JP5426850B2 - Influenza vaccine adjuvant - Google Patents
Influenza vaccine adjuvant Download PDFInfo
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- JP5426850B2 JP5426850B2 JP2008210484A JP2008210484A JP5426850B2 JP 5426850 B2 JP5426850 B2 JP 5426850B2 JP 2008210484 A JP2008210484 A JP 2008210484A JP 2008210484 A JP2008210484 A JP 2008210484A JP 5426850 B2 JP5426850 B2 JP 5426850B2
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- Prior art keywords
- strain
- positive
- lactic acid
- influenza vaccine
- adjuvant
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- 239000000126 substance Substances 0.000 description 1
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Description
本発明は、インフルエンザワクチンのアジュバントに関する。アジュバントとは、薬剤の効果を増強する添加剤（助剤、免疫強化剤、免疫調整剤などとも呼ばれている）のことであり、本発明のアジュバントは、インフルエンザウイルスＰＲ８株などから調製されたインフルエンザワクチンの効果を増強する作用を有するものである。 The present invention relates to an influenza vaccine adjuvant. An adjuvant is an additive (also called an adjuvant, immune enhancer, immunomodulator, etc.) that enhances the effect of the drug, and the adjuvant of the present invention was prepared from influenza virus PR8 strain or the like It has the effect | action which strengthens the effect of an influenza vaccine.
インフルエンザウイルスＰＲ８株などから調製されたインフルエンザワクチンのアジュバントとして、種々の物質が知られている。例えば、コレラ毒素、ポリリボ（イノシン：シチジル）酸、キチン微粉末、貝殻微粉末などが、インフルエンザワクチンのアジュバントとして検討されている（非特許文献１〜５参照）。これらの他、多数の非特許文献に見られるように、インフルエンザワクチンのアジュバントとしての効能を試験する際には、インフルエンザウイルスＰＲ８株を代表株として用いられることが知られている。
Various substances are known as adjuvants for influenza vaccines prepared from influenza virus strain PR8 and the like. For example, cholera toxin, polyribo (inosine: cytidyl) acid, chitin fine powder, shell fine powder and the like have been studied as adjuvants for influenza vaccines (see Non-Patent
本発明の目的は、インフルエンザウイルスＰＲ８株などから調製されたインフルエンザワクチンの効果を増強する作用を有する、安全な天然由来の乳酸菌（植物性乳酸菌）を有効成分として含有するインフルエンザワクチンのアジュバントを提供することである。 An object of the present invention is to provide an adjuvant for influenza vaccine containing as an active ingredient a safe naturally-derived lactic acid bacterium (plant lactic acid bacterium) having an action of enhancing the effect of an influenza vaccine prepared from influenza virus PR8 strain or the like. That is.
本発明者らは、上記目的を達成すべく種々検討した結果、パン生地から分離したラクトバチルス・プランタラム（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｐｌａｎｔａｒｕｍ）に属する特定の乳酸菌を、インフルエンザウイルスＰＲ８株などから調製されたインフルエンザワクチンの投与前に継続的に摂取しておくことにより、インフルエンザワクチンの効果が増強することを見出し、本発明を完成するに至った。
すなわち、本発明は、ラクトバチルス・プランタラムＡＹＡ株を有効成分として含有し、インフルエンザワクチンの経口投与前に摂取される、インフルエンザワクチンのアジュバントを提供するものである。
ラクトバチルス・プランタラムＡＹＡ株は、パン生地から分離された株であり、オリエンタル酵母工業株式会社（東京都板橋区小豆沢３丁目６番１０号）により、２００６年１１月２９日付で独立行政法人産業技術総合研究所特許生物寄託センター（茨城県つくば市東１丁目１番地１中央第６）に、受託番号ＦＥＲＭ Ｐ−２１１０６として寄託されている。
なお、ラクトバチルス・プランタラムＡＹＡ株は、特開２００８−１７９５９５号公報に記載された乳酸菌であり、これを用いて麦を乳酸菌発酵させた産物を有効成分とする脂肪細胞分化促進剤も同公開公報に記載されている。さらに、ラクトバチルス・プランタラムＡＹＡ株は、特願２００７−３９０１９号に係る腸管免疫力増強剤の有効成分としても提案されているが、ラクトバチルス・プランタラムＡＹＡ株単体がインフルエンザワクチンのアジュバントとしての効能を持つことは、本発明者らによって初めて見い出されたことである。
As a result of various studies to achieve the above object, the present inventors administered a specific lactic acid bacterium belonging to Lactobacillus plantarum isolated from bread dough as an influenza vaccine prepared from influenza virus PR8 strain or the like. It has been found that the effect of influenza vaccine is enhanced by continuously ingesting before, and the present invention has been completed.
That is, the present invention provides an influenza vaccine adjuvant that contains the Lactobacillus plantarum AYA strain as an active ingredient and is taken before oral administration of the influenza vaccine.
Lactobacillus plantarum AYA strain is a strain isolated from bread dough, and is produced by Oriental Yeast Industry Co., Ltd. (3-6-10 Shodozawa, Itabashi-ku, Tokyo) as of November 29, 2006. Deposited at the Research Institute Patent Biological Deposit Center (1st, 1st East, 1st Street, Tsukuba City, Ibaraki Prefecture, 6th) as deposit number FERM P-21106.
The Lactobacillus plantarum AYA strain is a lactic acid bacterium described in Japanese Patent Application Laid-Open No. 2008-179595, and an adipocyte differentiation promoter containing a product obtained by fermenting wheat using lactic acid bacteria as an active ingredient is also disclosed. It is described in the publication. Furthermore, the Lactobacillus plantarum AYA strain has also been proposed as an active ingredient of the intestinal immunity enhancing agent according to Japanese Patent Application No. 2007-39019, but the Lactobacillus plantarum AYA strain alone is used as an adjuvant for influenza vaccines. It has been found for the first time by the present inventors to have efficacy.
本発明のインフルエンザワクチンのアジュバントは、インフルエンザウイルスＰＲ８株などから調製されたインフルエンザワクチンの投与前に継続的に摂取しておくことにより、インフルエンザワクチンの効果を増強する作用を有する。また、本発明のインフルエンザワクチンのアジュバントは、有効成分であるラクトバチルス・プランタラムＡＹＡ株が食経験のある天然食品素材から分離した乳酸菌であるので、安全性にも優れている。 The adjuvant of the influenza vaccine of this invention has the effect | action which strengthens the effect of an influenza vaccine by ingesting continuously before administration of the influenza vaccine prepared from influenza virus PR8 strain | stump | stock. Moreover, since the Lactobacillus plantarum AYA strain which is an active ingredient is an lactic acid bacterium isolated from a natural food material with experience, the adjuvant of the influenza vaccine of the present invention is excellent in safety.
乳酸菌ラクトバチルス・プランタラムＡＹＡ株の菌学的性質を下記に示す。
ＭＲＳ液体培地（ＤＩＦＣＯ社）を用いて、３０℃、１８時間培養したときの菌の形態（１）菌の形態 桿菌
（２）グラム染色 陽性
（３）運動性 なし
（４）胞子 なし
（５）カタラーゼ なし
（６）通性嫌気性
（７）ブドウ糖の代謝 ５０％以上乳酸に転換する
（８）生育温度範囲 １５℃、３０℃および３５℃では生育を認めるが、４５℃では生育を認めない
（９）乳酸発酵 ホモ型
（１０）乳酸の旋光性 ＤＬ
（１１）炭水化物の発酵性 グリセロールは陽性、Ｄ−アラビノースは陰性、Ｌ−アラビノースは陽性、リボースは陽性、Ｄ−キシロースは陰性、ガラクトースは陽性、グルコースは陽性、フルクトースは陽性、マンノースは陽性、ラムノースは陽性、マンニトールは陽性、ソルビトールは陽性、αメチルＤグルコシドは陰性、アミグダリンは陽性、エスクリンは陽性、サリシンは陽性、セロビオースは陽性、マルトースは陽性、ラクトースは陽性、メリビオースは陽性、シュクロースは陽性、トレハロースは陽性、イヌリンは陰性、メレジトースは陽性、ラフィノースは陽性、スターチは陰性、グルコン酸は陽性。
The mycological properties of the lactic acid bacterium Lactobacillus plantarum AYA are shown below.
Bacteria morphology when cultured for 18 hours at 30 ° C. using MRS liquid medium (DIFCO) (1) Bacteria morphology Bacilli (2) Gram staining Positive (3) Motility None (4) Spore None (5) Catalase None (6) Facultative anaerobic (7) Glucose metabolism Convert to 50% or more lactic acid (8) Growth temperature range Growth is observed at 15 ° C, 30 ° C and 35 ° C, but growth is not observed at 45 ° C ( 9) Lactic acid fermentation Homo type (10) Optical rotation of lactic acid DL
(11) Carbohydrate fermentability Glycerol is positive, D-arabinose is negative, L-arabinose is positive, ribose is positive, D-xylose is negative, galactose is positive, glucose is positive, fructose is positive, mannose is positive, rhamnose Is positive, mannitol is positive, sorbitol is positive, α-methyl D-glucoside is negative, amygdalin is positive, esculin is positive, salicin is positive, cellobiose is positive, maltose is positive, lactose is positive, melibiose is positive, sucrose is positive Positive for trehalose, negative for inulin, positive for melezitose, positive for raffinose, negative for starch, positive for gluconic acid.
乳酸菌ラクトバチルス・プランタラムＡＹＡ株は、食経験が豊富な素材（パン生地）から分離したものであるため、安全に利用することができる。 Since the lactic acid bacterium Lactobacillus plantarum AYA strain is separated from a material (bread dough) rich in food experience, it can be used safely.
乳酸菌ラクトバチルス・プランタラムＡＹＡ株は、そのままあるいは必要に応じて薬学的に許容される種々の担体、賦形剤、その他の添加剤、その他の成分を適宜配合して製剤化することによって、インフルエンザワクチンのアジュバントとすることができる。 The lactic acid bacterium Lactobacillus plantarum AYA strain can be used to prepare various pharmaceutically acceptable carriers, excipients, other additives, and other ingredients as they are or as necessary. It can be an adjuvant for a vaccine.
また、本発明のインフルエンザワクチンのアジュバントは、食品の形態、例えば、パン、菓子、クッキー、ケーキ、麺、粥、雑炊、シリアルバー、ドリンク、ヨーグルトなどの形態で提供することもできる。 Moreover, the adjuvant of the influenza vaccine of this invention can also be provided with the form of foodstuffs, for example, forms, such as bread, confectionery, a cookie, a cake, noodles, rice cakes, miscellaneous cooking, a cereal bar, a drink, and a yoghurt.
本発明のインフルエンザワクチンのアジュバント中の乳酸菌ラクトバチルス・プランタラムＡＹＡ株の含有量は、制限されるものではなく、使用形態、アジュバントの剤形や投与又は摂取する者の年齢性別などによって適宜変化させることができる。本発明のアジュバントを経口投与又は摂取させる場合には、１人１日当たりのラクトバチルス・プランタラムＡＹＡ株の投与量又は摂取量が１ｍｇ〜２０ｇとなるように、ラクトバチルス・プランタラムＡＹＡ株を本発明のアジュバント中に含有させることが好ましい。 The content of the lactic acid bacteria Lactobacillus plantarum AYA strain in the adjuvant of the influenza vaccine of the present invention is not limited, and is appropriately changed depending on the use form, the dosage form of the adjuvant, the age sex of the person who administers or ingests, etc. be able to. When the adjuvant of the present invention is orally administered or ingested, the Lactobacillus plantarum AYA strain is selected so that the dose or ingestion amount of Lactobacillus plantarum AYA per person per day is 1 mg to 20 g. It is preferably contained in the adjuvant of the invention.
本発明のインフルエンザワクチンのアジュバントは、インフルエンザウイルスＰＲ８株などから調製されたインフルエンザワクチンの投与前に継続的に摂取しておくことが好ましく、インフルエンザワクチンの投与の少なくとも７日前から継続的に摂取しておくことがより好ましい。 The adjuvant of the influenza vaccine of the present invention is preferably taken continuously before the administration of an influenza vaccine prepared from influenza virus PR8 strain or the like, and is taken continuously from at least 7 days before the administration of the influenza vaccine. More preferably.
次に本発明をさらに具体的に説明するために実施例を挙げるが、本発明は、以下の実施例に制限されるものではない。 EXAMPLES Next, examples are given to describe the present invention more specifically, but the present invention is not limited to the following examples.
実施例１
（乳酸菌試料の調製）
ラクトバチルス・プランタラムＡＹＡ株を、１０μｇ／ｍｌシクロヘキシミドを含むＭＲＳ（ｄｅ Ｍａｎ−Ｒｏｇｏｓａ−Ｓｈａｒｐｅ）培地を用いて３７℃で４８時間培養した。その後、遠心分離によって集菌し、滅菌水で３回洗浄した後、滅菌水に懸濁し、１２１℃で３０分間オートクレーブ処理し、これを凍結乾燥して乳酸菌試料を得た。
Example 1
(Preparation of lactic acid bacteria sample)
The Lactobacillus plantarum AYA strain was cultured at 37 ° C. for 48 hours using MRS (de Man-Rogosa-Sharpe) medium containing 10 μg / ml cycloheximide. Thereafter, the cells were collected by centrifugation, washed three times with sterilized water, suspended in sterilized water, autoclaved at 121 ° C. for 30 minutes, and freeze-dried to obtain lactic acid bacteria samples.
ＢＡＬＢ／ｃマウス（各群４匹）に餌を７２日間投与した後、インフルエンザウイルスＰＲ８株をフォルムアミドで不活化したワクチン（１５０μｇ／２００μｌ ０．２Ｍ ＮａＨＣＯ3）を経口投与した。餌として、対照群にはＡＩＮ−９３Ｇ（カゼイン２０質量％、Ｌ-シスチン０．３質量％、コーンスターチ３９．７４８６質量％、α化コーンスターチ１３．２質量％、シュークロース１０質量％、大豆油７質量％、セルロースパウダー５質量％、ＡＩＮ−９３Ｇミネラル混合３．５質量％、ＡＩＮ−９３Ｇビタミン混合１質量％、重酒石酸コリン０．２５質量％、第三ブチルヒドロキノン０．００１４質量％）をペレット化し、γ線滅菌したものを投与し、乳酸菌試料投与群にはＡＩＮ−９３Ｇに上記乳酸菌試料を５質量％含有させたものをペレット化し、γ線滅菌したものを投与した。ワクチン投与後５９日目にインフルエンザウイルスＰＲ８株２０ＬＤ５０（８４０００ＴＣＩＤ５０／２０μｌ）をＢＡＬＢ／ｃマウスに経鼻感染させ、その３日目に解剖し、小腸を切除し、大腸側（回腸側）の洗浄液中のＰＲ８特異的ＩｇＡ濃度をＥＬＩＳＡ法により測定した。
その結果、図１に示すように、乳酸菌試料投与群の回腸側のＰＲ８特異的ＩｇＡ濃度は、対照群に比べて有意（危険率５％）に上昇していた。
BALB / c mice (4 mice in each group) were fed with food for 72 days, and were orally administered with a vaccine in which the influenza virus PR8 strain was inactivated with formamide (150 μg / 200 μl 0.2 M NaHCO 3 ). As a bait, the control group contained AIN-93G (casein 20 mass%, L-cystine 0.3 mass%, corn starch 39.7486 mass%, pregelatinized corn starch 13.2 mass%,
As a result, as shown in FIG. 1, the PR8-specific IgA concentration on the ileum side in the lactic acid bacteria sample administration group was significantly increased (risk rate 5%) as compared with the control group.
実施例２
ＢＡＬＢ／ｃマウス（各群６匹）に餌を４２日間投与した後、インフルエンザウイルスＰＲ８株をフォルムアミドで不活化したワクチン（１５０μｇ／２００μｌ ０．２Ｍ ＮａＨＣＯ3）を経口投与した。餌として、対照群にはＡＩＮ９７をペレット化し、γ線滅菌したものを投与し、乳酸菌試料投与群にはＡＩＮ９７に上記乳酸菌試料を５質量％含有させたものをペレット化し、γ線滅菌したものを投与した。ワクチン投与後１４日目にインフルエンザウイルスＰＲ８株２０ＬＤ５０（８４０００ＴＣＩＤ５０／２０μｌ）をＢＡＬＢ／ｃマウスに経鼻感染させ、その３日目に解剖し、小腸を切除し、大腸側（回腸側）の洗浄液中のＰＲ８特異的ＩｇＡ濃度をＥＬＩＳＡ法により測定した。
その結果、図２に示すように、乳酸菌試料投与群の回腸側のＰＲ８特異的ＩｇＡ濃度は、対照群に比べて有意に上昇していた。
Example 2
BALB / c mice (6 mice in each group) were fed with food for 42 days and then orally administered with a vaccine in which the influenza virus PR8 strain was inactivated with formamide (150 μg / 200 μl 0.2 M NaHCO 3 ). As the bait, the control group was pelleted with AIN97 and sterilized with γ-rays, and the lactic acid bacteria sample-administered group was pelleted with AIN97 containing 5% by mass of the lactic acid bacteria sample and sterilized with γ-rays. Administered. On day 14 after vaccine administration, influenza virus PR8 strain 20LD50 (84000TCID50 / 20 μl) was infected nasally in BALB / c mice, dissected on day 3, excised the small intestine, and in the large intestine side (ileal side) lavage fluid The PR8-specific IgA concentration was measured by ELISA.
As a result, as shown in FIG. 2, the PR8-specific IgA concentration on the ileum side in the lactic acid bacteria sample administration group was significantly higher than that in the control group.
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