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WO1993006211A1 - Vaccin pour la maladie mysterieuse du porc et procede de diagnostic de la maladie - Google Patents

Vaccin pour la maladie mysterieuse du porc et procede de diagnostic de la maladie Download PDF

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Publication number
WO1993006211A1
WO1993006211A1 PCT/US1992/007826 US9207826W WO9306211A1 WO 1993006211 A1 WO1993006211 A1 WO 1993006211A1 US 9207826 W US9207826 W US 9207826W WO 9306211 A1 WO9306211 A1 WO 9306211A1
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WIPO (PCT)
Prior art keywords
swine
msd
infectious agent
disease
vaccine
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Application number
PCT/US1992/007826
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English (en)
Inventor
James E. Collins
David A. Benfield
Original Assignee
Collins James E
Benfield David A
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Collins James E, Benfield David A filed Critical Collins James E
Publication of WO1993006211A1 publication Critical patent/WO1993006211A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • 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
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552—Veterinary vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/10011—Arteriviridae
    • C12N2770/10034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • MSD causes multiple symptoms in swine.
  • the first symptom of MSD in a breeding herd of swine is usually anorexia and mild pyrexia.
  • the herd animals may exhibit bluish discolorations in their skin, especially in their ears, teats, snout, and the frontal portions of their necks and shoulders.
  • the affected skin may become irreparably damaged.
  • MSD causes sows to bear stillborn piglets, undersized-weak piglets with respiratory distress, or piglets which die before they are weaned.
  • the serum for treatment of infected swine carries mammalian antibodies to the MSD. It is obtained from the blood plasma of a non-swine mammal pretreated with the above-described infectious agent. Alternatively, the serum is formulated from monoclonal antibodies to MSD produced by hybridoma methods.
  • the infectious agent can be inactivated or killed by treatment of the filtered homogenate with a standard chemical inactivating agent such as an aldehyde reagent including formalin, acetaldehyde and the like, reactive acidic alcohols including cresol, phenol and the like, acids such as benzoic acid, benzene sulfonic acid and the like, lactones such as beta propiolactone and caprolac one, and activated lactams, carbodiimides and carbonyl diheteroaromatic compounds such as carbonyl diimidazole.
  • Irradiation such as with ultraviolet and gamma irradiation can also be used to inactivate or kill the infectious agent.
  • Fecal contents may also be collected and examined for virus particles as previously described in Ritchie et al., Arch. Gesante. Virus-forsche, 23, 292-98 (1968). Blood can be collected for immunologic assays and tissues and cultured for bacteria as described in Example 3.
  • MSD agent(s) has an average diameter of 200 nm or smaller because the MSD symptoms re-occur in 3-day-old gnotobiotic pigs receiving the .20 lm filtrate.
  • the experiment described below tests whether MSD is caused by a filterable agent(s) (with an average diameter of 200 nm or less) that can be transmitted via the respiratory tract to produce clinical disease and lesions in experimental pigs that resemble those observed in pigs naturally infected with MSD.
  • the experimental plan is designed to narrow the list of potential etiologic agents and use this information for isolation of the agent.
  • an in vivo model may be used to further characterize the agent by various physical and chemical treatments of the inoculum followed by inoculation of gnotobiotic pigs to determine if the MSD agent(s) remain pathogenic (indicated by the presence of lesions).
  • a filtration method can be used to determine the approximate size range of the MSD agent(s).
  • the respiratory form of MSD can be transmitted using 0.20 lm filtrates. Bacteria, except for mycoplasma (0.25-0.80 lm diameter), do not pass through filters of this size, and can be eliminated as primary agent(s).
  • viruses 0.02-0.30 lm
  • chlamydia and rickettsia 0.30-0.50 lm
  • naked nucleic acids such as viroids
  • gnotobiotic pigs can be inoculated as follows: three pigs with a 0.20 lm filtrate of the MSD inoculum (positive controls); two with a 0.20 lm filtrate of the control inoculum (negative controls); three pigs with a 0.10 lm filtrate of the MSD inoculum and two pigs with similar filtrate of the control inoculum.
  • Each group of pigs can be maintained in separate isolators and observed daily for clinical signs (anorexia, huddling, rough hair coats, diarrhea, rhinitis), euthanized at 7 days after the inoculation and tissues removed for histopathology as described above.
  • MSD agent Once the MSD agent is isolated, its chemical properties can be determined. Many microbial agents with high lipid concentrations in their outer walls or envelope (enveloped DNA and RNA viruses, mycoplasma, chlamydia and rickettsia) are inactivated by organic solvents as taught in Fenner et al. , Veterinary Virology, Academic Press Inc., 21-38 (1987); Elisberg et al., Diagnostic Procedures for Viral, Rickettsial and Chlamydial Infections, 5th Edition, American Public Health Association, 1061-108 (1979); and Schachter et al.
  • enveloped DNA and RNA viruses enveloped DNA and RNA viruses, mycoplasma, chlamydia and rickettsia
  • Genetron/chloroform extraction indicates the absence of lipid in the outer membranes of the agent(s) and suggests that it may have an outer protein coat.
  • a Genetron/chloroform extracted filtrate can be treated with proteinase K (100 lg/ml) and 1% SDS at 37°C for 30 mins. to dissociate proteins.
  • the inactivation of the MSD infectious agent by this treatment indicates that the infectious agent is possibly a naked virus or an unidentified microbial agent with a protein coat.
  • Two pigs can be given the 0.20 lm untreated filtrate as a positive control inoculum; three pigs can receive the Genetron/chloroform extracted, proteinase K treated MSD filtrate and two pigs can be given a similar preparation of the control inoculum. If proteinase K digestion does not prevent transmission of the MSD agent, then this may indicate the possible presence of free RNA (viroid) or DNA in the inoculum. This last possibility is unlikely, because such agents have not been confirmed as causes of diseases in animals (Diener, American Computer, 71, 481-89 (1983)). In summary, results from these experiments provide information on the relative size of the MSD agent and whether it contains a outer lipid membrane or protein coat necessary for infectivity.
  • infectious agent may be to either viruses, mycoplasma, chlamydia, rickettsia, naked nucleic acids, a new class of unidentified agents or a combination of any of the above.
  • Example 1 will provide information on how the inoculum can be treated (filter size, organic solvent extraction and/or protease digestion) to provide the purest form of the MSD agent(s) for an inoculum. Because the MSD agent(s) has both a respiratory form in young pigs and a reproductive form in adult swine, it is necessary to reproduce the latter form of the syndrome to further verify that the infectious agent(s) is the putative cause of MSD. Field observations suggest that the MSD agent(s) can induce abortions in early, mid and late gestation (Mengeling et al. , Proceedings of the Mystery Swine Disease Committee Meeting, 88-90 (1990)). Thus, a 90 day gestational sow is used as the experimental animal because it is possible to experimentally induce abortion in these animals inoculated with the MSD infectious agent.
  • Sows can be purchased from a commercial herd free of ongoing reproductive problems and MSD. Complete epide iologic records on this herd can be computerized and information on gestation times, litter sizes, and average number of stillbirths can be made available for " comparative studies. Groups of three sows each can be intranasally inoculated at 90 days of gestation with either the 0.20 lm filtrate (positive controls), a pathogenic but modified inoculum as dictated by results from Example 1, a 0.20 lm filtrate of the control inoculum (negative control), and a control inoculum modified as indicated by results of experiments in Example 1. Each group of sows can be housed in separate isolation rooms and examined daily until gestation is complete.
  • the fetal sera can also be assayed for the presence of gammaglobulins and antibodies to PPV and EMCV (Joo et al. , In Proceedings of the Mystery Swine Disease Committee Meeting, 62-66 (1990) and Kim et al., J. Vet. Diagn. Invest., 1, 101-4 (1990)). Pigs born live can be observed for one week and morbidity and mortality recorded, after which these pigs can be euthanized and the tissues collected for light microscopic and microbiologic examination as described for the fetuses.
  • the 0.2 lm and the modified filtrates of the MSD inoculum are pathogenic for sows and induce anorexia, possibly a mild fever and premature farrowing with a large number of stillborn and weak pigs in each litter.
  • Sows inoculated with the control inoculum farrow near term and have litter sizes within the normal range for- the herd of origin as determined from the available epidemiologic database on this herd. No lesions in the stillborn pigs are found and a high rate of mortality among the surviving weak pigs within one week after birth is observed.
  • Turbinates and lung can be prepared as separate 10% (weight/volume) homogenates, whereas heart, liver and brain should be pooled.
  • Hanks balanced salt solution can be used as the diluent, but antibiotics can be omitted since these tissue suspensions can also be used for detection of chlamydia or rickettsia, which are sensitive to some antibiotics.
  • Approximately 0.5 ml of each homogenate can be adsorbed on sixteen replicates of each cell type. Eight replicates can be incubated at 35°C: four replicates on roller tubes (two replicates containing media with 5 lg/ l trypsin and two without trypsin) and four replicates on stationary cultures (two with and two without media containing trypsin) .
  • a similar set of eight replicates can be maintained at 37°C. Cultures should be examined daily for cytopathic effects (CPE) and if negative, blind passaged at weekly intervals for 5 passages. At each passage, freeze-thaw lysates of the cultures should be examined by electron microscopy for viral particles and scrapings of cells used in an immunofluorescence assay for viral antigens (Benfield et al., Arch. Virol., 82, 195-209 (1984)). The above tissues can also be examined for cell-associated viruses by either cocultivation of 2 mm 2 cubes of tissue or trypsinized cells (2X10 6 ) with each of the above cell cultures seeded in 6-well plastic plates.
  • Two pigs can be inoculated intranasally, and then given a subcutaneous booster of the MSD inoculum in Freund's incomplete adjuvant at 2 and 4 weeks after the initial inoculation. Sera can be harvested from this pig 2 weeks after the last booster.
  • a control sera is also prepared in two gnotobiotic pig using the control inoculum and the same immunization protocol described for the MSD inoculum. These sera can be used as primary antibody and goat or rabbit anti-porcine immunoglobulih conjugated with fluorescein isothiocyanate as secondary antibody to detect MSD antigens in frozen tissue sections and cell cultures.
  • Seroloqic assays Sera collected from control and inoculated pigs can be assayed for the presence or absence of antibody to PPV and SIV (hemagglutination inhibition) , Leptospira (micro-agglutination) , and EMCV (viral neutralization) (see Example 4 for definition of acronyms). Previous results indicated that serology to other common microbial agents were negative (Collins, et al. , 71st Meeting of the Conference of Research Workers in Animal Disease, Abstract No. 2 (1990)) and need not be repeated here.
  • Isotype specific monoclonal antibodies to porcine immunoglobulins are also available (Paul et al., J. Vet. Res., 50, 471-79 (1989)), and can be used at twice minimum saturating concentration for indirect fluorescent staining of leukocytes from peripheral blood, lymph node, and Peyer's patches (Hurley et al., Vet. Immunol. Immunopathol. , 25, 177-93 (1990)).
  • cells can also be stained with rPE labeled avidin after being tagged with biotin- bound (Pierce kit #21333) antibodies. Cells can be analyzed by flow cytometry or a two color analytical fluorescent microscope (PTI FSCAN system) .
  • three piglets inoculated with MSD and three inoculated with control inoculum can be injected with a 2% suspension of sheep erythrocytes and a 10 lg/ml solution of bovine serum albumin at separate sites at 5, 7, 10, 14, and 24 days after their original inoculation. Pigs are euthanized at 24 days after the original inoculation, and tissues are collected for histopathology as described in Example 1 and blood collected to assay for antibody. The total antibody level and the specific IgG and IgM responses to each antigen can be measured by antigen specific radial immunodiffusion or ELISA. Antigen specific plaque assays can be performed on spleen cells to assess the frequency of B cell clones in the infected and control animals (Kappler, J. Immunol. , 112, 1271-85 (1974)).
  • the virus isolation procedure includes methods to accommodate temperature sensitive viruses (incubation at 35 * C) , viruses (such as reoviruses, enteroviruses) that • are activated by proteases and cell-associated viruses (herpes viruses, paramyxoviruses, retroviruses) .
  • viruses such as reoviruses, enteroviruses
  • cell-associated viruses herepes viruses, paramyxoviruses, retroviruses
  • Five gnotobiotic piglets (3 inoculated intranasally with the purest form of MSD and 2 with control) can be euthanized at 1, 3, 5, 7, 10 and 14 days after being inoculated. Necropsy procedures and tissues to be removed for histopathology should be followed pursuant to the experimental design disclosed in Example 1.
  • Tissues for virus isolation should only be collected from pigs euthanized at 1, 3, 5 and 7 days after inoculation, since previous attempts to identify the MSD agent(s) with tissue from pigs sacrificed at 7 days after inoculation are usually unsuccessful.
  • Pigs euthanized at 10 and 14 days can be used as a source of tissues for histopathology to monitor progression of the lesions and in the immunologic assays.
  • the high rate of isolation of secondary pathogens from pigs with the respiratory form of MSD indicates that these pigs may be immunosuppressed (Keffaber, AASP Newsletter, 2 . , 1-10 (1990)), and the preliminary data (see Table in Addendum) indicates depressed responsiveness of various lymphocytes isolated from pigs inoculated with the MSD agent.
  • this study was done with a limited number animals. It is expected that the immunologic assays will permit a determination of whether the MSD agent(s) specifically suppress a specific subpopulation of either T or B lymphocytes and whether this suppression is expressed functionally in the in vitro and in vivo assays.

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Abstract

L'invention concerne un vaccin et des sérums pour traiter la maladie mystérieuse du porc (MSD), un procédé de production du vaccin, et des procédés de diagnostics de la maladie mystérieuse du porc. Le vaccin est dérivé d'un agent infectieux de MSD qui est isolé selon les procédés divulgués dans la présente invention. Le sérum de traitement d'un porc infecté est dérivé du plasma sanguin d'un mammifère autre qu'un porc et qui a été traité au préalable avec l'agent infectieux du MSD. Le sérum contient des anticorps mammifères qui sont efficaces pour le traitement de MSD.
PCT/US1992/007826 1991-09-16 1992-09-16 Vaccin pour la maladie mysterieuse du porc et procede de diagnostic de la maladie WO1993006211A1 (fr)

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US760,713 1991-09-16

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Cited By (30)

* Cited by examiner, † Cited by third party
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EP0610250B1 (fr) * 1991-10-14 1995-12-06 Akzo Nobel N.V. Vaccin contre le syndrome respiratoire reproductif porcin (prrs)
US5510258A (en) * 1993-02-08 1996-04-23 Bayer Corporation Porcine reproductive and respiratory syndrome virus antigen and processes for the preparation and use of said antigen in vaccines and diagnostics
US5695766A (en) * 1992-10-30 1997-12-09 Iowa State University Research Foundation Highly virulent porcine reproductive and respiratory syndrome viruses which produce lesions in pigs and vaccines that protect pigs against said syndrome
US5698203A (en) * 1994-04-11 1997-12-16 Akzo Nobel N.V. European vaccine strains of the Porcine Reproductive Respiratory Syndrome virus (PRRSV)
US6241990B1 (en) * 1991-08-26 2001-06-05 Regents Of The University Of Minnesota Immunogenic composition containing inactivated swine infertility and respiratory Syndrome virus
US6331439B1 (en) 1995-06-07 2001-12-18 Orchid Biosciences, Inc. Device for selective distribution of liquids
US6500662B1 (en) 1998-12-22 2002-12-31 Pfizer Inc. Infectious cDNA clone of North American porcine reproductive and respiratory syndrome (PRRS) virus and uses thereof
US6592873B1 (en) 1992-10-30 2003-07-15 Iowa State University Research Foundation, Inc. Polynucleic acids isolated from a porcine reproductive and respiratory syndrome virus (PRRSV) and proteins encoded by the polynucleic acids
US6773908B1 (en) 1992-10-30 2004-08-10 Iowa State University Research Foundation, Inc. Proteins encoded by polynucleic acids of porcine reproductive and respiratory syndrome virus (PRRSV)
US6982160B2 (en) 1991-08-26 2006-01-03 Boehringer Ingelheim Vetmedica, Inc. Immunogenic compositions that include SIRS virus
WO2006074986A2 (fr) 2005-01-13 2006-07-20 Boehringer Ingelheim Vetmedica Gmbh Vaccins ameliores contre le srrp
US7264802B2 (en) 1992-10-30 2007-09-04 Iowa State University Research Foundation Proteins encoded by polynucleic acids of porcine reproductive and respiratory syndrome virus (PRRSV)
US7335473B2 (en) 1991-06-06 2008-02-26 Boehringer Ingelheim Vetmedica Gmbh Causative agent of the Mystery Swine Disease, vaccine compositions and diagnostic kits
WO2012110489A2 (fr) 2011-02-17 2012-08-23 Boehringer Ingelheim Vetmedica Gmbh Nouvelle souche de prrsv européenne
WO2012110490A1 (fr) 2011-02-17 2012-08-23 Boehringer Ingelheim Vetmedica Gmbh Procédé de production de prrsv à l'échelon commercial
US8383131B2 (en) 2004-09-21 2013-02-26 Boehringer Ingelheim Vetmedica, Inc. Porcine reproductive and respiratory syndrome isolates and methods of use
US8399187B2 (en) 2004-06-18 2013-03-19 Regents Of The University Of Minnesota Identifying virally infected and vaccinated organisms
US8546124B2 (en) 1996-10-30 2013-10-01 Boehringer Ingelheim Vetmedica Gmbh Infectious clones of RNA viruses and vaccines and diagnostic assays derived thereof
RU2494760C1 (ru) * 2012-04-26 2013-10-10 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Ижевская государственная сельскохозяйственная академия" Способ получения гипериммунной сыворотки против цирковирусной инфекции, репродуктивно-респираторного синдрома и гемофилеза свиней
US8741309B2 (en) 1999-04-22 2014-06-03 The United States Of America As Represented By The Secretary Of Agriculture Porcine reproductive and respiratory syndrome vaccine based on isolate JA-142
US8790656B2 (en) 1996-10-30 2014-07-29 Boehringer Ingelheim Vetmedica Gmbh PRRSV vaccines
US9080143B2 (en) 2005-06-24 2015-07-14 University Of Minnesota PRRS viruses, infectious clones, mutants thereof, and method of use
US9187731B2 (en) 2011-07-29 2015-11-17 Boehringer Ingelheim Vetmedica Gmbh PRRS virus inducing type I interferon in susceptible cells
US9315781B2 (en) 2011-07-29 2016-04-19 Boehringer Ingelheim Vetmedica Gmbh Infectious CDNA clone of european PRRS virus and uses thereof
US9561270B2 (en) 2009-09-02 2017-02-07 Boehringer Ingelheim Vetmedica, Inc. Methods of reducing virucidal activity in PCV-2 compositions and PCV-2 compositions with an improved immunogenicity
US9579373B2 (en) 2013-03-15 2017-02-28 Boehringer Ingelheim Vetmedica, Inc. Porcine reproductive and respiratory syndrome virus, compositions, vaccine and methods of use
WO2017040672A1 (fr) 2015-08-31 2017-03-09 Boehringer Ingelheim Vetmedica Gmbh Vaccins à base de pestivirus pour les tremblements congénitaux
WO2017106079A1 (fr) 2015-12-14 2017-06-22 Boehringer Ingelheim Vetmedica, Inc. Vaccins pour félins à noyaux hybrides
WO2020206452A1 (fr) 2019-04-04 2020-10-08 Boehringer Ingelheim Animal Health USA Inc. Vaccins contre le circovirus porcin de type 3 (pcv3), sa production et ses utilisations
WO2022020593A2 (fr) 2020-07-24 2022-01-27 Boehringer Ingelheim Animal Health USA Inc. Vaccin porcin combiné

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Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897343B2 (en) 1991-06-06 2011-03-01 Boehringer Ingelheim Vetmedica Gmbh Causative agent of the mystery swine disease, vaccine compositions and diagnostic kits
US7335473B2 (en) 1991-06-06 2008-02-26 Boehringer Ingelheim Vetmedica Gmbh Causative agent of the Mystery Swine Disease, vaccine compositions and diagnostic kits
US6855315B2 (en) 1991-08-26 2005-02-15 Regents Of The University Of Minnesota Kits for detecting swine infertility and respiratory syndrome (SIRS) virus
US7264804B2 (en) 1991-08-26 2007-09-04 Boehringer Ingleheim Vetmedica, Inc. Kits for detecting anti-SIRS antibodies
US6241990B1 (en) * 1991-08-26 2001-06-05 Regents Of The University Of Minnesota Immunogenic composition containing inactivated swine infertility and respiratory Syndrome virus
US6982160B2 (en) 1991-08-26 2006-01-03 Boehringer Ingelheim Vetmedica, Inc. Immunogenic compositions that include SIRS virus
US6498008B2 (en) 1991-08-26 2002-12-24 Regents Of The University Of Minnesota Method for detecting swine infertility and respiratory virus
EP0610250B1 (fr) * 1991-10-14 1995-12-06 Akzo Nobel N.V. Vaccin contre le syndrome respiratoire reproductif porcin (prrs)
US7517976B2 (en) 1992-10-30 2009-04-14 Iowa State University Research Foundation, Inc. Polynucleic acids isolated from a porcine reproductive and respiratory syndrome virus (PRRSV)
US5695766A (en) * 1992-10-30 1997-12-09 Iowa State University Research Foundation Highly virulent porcine reproductive and respiratory syndrome viruses which produce lesions in pigs and vaccines that protect pigs against said syndrome
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