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WO2001054701A1 - Vaccination de personnes infectees par le vih apres une therapie antiretrovirale a haute activite - Google Patents

Vaccination de personnes infectees par le vih apres une therapie antiretrovirale a haute activite Download PDF

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Publication number
WO2001054701A1
WO2001054701A1 PCT/US2001/002766 US0102766W WO0154701A1 WO 2001054701 A1 WO2001054701 A1 WO 2001054701A1 US 0102766 W US0102766 W US 0102766W WO 0154701 A1 WO0154701 A1 WO 0154701A1
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WIPO (PCT)
Prior art keywords
hiv
virus
vaccine
cells
patient
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PCT/US2001/002766
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English (en)
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WO2001054701A9 (fr
Inventor
David Ho
Martin Markowitz
Michel Klein
Raphaelle El Habib
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Aventis Pasteur, S.A.
Aaron Diamond Aids Research Center
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Application filed by Aventis Pasteur, S.A., Aaron Diamond Aids Research Center filed Critical Aventis Pasteur, S.A.
Priority to AU2001233063A priority Critical patent/AU2001233063A1/en
Priority to US10/182,067 priority patent/US20040034209A1/en
Publication of WO2001054701A1 publication Critical patent/WO2001054701A1/fr
Publication of WO2001054701A9 publication Critical patent/WO2001054701A9/fr

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    • 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
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24041—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the method comprises administering a nucleic acid-based vaccine that enters the cells and intracellularly produces HTV-specific immunogens for presentation on the cell's MHC class I and MHC class II molecules in an amount sufficient to stimulate HIV- specific CD4+ and CD8+ T-cell responses, thereby reversing the otherwise observed population decline of these cells during antiretroviral therapy.
  • the human has been treated with HAART therapy that resulted in the human having a viral load of less than 1,000 viral copies per ml of blood serum and a CD4+ cell count of above 500 cells/ml.
  • Figures 7A-7F display anti-gpl20 and anti-p24 antibody titers for several patients as a function of days post vaccination.
  • Figures 8A-8F displays intracellular cytokine staining.
  • Figure 9A-9F display data relating to various HIV antigens.
  • the present invention provides a novel therapeutic modality for treating persons infected with a lymphotropic or immune-destroying retroviral infection.
  • a physician presented with a patient whose immune system is compromised by retroviral infection can select to treat that patient with a host of powerful antiviral agents, including inhibitors of viral proteases and reverse transcriptase.
  • This is known as highly active anti-retroviral therapy (HAART).
  • HAART highly active anti-retroviral therapy
  • the conventional HAART protocols are complex and difficult for patients to follow.
  • the drugs also have a number of problematic side effects.
  • these expensive and complicated treatments fail to eliminate the virus; they merely hold the virus in check. If the patient is non- compliant, the viral count rebounds. Accordingly, for the vast majority of patients, a lifetime of drugs is advised.
  • the present invention comprises the discovery that after HIV infection, HAART treatment that decreases the viral load can be discontinued using an anti-HIV vaccine that induces an immune response.
  • This response effectively maintains a low titer of virus or controls the viral rebound when the antiretroviral therapy is discontinued, permitting significant reduction of the patient's dependency on antiretroviral therapy.
  • some such vaccines have been suggested as useful for seropositive patients (U.S. Patent No. 5,863,542 column 18, lines 60-63)
  • the art has not recognized that administration to seropositive patients receiving anti-viral treatment permits cessation of the anti-viral treatment without virus rebound, with delayed virus rebound, or with decreased post-rebound set point.
  • the bDNA signal amplification method amplifies the signal obtained from a captured HIV RNA target by using sequential oligonucleotide hybridization steps, whereas the RT-PCR and NASBA® assays use enzymatic methods to amplify the target HIV RNA into measurable amounts of nucleic acid product.
  • Target HIV RNA sequences are quantitated by comparison with internal or external reference standards, depending upon the assay used.
  • nucleoside analog reverse transcriptase inhibitors There are two type of reverse transcriptase inhibitors: nucleoside analog reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Both types of inhibitors block infection by blocking the activity of the HIV reverse transcriptase, the viral enzyme that translates HIV RNA into DNA that can later be incorporated into the host cell chromosomes. Nucleoside and nucleotide analogs mimic natural nucleotides, molecules that act as the building blocks of DNA and RNA. Both nucleoside and nucleotide analogs must undergo phosphorylation by cellular enzymes to become active; however, nucleotide analogs used are already partially phosphorylated and is one step closer to activation when it enters a cell.
  • NRTIs Non-nucleoside reverse transcriptase inhibitors
  • the CD4+ T-cell number is the product of three laboratory techniques: the white blood cell (WBC) count; the percentage of WBCs that are lymphocytes (differential); and the percentage of lymphocytes that are CD4+ T-cells.
  • WBC white blood cell
  • WBCs Size and granularity, detected by light scattering, characterize the types of WBCs (i.e., granulocytes, monocytes, and lymphocytes). Fluorochrome-labeled antibodies distinguish C7 populations and subpopulations of WBCs.
  • Systems for measuring CD4+T-cells are commercially available. For example Becton Dickenson's FACSCount System automatically measure absolutes CD4+, CD8+, and CD3+ T lymphocytes. It is a self-contained system, incorporating instrument, reagents, and controls.
  • the method comprises administering to an HIV-infected patient as defined above a nucleic acid-based vaccine that enters the cells and intracellularly produces HIV-specific immunogens for presentation on the cell's MHC class I and MHC class II molecules in an amount sufficient to stimulate efficient HIV-specific CD4+ and CD8+ T-cell responses.
  • Attenuated recombinant virus refers to a virus that has been genetically altered by modern molecular biological methods, e.g., restriction endonuclease and ligase treatment, and rendered less virulent than wild type, typically by deletion of specific genes or by serial passage in a non-natural host cell line permissive primary cells or at cold temperatures.
  • viral expression vectors include adenoviruses as described in M. Eloit et al, "Construction of a Defective Adenovirus Vector Expressing the Pseudorabies Virus Glycoprotein gp50 and its Use as a Live Vaccine", J. Gen. Virol., 71(10):2425-2431 (Oct., 1990).), adeno-associated viruses (see, e.g., Sarnulskl et al., J. Virol. 61:3096-3101 (1987); Samulski et al, J. Virol.
  • the recombinant poxviruses are constructed in two steps known in the art and analogous to the methods for creating synthetic recombinants of poxviruses such as the vaccinia virus and avipox virus described in U.S. Pat. Nos. 4,769,330, 4,722,848, 4,603,112, 5,110,587, and 5,174,993, the disclosures of which are incorporated herein by reference.
  • ALVAC is an attenuated canarypox virus-based vector that was a plaque-cloned derivative of the licensed canarypox vaccine, Kanapox (Tartaglia et al, 1992).
  • Kanapox a plaque-cloned derivative of the licensed canarypox vaccine
  • ALVAC has some general properties which are the same as some general properties of Kanapox.
  • NYVAC and ALVAC have also been recognized as unique among all poxviruses in that the National Institutes of Health ("NIH")(U.S. Public Health Service), Recombinant DNA Advisory Committee (which issues guidelines for the safety containment of genetic material such as viruses and vectors, i.e., guidelines for safety procedures for the use of such viruses and vectors that are based upon the pathogenicity of the particular virus or vector) granted a reduction in physical containment level: from BSL2 to BSL1. No other poxvirus has a BSL1 physical containment level. Even the Copenhagen strain of vaccinia virus (the common smallpox vaccine) has a higher physical containment level; namely, BSL2. Accordingly, the NIH has recognized that NYVAC and ALVAC have a lower pathogenicity than any other poxvirus.
  • Another attenuated poxvirus of preferred use in the invention is Modified Vaccinia virus
  • the nucleic acid-based vaccine for use in the present invention further comprises sequences encoding HIV immunogens and intracellularly produces the HIV-specific immunogens.
  • the HIV antigen encoding DNA for insertion into the viral vectors of the invention or for use as naked nucleic acid are any that are known to be effective for protection against a retrovirus.
  • HIV-specific immunogens means any HIV protein, fragment, or epitope thereof that is recognized by an immune cell as an epitope of the native protein. HIV-specific immunogens are thus selected from both structural and non-structural proteins. Highly antigenic epitopes for provoking an immune response selective for a specific retroviral pathogen are known.
  • the naked or vectored nucleic acid may be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, Tris buffer or the like.
  • the vaccine of the invention may also comprise an adjuvant. Any adjuvant administrable to humans can be used.
  • Adjuvants useful in the invention include alum, calcium phosphate and, preferably PCPP (poly dicarboxylatopheoxylphosphazene), a synthetic hydrogel polymer developed for its adjuvant properties.
  • DNA may also be directly introduced into the cells of a patient.
  • This embodiment is defined in the present invention as naked-DNA vaccine.
  • This expression i.e., naked-DNA vaccine
  • naked-DNA vaccine thus encompasses naked DNA er se, including virus like particles, as well as formulated DNA-based vaccines as disclosed below.
  • This approach is described, for instance, in Wolff et. al, Science 247:1465 (1990) as well as U.S. Patent Nos. 5,580,859; 5,589,466; 5,804,566; 5,739,118; 5,736,524; 5,679,647; and WO 98/04720.
  • Purified plasmid DNA can be prepared for injection using a variety of formulations. The simplest of these is reconstitution of lyophilized DNA in sterile phosphate-buffer saline (PBS). This approach, known as "naked DNA,” is currently being used for intramuscular (EM) administration in clinical trials.
  • PBS sterile phosphate-buffer saline
  • glycolipids, fusogenic liposomes, peptides targeting sequences and compounds referred to collectively as protective, interactive, non-condensing compounds could also be complexed to purified plasmid DNA to influence variables such as stability, intramuscular dispersion, or trafficking to specific organs or cell types.
  • DNA expression vectors for direct introduction of DNA into the patient tissue can additionally be complexed with other components such as peptides, polypeptides, lipopeptides, carbohydrates, microspheres, immunostimulants and adjuvants. Expression vectors can also be complexed to particles or beads that can be administered to an individual, for example, using a vaccine gun.
  • the vaccines can be incorporated, if desired, into liposomes, microspheres or other polymer matrices (Feigner et al, U.S. Patent No. 5,703,055; Gregoriadis, Liposome Technology, Vols. I to III (2nd ed. 1993), each of which is incorporated herein by reference).
  • Liposomes for example, which consist of phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • Liposome carriers may serve to target a particular tissue or infected cells, as well as increase the half-life of the vaccine.
  • Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phosphohpid dispersions, lamellar layers and the like.
  • the vaccine to be delivered is incorporated as part of a liposome, alone or in conjunction with a targeting molecule which binds to, e.g., a receptor prevalent among lymphoid cells, such as monoclonal antibodies which bind to the CD45 antigen, or with other therapeutic or immunogenic compositions.
  • a targeting molecule which binds to, e.g., a receptor prevalent among lymphoid cells, such as monoclonal antibodies which bind to the CD45 antigen, or with other therapeutic or immunogenic compositions.
  • liposomes either filled or decorated with a desired immunogen of the invention can be directed to the site of lymphoid cells, where the liposomes then deliver the immuno
  • ALVAC HTV (vCP1452) is a recombinant canarypox virus expressing the gag LA i, protease LA i, env(120) M N, env(41) L Ai, nef, and pol genes.
  • VCP1452 is described in U.S. Patent Nos. 6,004,777 and 5,990,091.
  • vCP1452 is modified to include 2 vaccinia virus coding sequences to enhance expression in mammalian cells. The pol and nef sequences are scrambled such that no functional proteins can be expressed., Approximately 10 7 TCID 50 in 1.0 ml were given with each dose.
  • Subjects were allowed, if desired, to participate in this vaccine protocol without consenting to collection of tissue and or fluid other than blood. These were optional procedures and serve to establish the absence of virus replication as completely as possible. 3. Recruitment of subjects
  • Plasma HIV-1 RNA levels were monitored with the Ultrasensitive RT PCR Assay (Roche) and the Bayer signal amplification assay (version 3.0) as per manufacturer's instructions.
  • Subjects who discontinued therapy include 1306, 1308, 1309, and 1310 and

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Abstract

La présente invention concerne un procédé qui permet d'arrêter la thérapie antirétrovirale chez des sujets infectés par le virus VIH sans provoquer de rebond viral ou au moins un rebond viral retardé ou un point de consigne post-rebond réduit. Ce procédé consiste à réinduire les réponses immunitaires spécifiques au VIH à l'aide d'une stratégie vaccinale permettant d'induire à la fois l'immunité à médiation humorale et l'immunité à médiation cellulaire. La présente invention réalise un contrôle immunologique du virus infectieux persistant après l'interruption d'une thérapie antivirale. La stratégie vaccinale de cette invention est à la fois sans danger et immunogène chez la population infectée par le virus VIH étudiée.
PCT/US2001/002766 2000-01-31 2001-01-26 Vaccination de personnes infectees par le vih apres une therapie antiretrovirale a haute activite WO2001054701A1 (fr)

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AU2001233063A AU2001233063A1 (en) 2000-01-31 2001-01-26 Vaccination of hiv infected persons following highly active antiretroviral therapy
US10/182,067 US20040034209A1 (en) 2001-01-26 2001-01-26 Vaccination of hiv infected persons following highly active antiretrovial therapy

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US60/179,276 2000-01-31

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005027835A2 (fr) * 2003-09-18 2005-03-31 Merck & Co., Inc. Immunisation therapeutique d'individus infectes par le vih
WO2007018550A3 (fr) * 2004-09-08 2007-11-29 Us Health Compositions et methodes pour detecter une infection par le vih-1/vih-2
WO2011035082A1 (fr) * 2009-09-17 2011-03-24 Sanofi Pasteur, Inc. Compositions immunologiques pour le vih
US7943375B2 (en) 1998-12-31 2011-05-17 Novartis Vaccines & Diagnostics, Inc Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
US8133494B2 (en) 2001-07-05 2012-03-13 Novartis Vaccine & Diagnostics Inc Expression cassettes endcoding HIV-1 south african subtype C modified ENV proteins with deletions in V1 and V2

Families Citing this family (2)

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AU2221600A (en) 1998-12-31 2000-07-31 Chiron Corporation Improved expression of hiv polypeptides and production of virus-like particles
US20030170614A1 (en) 2001-08-31 2003-09-11 Megede Jan Zur Polynucleotides encoding antigenic HIV type B polypeptides, polypeptides and uses thereof

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WO2001008702A2 (fr) * 1999-07-28 2001-02-08 The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services Immunotherapie traitant les personnes infectees par le vih utilisant des vaccins apres une multi-therapie

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WO1998008539A1 (fr) * 1996-08-26 1998-03-05 Chiron Corporation Therapie de vaccination apres l'infection par le virus de l'immunodeficience humaine (vih)
WO2001008702A2 (fr) * 1999-07-28 2001-02-08 The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services Immunotherapie traitant les personnes infectees par le vih utilisant des vaccins apres une multi-therapie

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7943375B2 (en) 1998-12-31 2011-05-17 Novartis Vaccines & Diagnostics, Inc Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
US8133494B2 (en) 2001-07-05 2012-03-13 Novartis Vaccine & Diagnostics Inc Expression cassettes endcoding HIV-1 south african subtype C modified ENV proteins with deletions in V1 and V2
JP2007515386A (ja) * 2003-09-18 2007-06-14 メルク　エンド　カムパニー　インコーポレーテッド Ｈｉｖ感染個体の治療用免疫化
WO2005027835A3 (fr) * 2003-09-18 2007-08-16 Merck & Co Inc Immunisation therapeutique d'individus infectes par le vih
WO2005027835A2 (fr) * 2003-09-18 2005-03-31 Merck & Co., Inc. Immunisation therapeutique d'individus infectes par le vih
US8722324B2 (en) 2004-09-08 2014-05-13 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Methods for the detection of HIV-1-specific antibodies employing GP41 polypeptides
EP2295974A1 (fr) * 2004-09-08 2011-03-16 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Compositions et procédés pour la détection d'une infection par VIH-1/VIH-2
US7888003B2 (en) 2004-09-08 2011-02-15 The United States Of America As Represented By The Department Of Health And Human Services Methods for the detection of HIV-1 antibodies employing polypeptides obtained from gag P6 protein
WO2007018550A3 (fr) * 2004-09-08 2007-11-29 Us Health Compositions et methodes pour detecter une infection par le vih-1/vih-2
US9121855B2 (en) 2004-09-08 2015-09-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method for the detection of HIV-1 antibodies utilizing a peptide containing a novel gp41 epitope
WO2011035082A1 (fr) * 2009-09-17 2011-03-24 Sanofi Pasteur, Inc. Compositions immunologiques pour le vih
AU2010295497B2 (en) * 2009-09-17 2014-10-09 Global Solutions For Infectious Diseases Immunological compositions for HIV
EP2987500A1 (fr) * 2009-09-17 2016-02-24 Sanofi Pasteur Inc. Compositions immunologiques pour le vih

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