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WO1996030045A1 - Vaccin preventif contre le virus de l'immunodeficience feline chez le chat domestique - Google Patents

Vaccin preventif contre le virus de l'immunodeficience feline chez le chat domestique Download PDF

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Publication number
WO1996030045A1
WO1996030045A1 PCT/EP1996/001356 EP9601356W WO9630045A1 WO 1996030045 A1 WO1996030045 A1 WO 1996030045A1 EP 9601356 W EP9601356 W EP 9601356W WO 9630045 A1 WO9630045 A1 WO 9630045A1
Authority
WO
WIPO (PCT)
Prior art keywords
vaccine
virus
fiv
cells
infected
Prior art date
Application number
PCT/EP1996/001356
Other languages
English (en)
Inventor
Mauro Bendinelli
Donatella Matteucci
Mauro Pistello
Carlo Garzelli
Gino Maldavi
Alessandro Poli
Franco Tozzini
Original Assignee
Istituto Superiore Di Sanita'
Universita' Degli Studi Di Pisa
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 Istituto Superiore Di Sanita', Universita' Degli Studi Di Pisa filed Critical Istituto Superiore Di Sanita'
Priority to AU53982/96A priority Critical patent/AU5398296A/en
Publication of WO1996030045A1 publication Critical patent/WO1996030045A1/fr

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Classifications

    • 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
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • 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
    • 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
    • A61K2039/525—Virus
    • A61K2039/5252—Virus inactivated (killed)
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention provides an immunizing vaccine for the prophylaxis of the infection from feline immunodeficiency virus (FIV) and/or the pathological syndrome known as feline AIDS induced by said virus.
  • FV feline immunodeficiency virus
  • the present invention relates to vaccine prepared with strains of FIV which are of fresh isolation and/or are subtypes prevalent in the geographical area wherein one intends to use the vaccine.
  • Analogous viruses are found in several wild feline species.
  • the virus usually penetrates through the skin, following the bite of carrier or ill cats, and is progressively and rapidly amplified in lymphoid organs and in other body districts. Different ways of contagion are also possible.
  • the virus thus becomes easily detectable in peripheral blood and in some other body fluids, e.g. saliva.
  • the host exposed to the virus tries to react to its invasion by an intense antiviral immune response, which, at least in the initial phase, is capable of slowing down virus progression, nevertheless, such immune response never succeeds in eradicating the virus itself, which already too intimately settled in several types of cells.
  • the infected cats develop a state of immunodepression, easily detectable by analysing the classical immune functionality parameters, i.e. progressive f ⁇ .ll in T CD4+ lymphocytes, inverted CD4:CD8 ratio, hypergammaglobulinaemia, reduced antigen-induced antibodypoiesis, reduced cell-mediated responses, reduced lymphokine production, etc., as well as other proteiform immune dysfunctions whose significance is still under evaluation.
  • the decrease of immune response caused by the virus opens the way to the appearance neurological manifestations, to the development of various types of neoplasias and to very frequent and dangerous superinfections sustained by a wide range of infecting agents.
  • the anti-FIV vaccines described to date have not brought about significant protection levels or have produced modest or controversial protective effects. Paradoxically, in some cases they even enhanced the infection experimentally induced in immunized animals to evaluate the protective action thereof (Pedersen N.C., in "The Retroviruses” , vol. 2. J.A. Levy, ed. , Plenum Press, New York, 1993; Hosie et al., British Veterinary Journal, 150, 25-39, 199*4; Bendinelli M. et al.. Clinical Microbiology Review, 8, 87-112, 1995).
  • the authors of the present invention have found that the low or inexistent protective effectiveness of the anti-FIV vaccines disclosed up to now is, mainly, due to the use of strains of viruses repeatedly propagated in vitro on cell cultures. When passaged more than 20-30 times in vitro, such viruses fail to show the protective epitopes or show them in an inadequate way to induce an effective protective immunity when inoculated into cats. Summary of the invention The purpose of the authors of the present invention was to provide vaccines able to produce a strong immunity against the feline immunodeficiency virus and therefore to protect cats from infection acquisition and/or FAIDS onset.
  • a fundamental characteristic of the present invention is an anti-FIV vaccine preparared with freshly isolated virus.
  • Another characteristic of the invention is a vaccine prepared including subtypes of FIV virus prevalent in the geographical area wherein one intends to use them.
  • a further characteristic of the present invention is a vaccine, including a freshly isolated virus, for use as a therapeutic agent to reinforce the antiviral response in already infected cats.
  • the present invention also relates to an improved process for the preparation of a vaccine according to the invention.
  • the expression "vaccine against feline immunodeficiency virus or feline AIDS (FAIDS)” refers to a preparation consisting of (i) one or more FIV subtypes, known as A, B, C and D (e.g., see Bendinelli M, et al., 1995). freshly isolated, according to procedures, on lymphocytes or permissive non-trasformed lymphoid cultures and selected on the basis of the diverse epidemiological situations existing in different geographical areas or (ii) lymphoid cells infected productively with local freshly isolated virus strains or (iii) selected antigens of said freshly isolated viruses.
  • the vaccinal preparations are prepared or treated in such a way as to make them completely harmless to cats , though maintaining their immunogenic properties .
  • the virus or viruses utilized for the preparation of the anti-FIV vaccine according to the invention must be "strains of fresh isolation" , that is passed in cultures of non-transformed lymphoid cells and for a maximum, of 10-15 times , in order to avoid the loss of the immieuxicity properties which allow the virus to induce immune protective responses . That represents an essential prerequisite for the vaccines to be effective .
  • the vaccine preparations according to the invention are treated or prepared in order to render them absolutely innocuous for cats , though maintaining their immunogenic properties .
  • the vaccines of the invention are designated "anti-FIV immunizing vaccines" .
  • a very active form of said vaccine was developed by growing virus strains , selected in various local epidemiological situations , on cultures of feline cells of lymphoid origin or similar origin optionally in combination with a pharmaceutically acceptable adjuvant .
  • the selected subtype ( or clade ) was the B subtype , highly prevalent in Italy , and therefore the vaccine according to the invention will contain at least the B subtype, or a mixture comprising it.
  • the cultures infected with a convenient multiplicity were incubated at 36°-39°C (preferably 37 ⁇ C) for some days, preferably from 6 to 10, until the number of infected cells expressing surface viral antigens reached adequate levels (4 ⁇ -8 ⁇ /_, preferably 60 ).
  • the cells were then collected, cooled (preferably at 4 C C), concentrated by centrifugation (preferably by low-speed centrifugation at 4°C). Then the process could be improved compared to the known methods by treating the cells with 10/. glycerol for 1-5 min (preferably 3 minutes). This last treatment is very important as it causes a greater exposure of protective antigens on the cell surfaces and, therefore, makes them more immvmogenic. However, also a process without using the glycerol step can be performed.
  • the cells were treated with a disinfectant for the time required for viral infectivity inactivation and adapting the time of exposure to the strength and concentration of the inactivating agent as well as to the incubation temperature (e.g. 1-2% paraformaldehyde at 37°C for 24 hours).
  • a disinfectant for the time required for viral infectivity inactivation and adapting the time of exposure to the strength and concentration of the inactivating agent as well as to the incubation temperature (e.g. 1-2% paraformaldehyde at 37°C for 24 hours).
  • the cell suspension was then mixed with an equal volume of at least one adjuvant (preferably the Freund's incomplete adjuvant).
  • Each dose of vaccine consisted of about 10 million infected cells.
  • vaccinated cats develop a strong direct specific immune response to the virus as proved by the appearance of a high level of neutralizing and non-neutralizing antiviral antibodies as well as by the development of cell-mediated antiviral responses. Most importantly, vaccinated cats proved to resist, without being infected, when challenged with highly virulent FIV preparations (as obtained by using virus never passaged in vitro, e.g. plasma of infected cats) inoculated experimentally by a parenteral route.
  • the animals were subjected to challenge four months after the last dose of vaccine.
  • the challenge was carried out via intravenous route using a high virulent homologous FIV. Better results were obtained when the high virulent homologous FIV was never passed in vitro in order not to alter its invasive capacity.
  • the animals were subjected to challenge four months after the last dose of vaccine, using the same procedure and the same virus stock used in the experiment depicted in the above Table 1. • The vaccine was prepared and administered exactly as in the xperiment depicted in Table 1, except that the virus used for its preparation was grown in vitro in ⁇ trasformed lymphoid cell line for 30 passages.
  • Anti-FIV vaccines may alternatively be obtained in different ways, always starting from FIV viruses freshly isolated according to the invention.
  • Said anti-FIV vaccines consist of:
  • extracellular virus optionally concentrated, purified by physico- chemical methods and treated so as to destroy its infecting and/or pathogenic power; or ;ii) viral molecules; or (iii) specific selected fragments of said molecules produced by recombinant DNA technology or chemical synthesis.
  • said materials may be mixed with immunologic adjuvants of various
  • I ISOA ⁇ //EPPP types and used as vaccines though generally having lower immunizing and protective efficacy than the aforementioned vaccines based on infected cells .
  • the vaccine may be used to prevent infection in uninfec ted cats .
  • it can possibly have beneficial effects also when used as a therapeutic treatment to enhance the antiviral responses in infected cats ; in this case , it slows down or attenuates the development , in said animals , of the FIV-induced immunodepressive infec tion and pathology .
  • the invention provides a vaccine comprising freshly isolated virus ( es ) with or without a pharmaceutically acceptable excipient that can also be used as drug to reinforce the antiviral response in already infected cats .
  • the present invention further provides a method for determining whether a vaccine is indeed protec tive consis ting in the administration of a FIV derived directly from the tissues of infected cat as a challenge .
  • the vaccine according to the invention may be prepared from FIV , from viral molecules in general or one or more fragments thereof .
  • Such a viral molecule or fragments may be produced by recombinant DNA technology or chemical synthesis .
  • the invention will be now more properly illustrated with reference to a preferred embodiment .
  • Feline cells of lymphoid source were infected at high multiplicity with freshly isolated B subtype FIV, prevalent in Italy, and incubated at 37°C for 6 days, until the number of infected cells expressing surface viral antigens reached the level of 60/..
  • the cells were then collected, cooled at 4°C, concentrated by low- speed centrifugation at 4 ⁇ C, and treated with 10% glycerol for 3 min. Once glycerol had been removed, the cells were treated with 1 % paraformaldehyde at 37°C for 2k hours for viral infectivity inactivation.
  • the cell suspension was then mixed with an identical volume of Freund's incomplete adjuvant.
  • Each dose of vaccine consisted of about 10 million infected cells.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Virology (AREA)
  • Microbiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Mycology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un vaccin immunisant administré à titre préventif pour protéger contre les infections par le virus de l'immunodéficience féline et/ou l'état pathologique provoqué par ce virus et appelé SIDA félin. Ce vaccin est à usage vétérinaire et est utile pour traiter les chats domestiques. Le vaccin produit une forte réaction immunitaire spécifique protectrice contre les antigènes des virus, lorsque les virus utilisés pour la préparation de ce vaccin sont des souches fraîchement isolées et/ou des sous-types qui prédominent dans la zone géographique concernée.
PCT/EP1996/001356 1995-03-31 1996-03-28 Vaccin preventif contre le virus de l'immunodeficience feline chez le chat domestique WO1996030045A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53982/96A AU5398296A (en) 1995-03-31 1996-03-28 Vaccine for the immunoprophylaxis of the infection from feli ne immunodeficiency virus in the domestic cat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT95RM000209A IT1276509B1 (it) 1995-03-31 1995-03-31 Vaccino per la profilassiimmunitaria dell'infezione da virus della immunodeficienza felina del gatto domestico.
ITRM95A000209 1995-03-31

Publications (1)

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WO1996030045A1 true WO1996030045A1 (fr) 1996-10-03

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AU (1) AU5398296A (fr)
IT (1) IT1276509B1 (fr)
WO (1) WO1996030045A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6447993B1 (en) * 1995-08-25 2002-09-10 University Of Florida Research Foundation, Inc., Multi-subtype FIV vaccines
US6544528B1 (en) 1995-08-25 2003-04-08 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines
US7658927B2 (en) 2003-05-12 2010-02-09 University Of Florida Research Foundation, Inc. Materials and methods for immunizing against FIV infection
US8703145B2 (en) 2003-05-12 2014-04-22 University Of Florida Research Foundation, Inc. Materials and methods for immunizing against FIV infection

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001278A1 (fr) * 1991-07-05 1993-01-21 The Regents Of The University Of California Lignees cellulaires lymphoïdes felines susceptibles de produire le virus de l'immunodeficience feline (vif)
WO1993014195A1 (fr) * 1992-01-17 1993-07-22 Solvay Animal Health, Inc. Vaccin contenant de l'acemannane comme adjuvant
US5275813A (en) * 1987-08-26 1994-01-04 The Regents Of The University Of California Methods and compositions for vaccinating against feline immunodeficiency virus
WO1994006471A1 (fr) * 1992-09-21 1994-03-31 Mallinckrodt Veterinary,Inc. Vaccins destines a lutter contre le virus immunodeficitaire felin
EP0659885A1 (fr) * 1993-12-21 1995-06-28 Akzo Nobel N.V. Vaccins contre des virus associés avec l'augmentation dépendant de l'anticorps (ADE) de l'infectivité virale

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5275813A (en) * 1987-08-26 1994-01-04 The Regents Of The University Of California Methods and compositions for vaccinating against feline immunodeficiency virus
WO1993001278A1 (fr) * 1991-07-05 1993-01-21 The Regents Of The University Of California Lignees cellulaires lymphoïdes felines susceptibles de produire le virus de l'immunodeficience feline (vif)
WO1993014195A1 (fr) * 1992-01-17 1993-07-22 Solvay Animal Health, Inc. Vaccin contenant de l'acemannane comme adjuvant
WO1994006471A1 (fr) * 1992-09-21 1994-03-31 Mallinckrodt Veterinary,Inc. Vaccins destines a lutter contre le virus immunodeficitaire felin
EP0659885A1 (fr) * 1993-12-21 1995-06-28 Akzo Nobel N.V. Vaccins contre des virus associés avec l'augmentation dépendant de l'anticorps (ADE) de l'infectivité virale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAMMAROTA, GIANCARLO ET AL: "Reduced sensitivity to strain-specific neutralization of laboratory-adapted feline immunodeficiency virus after one passage in vivo: association with amino acid substitutions in the V4 region of the surface glycoprotein", AIDS RESEARCH AND HUMAN RETROVIRUSES (1996), 12(2), 173-5 CODEN: ARHRE7;ISSN: 0889-2229, 1996, XP002009976 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6447993B1 (en) * 1995-08-25 2002-09-10 University Of Florida Research Foundation, Inc., Multi-subtype FIV vaccines
US6544528B1 (en) 1995-08-25 2003-04-08 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines
US6605282B2 (en) 1995-08-25 2003-08-12 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines
US7267824B2 (en) 1995-08-25 2007-09-11 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines
US7311921B2 (en) 1995-08-25 2007-12-25 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines
US7658927B2 (en) 2003-05-12 2010-02-09 University Of Florida Research Foundation, Inc. Materials and methods for immunizing against FIV infection
US8703145B2 (en) 2003-05-12 2014-04-22 University Of Florida Research Foundation, Inc. Materials and methods for immunizing against FIV infection

Also Published As

Publication number Publication date
IT1276509B1 (it) 1997-10-31
ITRM950209A0 (it) 1995-03-31
ITRM950209A1 (it) 1996-10-01
AU5398296A (en) 1996-10-16

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