WO2008074783A1 - Stimulant immunitaire contre des bactéries pathogènes de poissons - Google Patents

Stimulant immunitaire contre des bactéries pathogènes de poissons Download PDF

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Publication number
WO2008074783A1
WO2008074783A1 PCT/EP2007/064082 EP2007064082W WO2008074783A1 WO 2008074783 A1 WO2008074783 A1 WO 2008074783A1 EP 2007064082 W EP2007064082 W EP 2007064082W WO 2008074783 A1 WO2008074783 A1 WO 2008074783A1
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fish
bacterium
challenge
use according
nocardial
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PCT/EP2007/064082
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English (en)
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Luc Grisez
Laura Labrie
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Intervet International B.V.
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Publication of WO2008074783A1 publication Critical patent/WO2008074783A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/0208—Specific bacteria not otherwise provided for
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/522—Bacterial cells; Fungal cells; Protozoal cells avirulent or attenuated

Definitions

  • the present invention relates to the use of a bacterium of the genus Nocardia for the manufacture of a vaccine for combating non-Nocardial bacterial infection in fish.
  • Bacteria found to be pathogenic to fish belong i.a. to the genus Vibrio, Photobacterium damselae, Tenacibaculum, Flavobacterium, Flexibacter, Cytophaga, Streptococcus, Lactococcus or Edwardsiella.
  • bacteria of the genus Nocardia are capable of providing a significant level of protection against non-Nocardial fish-pathogenic Gram-negative bacteria in fish.
  • immersion vaccine comprises Nocardia in an inactivated form.
  • immersion vaccination with inactivated bacteria is significantly less effective compared to immersion vaccination with live attenuated bacteria.
  • Nocardia as an adjuvant, i.e. as a general but non-specific stimulator of the immune system as such have been described in the art, i.a. NL 7306964, DT 2713-680, BE- 861-782.
  • this has only be described in mammals. In fish, this phenomenon has to our knowledge never been described, most likely because the immune system of mammals and fish are very different systems.
  • Nocardial components are merely another form of the classical adjuvant.
  • the Nocardial components could be expected to improve the immune response to the vaccine.
  • the Nocardial components could of course not be expected to protect against the bacterial disease in the absence of the vaccine, i.e. to replace the vaccine.
  • the invention relates to the use of a bacterium of the genus Nocardia for the manufacture of a vaccine for combating non-Nocardial Gram-negative bacterial infection in fish.
  • the status of the bacterium; live or inactivated is not really important. What is important is the fact that the stimulator of cross-specific immunity in fish against non-Nocardial fish-pathogenic bacteria is still present. This can be assured by using whole bacterial preparations. As said above, it is not important if the bacterium in the preparation is alive, killed or even fragmented (e.g. by pressing it through a French Press).
  • Live attenuated bacteria are very suitable, because they by definition carry the factor stimulating the cross-specific immunity against non-Nocardial fish-pathogenic bacteria. And live attenuated bacteria have the advantage over bacterins, that they can easily be given without an adjuvant. Moreover they self-replicate to a certain extent until they are stopped by the immune system, as a result of which a lower number of cells can be given. Therefore, in a preferred form, the invention relates to the use of a bacterium of the genus Nocardia according to the invention wherein the Nocardia is a live attenuated Nocardia bacterium.
  • the factor stimulating the cross-specific immunity against non-Nocardial fish-pathogenic bacteria is also present on bacteria when these bacteria are in the form of a bacterin.
  • Bacterins have the advantage over live attenuated bacteria that they are very safe. Therefore, in an equally preferred form, the invention relates to the use of a bacterium of the genus Nocardia according to the invention wherein the Nocardia is in the form of a bacterin.
  • Nocardia There are several species of the genus Nocardia known in the art, e.g.: N. asteroides, N salmonicida, N. crassostreae, N. brasiliensis, N. rhodocrans, N. opaca, N. rubra and N. seriolae (formerly known as N. kampach ⁇ ).
  • the Nocardia species for use according to the invention is Nocardia seriolae.
  • the vaccine is manufactured for combating non-Nocardial bacterial infection in fish wherein the bacterium causing said non-Nocardial bacterial infection is a bacterium causing Big Belly syndrome or a fish-pathogenic bacterium of the genus Vibrio, Photobacterium damselae, Tenacibaculum, Flavobacterium, Flexibacter or Edwardsiella.
  • the vaccine is manufactured for combating non-Nocardial bacterial infection in fish wherein the bacterium causing said non-Nocardial bacterial infection is a bacterium causing Big Belly syndrome, Vibrio anguillarum, Photobacterium damselae subspecies piscicida, Tenacibaculum maritimum, Flavobacterium columnare, Flexibacter maritimus, Edwardsiella tarda or Edwardsiella ictaluri.
  • the vaccine is manufactured for combating non-Nocardial bacterial infection in fish wherein the bacterium causing said non-Nocardial bacterial infection is a bacterium causing Big Belly syndrome or Flavobacterium columnare.
  • Vaccines manufactured according to the invention can be prepared starting from a bacterial culture according to techniques well known to the skilled practitioner.
  • a live attenuated bacterium is a bacterium that is less pathogenic than its wild-type counterpart, while nevertheless inducing an efficacious immune response. Attenuated strains can be obtained along classical routes, long known in the art such as chemical mutagenesis, UV-radiation and the like, or by site-directed mutagenesis.
  • a bacterin is defined here as bacteria in an inactivated form.
  • the method used for inactivation appears to be not relevant for the activity of the bacterin.
  • Classical methods for inactivation such as heat-treatment, treatment with formalin, binary ethylene imine, thimerosal and the like, all well-known in the art, are equally applicable.
  • Inactivation of bacteria by means of physical stress using e.g. a French Press provides an equally suitable starting material for the manufacturing of a vaccine according to the invention.
  • Vaccines manufactured according to the invention basically comprise an effective amount of a bacterium for use according to the invention and a pharmaceutically acceptable carrier.
  • the term "effective” as used herein is defined as the amount sufficient to induce an immune response in the target fish.
  • the amount of Nocardia cells administered will depend on the route of administration, the presence of an adjuvant and the moment of administration.
  • vaccines manufactured according to the invention that are based upon bacterins can be administered by injection in general in a dosage of 10 3 to 10 10 , preferably 10 6 to 10 9 , more preferably between 10 8 and 10 9 bacteria.
  • a dose exceeding 10 10 bacteria, although immunologically suitable, will be less attractive for commercial reasons.
  • the examples below will provide ample guidance.
  • Vaccines according to the invention that are based upon live attenuated bacteria can be given in a lower dose, due to the fact that the bacteria will continue replicating for a certain time after administration.
  • pharmaceutically acceptable carriers that are suitable for use in a vaccine for use according to the invention are sterile water, saline, aqueous buffers such as PBS and the like.
  • a vaccine according to the invention may comprise other additives such as adjuvants, stabilisers, anti-oxidants and others, as described below.
  • Vaccines for use according to the present invention may in a preferred presentation also contain an immunostimulatory substance, a so-called adjuvant.
  • adjuvants in general comprise substances that boost the immune response of the host in a non-specific manner. A number of different adjuvants are known in the art.
  • the vaccine may also comprise a so-called "vehicle".
  • a vehicle is a compound to which the bacterium adheres, without being covalently bound to it. Such vehicles are i.a. bio- microcapsules, micro-alginates, liposomes and macrosols, all known in the art.
  • the vaccine may comprise one or more suitable surface-active compounds or emulsifiers, e.g. Span or Tween.
  • Oil adjuvants suitable for use in water-in-oil emulsions are e.g. mineral oils or metabolisable oils.
  • Mineral oils are e.g. Bayol ® , Marcol ® and Drakeol ® .
  • An example of a non-mineral oil adjuvants is e.g. Montanide-ISA-763-A.
  • Metabolisable oils are e.g. vegetable oils, such as peanut oil and soybean oil, animal oils such as the fish oils squalane and squalene, and tocopherol and its derivatives.
  • Suitable adjuvants are e.g. w/o emulsions, o/w emulsions and w/o/w double- emulsions
  • An example of a water-based nano-particle adjuvant is e.g. Montanide-IMS-2212.
  • the vaccine is mixed with stabilisers, e.g. to protect degradation-prone proteins from being degraded, to enhance the she If- life of the vaccine, or to improve freeze-drying efficiency.
  • Useful stabilisers are i.a. SPGA (Bovarnik et al; J. Bacteriology 59: 509 (1950)), carbohydrates e.g. sorbitol, mannitol, trehalose, starch, sucrose, dextran or glucose, proteins such as albumin or casein or degradation products thereof, and buffers, such as alkali metal phosphates.
  • the vaccine may be suspended in a physiologically acceptable diluent. It goes without saying, that other ways of adjuvating, adding vehicle compounds or diluents, emulsifying or stabilizing a protein are also embodied in the present invention.
  • Nocardia vaccine for use according to the invention are preferably administered to the fish via injection, immersion, dipping or per oral.
  • the Nocardia bacterium now used for the manufacture of a vaccine for combating non-Nocardial bacterial infection in fish is e.g. a live attenuated bacterium
  • the vaccine could i.a. be administered by immersion or bath vaccination, due to the ease of administration.
  • Such vaccines are often applied by immersion vaccination.
  • Nocardial bacterium now used for the manufacture of a vaccine for combating non-Nocardial bacterial infection in fish is in the form of a bacterin
  • oral application and e.g. intraperitoneal application are attractive ways of administration.
  • intraperitoneal application the presence of an adjuvant would be preferred.
  • the way of administration would preferably be the intraperitoneal route.
  • intraperitoneal vaccination with a bacterin is a very effective route of vaccination, especially because it allows the incorporation of adjuvants.
  • This route of administration is preferred for its ease of administration of the vaccine.
  • the administration protocol can be optimized in accordance with standard vaccination practice. The skilled artisan would know how to do this, or he would find guidance in the papers mentioned above.
  • the age of the fish to be vaccinated is not critical, although clearly one would want to vaccinate against the non-Nocardial fish-pathogenic bacteria in as early a stage as possible, i.e. prior to possible exposure to the pathogen.
  • Immersion vaccination would be the vaccination of choice especially when fish are still small, e.g. between 2 and 5 grams. Fish from 5 grams and up can, if necessary or desired, also be vaccinated by means of injection.
  • the vaccine is preferably mixed with a suitable carrier for oral administration i.e. cellulose, food or a metabolisable substance such as alpha-cellulose or different oils of vegetable or animals origin.
  • a suitable carrier for oral administration i.e. cellulose, food or a metabolisable substance such as alpha-cellulose or different oils of vegetable or animals origin.
  • an attractive method is administration of the vaccine to high concentrations of live-feed organisms, followed by feeding the live-feed organisms to the fish.
  • Particularly preferred food carriers for oral delivery of the vaccine according to the invention are live-feed organisms which are able to encapsulate the vaccine.
  • the Nocardia bacterium for use according to the invention is of the species seriolae.
  • Nocardia bacteria and at least one non-Nocardial fish-pathogenic bacterium for the manufacture of the vaccine would have the benefit that the specific protection that builds up against said non-Nocardial fish-pathogenic bacterium, lasts longer.
  • Nocardia bacteria and at least one fish-pathogenic virus for the manufacture of the vaccine would have the benefit that protection is obtained against both bacterial infection and infection with said fish-pathogenic virus.
  • a preferred form of this embodiment relates to the use of Nocardia bacteria and at least one non-Nocardial fish-pathogenic microorganism or a fish-pathogenic virus, an antigen of such microorganism or virus or genetic material encoding such an antigen, for the manufacture of the vaccine.
  • Examples of commercially important fish pathogens in tropical and/or Mediterranean fish are Vibrio anguillarum, Photobacterium damselae subspecies piscicida, Tenacibaculum maritimum, Flavobacterium sp., Flexibacter sp., Lactococcus garviae, Edwardsiella tarda, E. ictaluri, Streptococcus iniae, Streptococcus difficile, Streptococcus agalactiae, Streptococcus dysgalactiae, Viral Haemorrhagic Septicaemia virus, Viral Necrosis virus, iridovirus and Koi Herpesvirus.
  • the other microorganism or virus is selected from the following group of fish pathogens: Vibrio anguillarum, Photobacterium damselae subspecies piscicida, Tenacibaculum maritimum, Flavobacterium sp., Flexibacter sp., Lactococcus garviae, Edwardsiella tarda, E.
  • Big Belly infection also referred to as BB infection, and see reference above
  • Big Belly infection caused by the species tested is one of the major infections in juvenile Asian sea bass farming. Outbreaks of BB- disease occur predominantly at early stages of the culture process.
  • a culture of BB-bacteria grown on Chocolate agar and harvested in tryptone/yeast broth was inactivated with 0.5% formalin and the OD 6 6o was measured to be 0.5. No total cell count or other means of quantifying the cells was performed mainly because of the strongly pleomorphic nature of the cells in question.
  • the N. seriolae antigen used is derived from a field strain of N. seriolae.
  • the antigen concentration of the N. seriolae antigen was determined as follows:
  • Antigen Concentration (((OD 660 ).! + (OD 660 ).2)/2)-0.2118)/0.0018 * DF * 10 6 wherein (OD 6 6o)- 1 + (OD 6 6o)-2 are different batches of the same N. seriolae bacteria, and DF is the dilution factor.
  • the antigenic strength of this batch was 9.1 x 10 8 ODU/ml.
  • the N. seriolae is further also referred to as the Immune Stimulant (IS).
  • the BB-culture and the Nocardia-cx ⁇ ture are termed "antigen" in the following.
  • Asian sea bass (Lates calcarifer) having an average weight at the start of the experiment of 0.5 g.
  • the fish were kept in full strength sea water of 26 ⁇ 2°C with a density of maximum 20 kg/m fish tank volume.
  • the fish were starved for 24 h prior to vaccination. Groups of 110 fish were caught and transferred to the respective treatments. The treatments given, the tank allocation and designation of treatments is given in Table 1. Both antigen solutions were diluted approximately 10 and 100 fold for the BB-antigen and Nocardia respectively.
  • RPS ⁇ 1 - ( ) ⁇ x 100 I % mortality in controls J Mortality after challenge
  • the sequential graphs unambiguously show a clear relation between challenge dose and occurrence of first mortality.
  • the higher doses applied yield 100% mortality whereas in the lower doses, at least in some groups some fish survive the challenge.
  • a third observation from these graphs is that in most cases the BB-immersed group displays the highest peak mortality and this peak occurs in general earlier in the BB-group then in the other groups. All dead fish clearly displayed typical Big Belly disease signs and the occurrence of BB-bacteria was apparent in all fish sampled.
  • Example 2 "Columnaris disease” caused by F. columnare is a major diseases causing mortality in most cultured freshwater fish species. Tilapia is a highly susceptible species and was used as the target species in this Example.
  • non-specific immune stimulator also referred to as the immune stimulant
  • formalin inactivated whole cell fermentor produced N. seriolae at 9x10 8 ODU/ml was used. Challenge strains
  • Table 2 Immune stimulant concentration, number of fish used, application time and distribution after immune stimulation.
  • a total of 240 fish were selected as they came at hand.
  • the F. columnare USA strain was reactivated by using 1 vial (ImI) of a ⁇ -50°C stock culture. 0.5ml of the vial was collected and a ten fold dilution was made in distilled water. 1% was inoculated into 100ml Cytophaga broth. The broth was incubated at 26°C for 22h. When an OD 6 6o of 0.433 was obtained the culture was used to inoculate a larger volume of Cytophaga broth. The inoculum size was 1% of the culture volume. Cultures were incubated at 26°C for app. 17h, aeration was provided using a stirrer bar. An OD 6 6o of 0.405 was obtained and the culture was used for challenge. The number of colony forming units in the challenge culture was determined by standard spread plating of 100 ⁇ l aliquots of ten- fold diluted bacterial suspensions on Cytophaga agar and subsequent incubation at 26°C for 24-48 hours.
  • the F. columnare Asian strain was reactivated by streaking a portion of a ⁇ -50°C stock culture on Cytophaga agar. Plates were incubated at 26 0 C for app. 24h. Growth was collected in DIH 2 O until an OD 6 6o of app. 0.18-0.20 was reached. The collected growth was subsequently diluted 10 fold in distilled water and inoculated into modified Cytophaga broth containing trace elements. The inoculum size was 1% of the culture volume. The broth was incubated at 26°C for 16-2Oh. Aeration was provided using a stirrer bar. An OD 6 6o of approximately 0.350-0.395 was obtained. The number of colony forming units in the challenge culture was determined by standard spread plating of 100 ⁇ l aliquots of ten- fold diluted bacterial suspensions on Cytophaga agar and subsequent incubation at 26°C for 24-48 hours.
  • Challenge was performed by immersion with both challenge strains at day 6 and day 1 post immune-stimulation.
  • 40 fish from each treated group were collected and divided into 2 groups of 20 fish each. These fish were either immersion challenged for 15 min (USA strain) or 30 min (Asian strain). There were 2 treated groups and one control group and therefore a total of 3x20 fish were used for immersion challenge with each challenge strain.
  • the challenge suspension was 5L and 2L for USA strain and Asian strain respectively.
  • the challenge was performed by transferring the fish from the treatment room to the challenge containers. After challenge, fish were transferred into the challenge tanks. An overview of the distribution of the different challenge groups is indicated in table 3.
  • Table 3 Distribution of different challenge groups after challenge.
  • External examination consisted of the indication of the presence of gill and/or skin lesions on a special recording sheet. From a representative number of fish the gill/skin lesions were sampled for bacteriological analysis and plated on Cytophaga agar. Plates were incubated for 24h-48h at 26°C and evaluated for the presence of typical F. columnare growth (flat, rhizoid, swarming, adherent, and yellow). It was concluded that the observed mortality was caused by F. columnare when typical gill/skin lesions were observed and/or this organism was re- isolated from the lesion.
  • Efficacy of the immune stimulation was expressed as relative percent survival. The formula stated below was used.
  • the concentrations of the challenge cultures used for preparation of the challenge baths as well as the effective challenge concentrations used for wk3, wk 3 repeat and wk 4 challenges are given in table 4. All challenge suspensions were pure when used.
  • Table 4 CFU determinations for challenge cultures and challenge baths used.
  • Figure 1 Daily mortality per vaccine condition over time after BB challenge performed 3 weeks post stimulation using different challenge doses.
  • BB vax Big Belly vaccinated
  • Immuno-S N. seriolae immune stimulated
  • FIG. 1 RPS values per treatment condition as compared to the controls for each BB challenge concentration.
  • Vacc Big Belly vaccinated.
  • IS N. seriolae immune stimulated

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Abstract

La présente invention porte sur l'utilisation d'une bactérie du genre Nocardia pour la fabrication d'un vaccin pour combattre une infection bactérienne non-nocardienne dans les poissons.
PCT/EP2007/064082 2006-12-18 2007-12-17 Stimulant immunitaire contre des bactéries pathogènes de poissons WO2008074783A1 (fr)

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EP06126409 2006-12-18

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080767A1 (fr) * 2007-12-21 2009-07-02 Intervet International B.V. Vaccin pour poisson
CN111304131A (zh) * 2020-03-17 2020-06-19 中国水产科学研究院黄海水产研究所 强致病力的美人鱼发光杆菌美人鱼亚种菌株及应用
CN113648407A (zh) * 2021-08-20 2021-11-16 广东渔跃生物技术有限公司 一种诺卡氏菌免疫增强剂在鱼用疫苗中的应用
WO2022121109A1 (fr) * 2020-12-07 2022-06-16 广东海洋大学 Nocardia seriolae atténué, procédé de fabrication et son application

Citations (1)

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Publication number Priority date Publication date Assignee Title
US3876779A (en) * 1972-05-19 1975-04-08 Carter Wallace Agents effective as non-specific stimulants for antitumoral immunity derived from micro-organisms of the mycobacteria type and methods for their manufacture

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US3876779A (en) * 1972-05-19 1975-04-08 Carter Wallace Agents effective as non-specific stimulants for antitumoral immunity derived from micro-organisms of the mycobacteria type and methods for their manufacture

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Title
ANDERSON D P: "IMMUNOSTIMULANTS, ADJUVANTS, AND VACCINE CARRIERS IN FISH: APPLICATIONS TO AQUACULTURE", ANNUAL REVIEW OF FISH DISEASES, vol. 2, 1992, pages 281 - 307, XP008038231, ISSN: 0959-8030 *
ITANO TOMOKAZU ET AL: "Live vaccine trials against nocardiosis in yellowtail Seriola quinqueradiata", AQUACULTURE, vol. 261, no. 4, December 2006 (2006-12-01), pages 1175 - 1180, XP002422089, ISSN: 0044-8486 *
LEONG JO-ANN C: "Molecular and biotechnological approaches to fish vaccines", CURRENT OPINION IN BIOTECHNOLOGY, vol. 4, no. 3, 1993, pages 286 - 293, XP002422095, ISSN: 0958-1669 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080767A1 (fr) * 2007-12-21 2009-07-02 Intervet International B.V. Vaccin pour poisson
CN111304131A (zh) * 2020-03-17 2020-06-19 中国水产科学研究院黄海水产研究所 强致病力的美人鱼发光杆菌美人鱼亚种菌株及应用
WO2022121109A1 (fr) * 2020-12-07 2022-06-16 广东海洋大学 Nocardia seriolae atténué, procédé de fabrication et son application
CN113648407A (zh) * 2021-08-20 2021-11-16 广东渔跃生物技术有限公司 一种诺卡氏菌免疫增强剂在鱼用疫苗中的应用

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