛋白的基于乳清的部分来生产。
3.如权利要求1或2的制剂，其特征在于其含有流感嗜血菌(非乙型)和/或肺炎链球菌和/或粘膜炎布兰汉氏(莫拉氏)球菌特异抗体。
4.如权利要求1-3中任一项的制剂，其特征在于其还含有牙龋抑制剂，其使得能长时间地向有牙儿童给药该制剂而没有增加的生龋的危险。
5.如权利要求4的制剂，其特征在于其含有生龋的变异链球菌和/或表兄链球菌的特异抗体。
6.如权利要求4或5的制剂，其特征在于用向目标区域缓释活性剂的安慰器型或口滤网型给药装置来向儿童长时间给药。
7.如权利要求1-6中任一项的制剂，其特征在于含有作为止龋剂、抑制中耳炎的增甜剂和蛋白质稳定剂的木糖醇。
8.一种生物活性产品，其特征在于其含有
-一种抗一种或多种引起中耳炎的细菌的特异抗体；和/或
-一种抗一种或多种引起龋牙的细菌的特异抗体，和
-一种防止牙或中耳的病原菌粘附，累积或繁殖的药剂。
9.如权利要求8的产品，其特征在于其为一种用于幼儿的儿童食品或基于牛奶的乳制品。
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-
1995
- 1995-11-09 FI FI955389A patent/FI955389A0/fi not_active Application Discontinuation
-
1996
- 1996-11-11 AU AU75734/96A patent/AU7573496A/en not_active Abandoned
- 1996-11-11 EP EP96938235A patent/EP0871484B9/en not_active Expired - Lifetime
- 1996-11-11 WO PCT/FI1996/000609 patent/WO1997017037A1/en not_active Application Discontinuation
- 1996-11-11 WO PCT/FI1996/000610 patent/WO1997017089A1/en active IP Right Grant
- 1996-11-11 BR BR9611462A patent/BR9611462A/pt not_active Application Discontinuation
- 1996-11-11 US US09/068,394 patent/US5993413A/en not_active Expired - Fee Related
- 1996-11-11 AU AU75733/96A patent/AU7573396A/en not_active Abandoned
- 1996-11-11 DE DE69627024T patent/DE69627024T2/de not_active Expired - Fee Related
- 1996-11-11 EP EP96938234A patent/EP0866676A1/en not_active Withdrawn
- 1996-11-11 AT AT96938235T patent/ATE235253T1/de not_active IP Right Cessation
- 1996-11-11 US US09/068,393 patent/US6143330A/en not_active Expired - Fee Related
- 1996-11-11 CN CNB961995076A patent/CN1229139C/zh not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294860A (zh) * | 2015-11-02 | 2016-02-03 | 张国强 | 一种抗龋齿菌抗体的制备方法及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69627024T2 (de) | 2004-01-08 |
| WO1997017089A1 (en) | 1997-05-15 |
| DE69627024D1 (de) | 2003-04-30 |
| EP0871484A1 (en) | 1998-10-21 |
| CN1229139C (zh) | 2005-11-30 |
| US6143330A (en) | 2000-11-07 |
| EP0866676A1 (en) | 1998-09-30 |
| EP0871484B1 (en) | 2003-03-26 |
| FI955389A0 (fi) | 1995-11-09 |
| AU7573396A (en) | 1997-05-29 |
| ATE235253T1 (de) | 2003-04-15 |
| EP0871484B9 (en) | 2004-01-02 |
| WO1997017037A1 (en) | 1997-05-15 |
| US5993413A (en) | 1999-11-30 |
| AU7573496A (en) | 1997-05-29 |
| BR9611462A (pt) | 1999-02-17 |
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