JP2006001849A - Vaccine for photobacterium infection of fishes - Google Patents

Vaccine for photobacterium infection of fishes Download PDF

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JP2006001849A
JP2006001849A JP2004177683A JP2004177683A JP2006001849A JP 2006001849 A JP2006001849 A JP 2006001849A JP 2004177683 A JP2004177683 A JP 2004177683A JP 2004177683 A JP2004177683 A JP 2004177683A JP 2006001849 A JP2006001849 A JP 2006001849A
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vaccine
fish
logarithmic growth
photobacterium
growth phase
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Shunichiro Oshima
俊一郎 大島
Arata Ogasawara
新 小笠原
Kenji Kawai
研兒 川合
Hiroyuki Ichinose
弘幸 一ノ瀬
Eiji Sasaki
英治 佐々木
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KAWASAKI MITAKA SEIYAKU KK
MATSUOKA INST FOR SCIENCE
MATSUOKA INSTITUTE FOR SCIENCE
Kyushu University NUC
Kochi University NUC
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KAWASAKI MITAKA SEIYAKU KK
MATSUOKA INST FOR SCIENCE
MATSUOKA INSTITUTE FOR SCIENCE
Kyushu University NUC
Kochi University NUC
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
    • Y02A40/80—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in fisheries management
    • Y02A40/81—Aquaculture, e.g. of fish

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Abstract

<P>PROBLEM TO BE SOLVED: To provide a vaccine for photobacterium infection of fishes and a prophylactic method for the photobacterium infection of the fishes using the vaccine. <P>SOLUTION: The vaccine for photobacterium infection of the fishes comprises an inactivated microbial cell in the logarithmic growth phase of Photobacterium damselae subsp. piscicida or its component as an active ingredient. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

本発明は魚類類結節症ワクチン及びこれを用いた魚類類結節症の予防法に関する。   The present invention relates to a fish nodule vaccine and a method for preventing fish nodule using the same.

類結節症は、ブリ、カンパチ、マダイ、ヒラメ等に春〜秋の比較的高水温期に発病する病気である。以前は、ブリ類にのみ発生が見られた疾病であったが、近年、養殖魚種拡大に伴い、感染魚種は広がりつつある。死亡率はほぼ１００％である。   An tuberculosis is a disease that occurs in spring, autumn, and relatively high water temperatures in yellowtail, amberjack, red sea bream, and Japanese flounder. In the past, it was a disease that only occurred in yellowtails, but recently, with the expansion of aquacultured fish species, infected fish species are spreading. The mortality rate is almost 100%.

類結節症の治療手段としては、アミノベンジルペニシリン、オキソリン酸、ホスホマイシン、ビコザマイシン、フロルフェニコール等の経口投与が行われているが、長期間の治療を必要とする為、経済的負担も大きく、一方で耐性菌出現も懸念される。   As a means of treating nodule, oral administration of aminobenzylpenicillin, oxophosphate, fosfomycin, bicozamycin, florfenicol, etc. is performed, but since long-term treatment is required, the economic burden is large, On the other hand, the emergence of resistant bacteria is also a concern.

類結節症の原因菌はフォトバクテリウム ダムセラ サブスピース ピシシ−ダ(Photobacterium damselae subsp.piscicida)であることが判明している。しかし日本では現在までこれに対するワクチンは販売されていない。なお、フォトバクテリウム ダムセラ サブスピース ピシシ−ダはパスツレラ ピシシーダと呼ばれることもある。   It has been found that the causative agent of nodose disease is Photobacterium damselae subsp. Piscicida. However, no vaccine for this has been sold in Japan. Photobacterium damsela subspice picicida is sometimes called Pasteurella picicida.

本発明の目的は魚類類結節症ワクチンを提供することにある。   An object of the present invention is to provide a fish nodule vaccine.

そこで発明者は類結節症の原因菌であるフォトバクテリウム ダムセラ サブスピース ピシシ−ダの各種培養条件による病原性及びワクチン活性について検討してきたところ、全く意外にも定常期の菌体よりも対数増殖期の菌体を用いた場合に特にワクチン活性が高いことを見出し、本発明を完成するに至った。   Therefore, the inventor has examined the pathogenicity and vaccine activity of Photobacterium damsella subspise picicida, which is the causative agent of nodule disease, under various culture conditions. The present inventors have found that the vaccine activity is particularly high when the bacterial cells are used, and have completed the present invention.

すなわち本発明は、フォトバクテリウム ダムセラ サブスピース ピシシ−ダの対数増殖期の不活化菌体又はその成分を有効成分とする魚類類結節症ワクチンを提供するものである。   That is, this invention provides the fish nodule vaccine which uses the inactivated microbial cell of the logarithmic growth phase of Photobacterium damcera subspice picicida, or its component as an active ingredient.

また本発明は、フォトバクテリウム ダムセラ サブスピース ピシシ−ダの対数増殖期の不活化菌体又はその成分を含有する魚類類結節症ワクチン組成物を提供するものである。   The present invention also provides a fish nodule vaccine composition containing inactivated cells or components thereof in the logarithmic growth phase of Photobacterium damsella subspice picicida.

さらに本発明は、フォトバクテリウム ダムセラ サブスピース ピシシ−ダの対数増殖期の不活化菌体又はその成分の有効量を投与することを特徴とする魚類類結節症の予防法を提供するものである。   Furthermore, the present invention provides a method for preventing fish nodules, characterized by administering an effective amount of an inactivated cell or its component in the logarithmic growth phase of Photobacterium damsella subspise picicida.

本発明のワクチンを用いれば、ブリ、カンパチ等のブリ属魚類、マダイ、ヒラメ等の類結節症が効率的に予防できる。   By using the vaccine of the present invention, it is possible to efficiently prevent tuberculosis fish such as yellowtail and amberjack, and nodules such as red sea bream and flounder.

本発明のワクチンは、フォトバクテリウム ダムセラ サブスピース ピシシ−ダ(以下本菌ということがある)の対数増殖期の不活化菌体又はその成分を用いる。通常、細菌を培養した場合、誘導期、対数増殖期、定常期、死滅期及び生残期に分けられる。   The vaccine of the present invention uses an inactivated cell or its component in the logarithmic growth phase of Photobacterium damsella subspise picicida (hereinafter sometimes referred to as the present bacterium). Usually, when bacteria are cultured, they are divided into an induction phase, a logarithmic growth phase, a stationary phase, a death phase, and a survival phase.

本発明のワクチンに用いる菌体は、本菌を常法により培養し、対数増殖期に採取することにより得られる。本菌の培養は、本菌を適当な培地に接種し常法に従って培養すればよい。培養中には、資化し得る炭素源及び窒素源を適当量含有させておくのが好ましい。   The microbial cells used in the vaccine of the present invention can be obtained by culturing the bacterium by a conventional method and collecting it in the logarithmic growth phase. The bacterium can be cultured by inoculating the bacterium into an appropriate medium and culturing according to a conventional method. It is preferable to add appropriate amounts of carbon sources and nitrogen sources that can be assimilated during the culture.

この炭素源及び窒素源については特に制限はないが、その例としては、窒素源としてトリプトン、各種動物血清、コーングルテンミール、大豆粉、コーンスチープリカー、カザミノ酸、酵母エキス、ファーマメディア、イワシミール、肉エキス、ペプトン、ハイプロ、アジパワー、コーンミール、ソイビーンミール、コーヒー粕、綿実油粕、カルチベータ、アミフレックス及びアジプロン、ゼスト、アジックスなどが挙げられる。また、炭素源としては資化し得る炭素源、例えば、アラビノース、キシロース、グルコース、マンノース、蔗糖、麦芽糖、可溶性デンプン、乳糖、廃糖蜜や資化し得る有機酸、例えば酢酸等が挙げられる。また、その他、リン酸、Mg2+、Ca2+、Mn2+、Co2+、Na+、K+等の無機塩や、必要であれば、無機、有機微量栄養源を培地中に適宜添加することもできる。
またNaCl濃度を2.0%に調製したBHI培地を用いることもできる。 There are no particular restrictions on the carbon source and nitrogen source. Examples of the nitrogen source include tryptone, various animal sera, corn gluten meal, soy flour, corn steep liquor, casamino acid, yeast extract, pharma media, and sardine meal. , Meat extract, peptone, hypro, adipower, corn meal, soy bean meal, coffee lees, cottonseed oil lees, cultivator, amiflex and adipron, zest, azix and the like. Examples of the carbon source include assimilable carbon sources such as arabinose, xylose, glucose, mannose, sucrose, maltose, soluble starch, lactose, molasses and assimilable organic acids such as acetic acid. In addition, other inorganic salts such as phosphate, Mg 2+ , Ca 2+ , Mn 2+ , Co 2+ , Na + , K + , and if necessary, inorganic and organic trace nutrients in the medium It can also be added.
A BHI medium prepared with a NaCl concentration of 2.0% can also be used.

培養条件は、NaCl濃度2.0％、pH7.2〜7.6、25℃とするのが好ましい。   The culture conditions are preferably a NaCl concentration of 2.0%, pH 7.2 to 7.6, and 25 ° C.

本菌が対数増殖期にあるか否かの確認は、595nmでの光学密度を測定することにより行われる。すなわち595nmでの光学密度が急激に上昇する時期が対数増殖期である。例えばpH7.2、25℃で培養した場合、培養12〜24時間が対数増殖期である。   Whether or not the bacterium is in the logarithmic growth phase is confirmed by measuring the optical density at 595 nm. That is, the time when the optical density at 595 nm suddenly increases is the logarithmic growth phase. For example, when cultured at pH 7.2 and 25 ° C., the culture period is 12 to 24 hours in the logarithmic growth phase.

対数増殖期にある本菌を遠心分離、濾過等により分離するか、培養物をそのまま不活化する。不活化処理としては加熱処理、ホルマリン処理等が挙げられる。   The bacteria in the logarithmic growth phase are separated by centrifugation, filtration, or the culture is inactivated as it is. Examples of the inactivation treatment include heat treatment and formalin treatment.

本菌の成分には、菌体の膜成分及び分泌物が含まれる。これらの成分を採取するには、不活化菌体の超音波破砕等により行うのが好ましい。   The components of this bacterium include membrane components and secretions of microbial cells. In order to collect these components, it is preferable to carry out ultrasonic disruption of inactivated cells.

得られた不活化菌体又はその成分は、濾過、エバポレーション、濃縮、凍結乾燥等により濃縮して用いるのが好ましい。   The obtained inactivated cells or components thereof are preferably used after being concentrated by filtration, evaporation, concentration, lyophilization or the like.

本菌の不活化菌体又はその成分は、そのままワクチンとして使用してもよいが、薬学的に許容される液状又は固体状の担体とともにワクチン組成物として使用してもよい。当該ワクチン組成物の形態としては注射用組成物、経口投与組成物、魚類浸漬用組成物、飼料組成物等が挙げられる。液状の担体としては、リン酸緩衝液が挙げられる。固体状の担体としては、タルク、シュークロースなどの賦形剤が挙げられる。飼料組成物とするには、通常の魚類の飼料に本菌の不活化菌体又はその成分を混合すればよい。また、これらのワクチン組成物にはアジュバントを添加して抗原性を高めてもよい。   The inactivated cells of this bacterium or its components may be used as a vaccine as it is, but may be used as a vaccine composition together with a pharmaceutically acceptable liquid or solid carrier. Examples of the form of the vaccine composition include injectable compositions, oral administration compositions, fish immersion compositions, feed compositions and the like. Examples of the liquid carrier include a phosphate buffer. Examples of the solid carrier include excipients such as talc and sucrose. In order to obtain a feed composition, inactivated cells of the present bacterium or components thereof may be mixed with normal fish feed. In addition, an adjuvant may be added to these vaccine compositions to enhance antigenicity.

本発明のワクチン又はワクチン組成物の投与は、成魚でもよいが類結節症に罹患する前、例えば稚魚の段階が好ましい。その投与量は、１尾あたり不活化菌又はその成分として約１０8〜１０10CFUが好ましい。投与回数は1回でもよいが、２回が好ましく、また、２回目の投与までの間隔は３週間以上あけてから接種したほうが良い。 Administration of the vaccine or vaccine composition of the present invention may be an adult fish, but is preferably performed at a stage of juvenile fish, for example, before suffering from nodose. The dose is preferably about 10 8 to 10 10 CFU as an inactivated bacterium or a component thereof per fish. The administration frequency may be 1 time, but 2 times are preferable, and it is better to inoculate after the interval of 3 weeks or more until the second administration.

本発明のワクチン又はワクチン組成物の対象魚種としては、本菌による類結節症になる魚類であれば制限されず、例えばブリ、カンパチ等のブリ属魚類の他、マダイ、ヒラメ等が挙げられる。   The target fish species of the vaccine or vaccine composition of the present invention is not limited as long as it is a fish that causes nodose due to this bacterium, and examples include yellowtail fish such as yellowtail, amberjack, red sea bream, flounder and the like. .

次に実施例を挙げて本発明をさらに詳細に説明するが、本発明は何らこれらに限定されるものではない。   EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these at all.

実施例１
(1) フォトバクテリウム ダムセラ サブスピース ピシシ−ダP3529(以下でもこの株を使用した。)の凍結保存した菌0.2mLを200mLの2％NaCl加BHI液体培地に接種し25℃で静置培養した。培養時間と菌体数及び595nmにおける光学密度(OD)との関係を図1に示す。図1から明らかなように、本菌は0〜12時間までが誘導期であり、12〜20時間までが対数増殖期であり、20時間以降が定常期であることがわかる。 Example 1
(1) 0.2 mL of a cryopreserved bacterium of Photobacterium damcera subspise Piscida P3529 (this strain was also used below) was inoculated into 200 mL of a 2% NaCl-added BHI liquid medium and statically cultured at 25 ° C. FIG. 1 shows the relationship between the culture time, the number of cells and the optical density (OD) at 595 nm. As is clear from FIG. 1, it can be seen that 0 to 12 hours is the induction phase, 12 to 20 hours is the logarithmic growth phase, and 20 hours and later is the stationary phase.

(2) 本菌の各種培養条件によるブリに対する病原性の差異について検討した。すなわち、対数増殖中期、対数増殖後期、定常期及び死滅期の本菌をブリ1尾あたり103〜105CFUとなるように腹腔内注射し、病原性を検討した。なお、対照としたブリは20〜24gであり、水槽の温度は25℃とした。その結果、図2、3、4及び5に示すように、生残率が、対数増殖中期の本菌感染群では25.0〜6.6％、対数増殖後期では13.3〜1.6％、定常期では53.3〜26.7％、死滅期では80.0〜43.3％であり、対数増殖後期の菌の病原性が高いことが判明した。 (2) The difference in pathogenicity against yellowtail caused by various culture conditions of this bacterium was examined. That is, the pathogenicity was examined by intraperitoneally injecting the bacteria at mid-logarithmic phase, late-logarithmic growth phase, stationary phase, and dead phase to 10 3 to 10 5 CFU per yellowtail. In addition, the yellowtail used as a control was 20 to 24 g, and the temperature of the water tank was 25 ° C. As a result, as shown in FIGS. 2, 3, 4 and 5, the survival rate was 25.0 to 6.6% in the group infected with this fungus in the mid-logarithmic growth phase, 13.3% to 1.6% in the late logarithmic growth phase, and 53.3 to 26.7 in the stationary phase. %, And 80.0 to 43.3% in the death period, and the pathogenicity of the bacteria in the late logarithmic growth stage was found to be high.

実施例２
フォトバクテリウム ダムセラ サブスピース ピシシ−ダP3529の0.2mLを三角フラスコ中で200mLの2%NaCl加BHI培地に接種し、25℃で培養した。OD595nmが0.85から0.95のものを対数増殖菌体として用いた。すなわち、培養19〜21時間の間の培養物を0.3％ホルマリン中で25℃、1日間インキュベーションして不活化菌体とし、次いで4℃で8,000〜10,000×ｇで遠心分離して菌体を採取した。得られた菌体をさらに0.3％ホルマリン生理食塩水に再懸濁し、本菌の不活化菌体を含むワクチン組成物を得た。また、対照として培養32時間後（OD595nm＝0.95）の培養物を同様に不活化して定常期不活化菌体を含むワクチン組成物を得た。 Example 2
0.2 mL of Photobacterium damcera subspice Piscida P3529 was inoculated into 200 mL of 2% NaCl-added BHI medium in an Erlenmeyer flask and cultured at 25 ° C. An OD595nm of 0.85 to 0.95 was used as a logarithmic growth cell. That is, the culture for 19 to 21 hours was incubated in 0.3% formalin at 25 ° C. for 1 day to inactivate cells, and then centrifuged at 4 ° C. at 8,000 to 10,000 × g to collect the cells. did. The obtained microbial cells were further resuspended in 0.3% formalin saline to obtain a vaccine composition containing inactivated microbial cells of the present bacterium. Further, as a control, the culture after 32 hours of culture (OD595nm = 0.95) was similarly inactivated to obtain a vaccine composition containing stationary phase inactivated cells.

平均体重23.6gのブリに、上記で得たワクチン組成物を用いてワクチン効果を検討した。すなわち、ワクチンを1尾あたり0.1mL腹腔内注射し、2週間免疫活性を上昇させる為に飼育した。
2週間後、これらの免疫したブリに対して腹腔内注射攻撃試験を行った。対照として等量のＰＢＳを腹腔内注射したブリを同様に試験に供試した。なお、攻撃菌には、対数増殖期及び定常期の菌体を用いた。その結果を表1、図6及び7に示す。 The vaccine effect was examined using the vaccine composition obtained above on yellowtail with an average weight of 23.6 g. That is, 0.1 mL of the vaccine was injected intraperitoneally per animal and reared for 2 weeks to increase immune activity.
Two weeks later, these immunized yellowtails were subjected to an intraperitoneal injection challenge test. As a control, yellowtails injected intraperitoneally with an equal volume of PBS were similarly tested. In addition, logarithmic growth phase and stationary phase cells were used as the attacking bacteria. The results are shown in Table 1 and FIGS.

Figure 2006001849
Figure 2006001849

その結果、対数増殖期群が定常期群及び対照群に対して生存率に有意差があり、ワクチンとして有用であることが判明した。   As a result, it was found that the logarithmic growth phase group had a significant difference in survival rate from the stationary phase group and the control group, and was useful as a vaccine.

本試験期間中に死亡魚について、2％NaCl加ＢＨＩ平板培地を用いて腎臓および脾臓より菌分離を行った。本菌による死亡か否かを分離菌と抗血清による凝集にて確認した結果、全ての死亡魚からの分離菌が抗血清と凝集した。このことから、本試験期間中に死亡した試験魚は、本菌感染を原因とするものであることが明らかになった。   During the test period, dead fish were isolated from the kidney and spleen using 2% NaCl-added BHI plate medium. As a result of confirming whether or not the death was caused by this bacterium by agglutination with the isolated bacterium and antiserum, the bacterium isolated from all dead fish aggregated with the antiserum. From this, it became clear that the test fish that died during the test period was caused by infection with the fungus.

本菌培養時間と595nmにおける光学密度(OD)及び菌数(CFU/mL)との関係を示す図である。It is a figure which shows the relationship between this microbe culture time, optical density (OD) in 595 nm, and the number of bacteria (CFU / mL). 本菌の対数増殖中期の菌体によるブリに対する病原性(生残率)を示す図である。It is a figure which shows the pathogenicity (survival rate) with respect to yellowtail by the bacterial body of the logarithmic growth middle stage of this microbe. 本菌の対数増殖後期の菌体によるブリに対する病原性(生残率)を示す図である。It is a figure which shows the pathogenicity (survival rate) with respect to yellowtail by the bacterial body of the logarithmic growth late stage of this microbe. 本菌の定常期の菌体によるブリに対する病原性(生残率)を示す図である。It is a figure which shows the pathogenicity (survival rate) with respect to yellowtail by the microbial cell of a stationary phase of this microbe. 本菌の死滅期の菌体によるブリに対する病原性(生残率)を示す図である。It is a figure which shows the pathogenicity (survival rate) with respect to yellowtail by the microbial cell of the dead time of this microbe. 攻撃1(攻撃量2.0×104CFU/mL)における生残率を示す図である。It is a figure which shows the survival rate in the attack 1 (attack amount 2.0 * 10 < 4 > CFU / mL). 攻撃2(攻撃量4.0×104CFU/mL)における生残率を示す図である。It is a figure which shows the survival rate in the attack 2 (attack amount 4.0 * 10 < 4 > CFU / mL).

Claims (3)

フォトバクテリウム ダムセラ サブスピース ピシシーダの対数増殖期の不活化菌体又はその成分を有効成分とする魚類類結節症ワクチン。   Photobacterium damsella subspice fish nodule vaccine containing inactivated cells in the logarithmic growth phase of Pissicida or its components as an active ingredient. フォトバクテリウム ダムセラ サブスピース ピシシーダの対数増殖期の不活化菌体又はその成分を含有する魚類類結節症ワクチン組成物。   A fish nodule vaccine composition containing inactivated cells or components thereof in the logarithmic growth phase of Photobacterium damsella subspise Pisicida. フォトバクテリウム ダムセラ サブスピース ピシシーダの対数増殖期の不活化菌体又はその成分の有効量を投与することを特徴とする魚類類結節症の予防法。

A method for preventing fish tuberculosis, comprising administering an effective amount of an inactivated cell or a component thereof in the logarithmic growth phase of Photobacterium damsella subspice Pisicida.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014033665A (en) * 2012-08-10 2014-02-24 Fisheries Research Agency Pathogen antigen polypeptide to bacterial hemolytic jaundice of seriola, and fisheries vaccine containing the same

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JP2003506412A (en) * 1999-08-07 2003-02-18 ノバルテイス・アクチエンゲゼルシヤフト vaccine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003506412A (en) * 1999-08-07 2003-02-18 ノバルテイス・アクチエンゲゼルシヤフト vaccine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014033665A (en) * 2012-08-10 2014-02-24 Fisheries Research Agency Pathogen antigen polypeptide to bacterial hemolytic jaundice of seriola, and fisheries vaccine containing the same

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