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WO2002053183A1 - Vaccin contre l'hantavirus renfermant un adjuvant - Google Patents

Vaccin contre l'hantavirus renfermant un adjuvant Download PDF

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Publication number
WO2002053183A1
WO2002053183A1 PCT/SE2001/002788 SE0102788W WO02053183A1 WO 2002053183 A1 WO2002053183 A1 WO 2002053183A1 SE 0102788 W SE0102788 W SE 0102788W WO 02053183 A1 WO02053183 A1 WO 02053183A1
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WO
WIPO (PCT)
Prior art keywords
vaccine formulation
protein
formulation according
hantavirus
adjuvant
Prior art date
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Ceased
Application number
PCT/SE2001/002788
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English (en)
Inventor
Ulf SCHRÖDER
Cristina Afua De Carvalho Nicacio
Åke LUNDKVIST
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Eurocine AB
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Eurocine AB
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Filing date
Publication date
Application filed by Eurocine AB filed Critical Eurocine AB
Publication of WO2002053183A1 publication Critical patent/WO2002053183A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • 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
    • 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
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/12011—Bunyaviridae
    • C12N2760/12111—Hantavirus, e.g. Hantaan virus
    • C12N2760/12134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to a novel vaccine formulation against Hantavirus.
  • the preferred route of administration of the vaccine formulation is via the mucosal membranes.
  • the intranasal route has attracted increased attention because of the greater efficacy in inducing mucosal immune responses than the more conventional regimes of parenteral immunisation. Furthermore, the realisation that approximately 80% of the immune system reside in the mucosa combined with the fact that an equal percentage of the known pathogens enter our bodies via the mucosal membranes has pushed the interest towards the application of mucosal immunisation.
  • parenteral vaccines do not induce immune response at mucosal sites.
  • appropriate stimulation of a mucosal site such as the nose or the gut, can generate immune response at other mucosal sites.
  • the mucosal immune response is very rapid with onset only hours after being subjected to stimulation by a pathogen, as compared to parenteral immunity having a response time of several days.
  • Hantaviruses belong to the Bunyaviridae family, which consists of more than 350 viruses, making them one of the largest groupings of animal viruses.
  • Hantavirus has been implicated as aetiologic agents of two acute syndromes: haemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome (HPS). Both diseases are transmitted from rodents.
  • HFRS viruses are carried by Old World rodents and HPS viruses by New World rodents.
  • HFRS is an acute febrile illness, first recognised in the western world after an outbreak among American troops stationed in Korea in the 1950ies.
  • the disease later referred to as Korean haemorrhagic fever (KHF)
  • KHF Korean haemorrhagic fever
  • the disease progresses to haemorrhage (gastrointestinal, subconjunctival), haemodynamic instability, and occasionally to shock.
  • Thrombocytopenia, neutrophilia, atypical lymphocytes and haemoconcentration are common.
  • Mortality is due to shock or haemorrhage. Similar symptoms although generally less severe, are caused by the related SEO virus.
  • the mortality rate in SEO virus infections appears to be lower ( ⁇ 1%) than in HTN virus infections (5-15%).
  • PUU is the causative agent of nephropathia epidemica (NE) a milder form of HFRS, which is endemic in Scandinavia, Finland, the European parts of Russia, and Central Europe.
  • NE demonstrates strong clinical similarities to severe HFRS (caused by HTN or DOB hantaviruses) but is characterised by lower frequency of shock and haemorrhages.
  • NE 0.1-1%)
  • HTN DOB/SEO hantavirus infections The mortality rates for NE (0.1-1%) are considerably lower than for HTN DOB/SEO hantavirus infections, and only a few cases with a fatal outcome are known.
  • the most common clinical findings in NE patients are acute onset of symptoms; fever, headache, nausea, backpain, vomiting, myalgia, abdominal pain and visual disturbances.
  • One third of the patients have haemorrhagic manifestations and the majority have signs of renal failure, i. e. increased levels of serum creatinin, proteinuria and haematuria.
  • the Hanta viral particles are spherical/pleomorphic with varying diameters of 75-115 nm.
  • the nucleocapsids have a helical, filamentous structure, 200-3000 nm. long (depending on arrangement) with a diameter of 2-2.5 nm.
  • Hantaviruses are enveloped and have a three-segment negative stranded RNA genome packed in helical nucleo capsids.
  • the genome encodes four structural proteins: an RNA polymerase, two envelope glycoproteins (Gl and G2) and a nucleocapsid (N) protein. Distinct spikes of about 10 nm. consisting of the glycoproteins extend from the envelope.
  • the virus has no internal matrix protein; therefore, the virion structure is stabilised by direct interaction of the internal nucleocapsids with the cytoplasmic domain of the inserted glycoproteins.
  • Each virion contains approximately 25 copies of the L protein associated with 2100 molecules of the N protein, and 270-1400 widely distributed spike proteins extending from the surface.
  • the virions are composed of 1-2 % nucleic acid, over 50 % protein, 20-30 % lipid, and 2-7% carbohydrates, by weight.
  • the route by which the virus is transmitted to humans is via aerosols of infected excreta of rodents.
  • the rodent reservoir has been identified as being the bank vole. Infected rodents appear to be persistently infected.
  • HPS was first recognised in 1993, when a cluster of three unexplained adult respiratory distress syndrome cases occurring in the Four Corners region of the United States. HPS is characterised by an initial fever followed by the abrupt onset of acute pulmonary oedema and shock. The most common prodromal symptoms are fever, myalgia, dyspnea, gastrointestinal symptoms, and headache. Physical findings are tachypnea, tachycardia and hypotension.
  • the basic response after immunising a mammal may be described as being humural or cellular:
  • a humural response is characterised by the formation of antibodies against the invading pathogen and the cellular is characterised by the activation of the T cells in the immune system.
  • N protein is capable of generating protective immunity based on a cellular response, not only against virus challenge from the homologous strain of the virus, but also from distant hantaviruses (e.g. DOB and AND) causing the more severe form of HFRS and HPS.
  • amino acid sequence of the N-protein from PUU-KAZ has been determined (Lunkvist, A. et al, J. Virology (1997) 71:9515-9523) and the 433 amino acids has the following sequence:
  • virus vaccines which comprise, as an immunising component, at least one member of the group consisting of a) a recombinant N protein b) fragments of said protein which comprise B-cell and/or T-cell epitopes and, c) amino-acid sequences which are at least 80% homologous to the sequences of a) or b) and which comprise B-cell and/or T-cell epitopes.
  • Example 3 the voles were partially protected after challenge with DOB and AND viruses, both of which are known as "killer virus” and furthermore, coming from distant parts of the world, as compared to the PUU virus from which the rN protein was cloned.
  • Adjuvants are a heterogeneous group of substances that enhance the immunological response against an antigen that is administered simultaneously. Almost all adjuvants used today for enhancement of the immune response against antigens are particles or are forming particles together with the antigen. In the book “Vaccine Design - the subunit and adjuvant approach” (Ed: Powell & Newman, Plenum Press, 1995) almost all known adjuvants are described both regarding their immunological activity and regarding their chemical characteristics. As described in the book more than 80% of the adjuvants tested today are particles or polymers that together with the antigens (in most cases proteins) are forming particles.
  • the type of adjuvants that are not forming particles are a group of substances that are acting as immunological signal substances and that under normal conditions consist of the substances that are formed by the immune system as a consequence of the immunological activation after administration of particulate adjuvant systems.
  • the antigens are associated or mixed with or to a matrix, which has the characteristics of being slowly biodegradable. Of great importance using such matrix systems are that the matrices do not form toxic metabolites.
  • the kinds of matrices that can be used are mainly substances originating from a body. With this background there are only a few systems available that fulfil these demands: lactic acid polymers, poly-amino acids (proteins), carbohydrates, lipids and biocompatible polymers with low toxicity. Combinations of these groups of substances originating from a body or combinations of substances originating from a body and biocompatible polymers can also be used.
  • Lipids are the preferred substances since they display structures that make them biodegradable as well as the fact that they are the most important part in all biological membranes. Lipids are characterised as polar or non-polar. The lipids that are of most importance in the present invention are the polar lipids since they have the capacity to interact and form particulate systems in water. Another way of defining these lipids are as amphiphilic due to their chemical structure with one hydrophobic and one hydrophilic part in the molecule thereby being useable as surface active substances. Examples of main groups of polar lipids are mono-glycerides, fatty acids, phospholipids and glycosphingolipids.
  • the lipids may spontaneously form, or can be forced to form, stabile systems.
  • other surface-active substances have to be introduced in order to achieve stability.
  • Such surface-active systems can be of non-lipid character but possess the characteristics of the polar lipids having hydrophobic and hydrophilic parts in their molecular structure.
  • lipids exhibit different physical chemical phases, these phases have in different test systems been shown to enhance uptake of biological substances after administration to mucous membranes.
  • physical chemical phases described are L2, lamellar, hexagonal, cubic and L3.
  • the disclosed formulation comprises monoglycerides and fatty acids.
  • the monoglycerides comprise one or more substances selected from monoglycerides wherein the acyl group contains from 6 to 24 carbon atoms, preferably 8 to 20 carbon atoms, even more preferably 14 - 20 carbon atoms and where the acyl chain may contain unsaturated bonds.
  • the acyl chain of the fatty acid may be varied between 4 and 22, preferably 8 to 18 and where the acyl chain may contain one or more unsaturated bonds.
  • a combination of the monoglyceride mono-olein and oleic acid has shown to be an L3 phase, which can be described as sponge-like structure, in contrast to liposomes that form onion-like lamellar structures.
  • Said combination of monoglycerides and fatty acids may be further formulated by the addition of a biocompatible and biodegradable oil thus forming an oil in water (o/w) or w/o/w emulsion.
  • a biocompatible and biodegradable oil thus forming an oil in water (o/w) or w/o/w emulsion.
  • Such emulsions have been shown in the literature to be very effective in enhancing the cellular response against an antigen after administration to an animal (Singh, M., et al 1997, Vaccine 15, 1773-78). It is generally accepted that in order to have an acceptable vaccine against most viruses there is a need for a cellular immune response.
  • One way of producing such a system would be to use antigenic components from virus which would have the capacity to provoke an immune response in a body, preferably producing a protective immunity against the pathogen which was the origin of the antigen.
  • the present invention is directed to a vaccine formulation against a microorganism comprising, as adjuvant, one or more substances selected from a) monoglyceride preparations having at least 80 % monoglyceride content and having the general formula CH — CH CH 2
  • R ⁇ and R 2 is H and R 3 is one acyl group containing from 6 to 24 carbon atoms, and where the acyl chains may contain one or more unsaturated bonds and b) fatty acids of the general formula CH 3 - (CH 2 ) n - COOH where "n" may be varied between 4 and 22, and where the acyl chain may contain one or more unsaturated bonds, and the recombinantly produced N protein from a Hantavirus.
  • the adjuvant of the vaccine formulation of the invention preferably has a monoglyceride preparation content of at least 90 %, preferably at least 95 %, and the acyl chains of the monoglyceride preparation contains 8 to 20 carbon atoms, preferably 14 to 20 carbon atoms, and the acyl chains optionally contains one or more unsaturated bonds, and the recombinantly produced N protein from a Hantavirus.
  • the vaccine formulation according to the invention may further comprise pharmaceutical excipients selected from the group consisting of biocompatible oils, such as such as rape seed oil, sunflower oil, peanut oil, cotton seed oil, jojoba oil, squalan or squalene, physiological saline solution, preservatives and osmotic pressure controlling agents, carrier gases, pH-controlling agents, organic solvents, hydrophobic agents, enzyme inhibitors, water absorbing polymers, surfactants, absorption promoters, and anti-oxidative agents.
  • biocompatible oils such as such as rape seed oil, sunflower oil, peanut oil, cotton seed oil, jojoba oil, squalan or squalene, physiological saline solution, preservatives and osmotic pressure controlling agents, carrier gases, pH-controlling agents, organic solvents, hydrophobic agents, enzyme inhibitors, water absorbing polymers, surfactants, absorption promoters, and anti-oxidative agents.
  • a most preferred embodiment of the invention is a vaccine formulation which comprises, as adjuvant, a mixture of mono-olein and oleic acid, and possibly soybean oil, and, as immunizing component, the recombinantly produced N protein from a Hantavirus.
  • the formulation is formulated into a preparation for mucosal administration, such as nasal, pulmonary, oral, rectal or vaginal administration.
  • a preparation for mucosal administration such as nasal, pulmonary, oral, rectal or vaginal administration.
  • Another aspect of the invention is directed to an aerosol or spray package comprising a vaccine formulation according to the invention.
  • Yet another aspect of the invention is directed to a nose-drop package comprising a vaccine formulation according to the invention.
  • a further aspect of the invention is directed to a method of vaccinating a mammal against a virus having the recombinantly produced N protein from a Hantavirus, which comprises mucosal administration to the mammal of an protection- inducing amount of a Hanta vaccine formulation according to the invention.
  • the present invention describes a formulation that may be prefabricated, and therefore no need for skilled personnel is needed upon nasal administration, thereby eliminating injection systems such as needles and syringes which in developing world often are contaminated and thus is spreading diseases between patients. Furthermore, a device for multidose aerosol delivery of a nasal vaccine can easily be constructed in way that no person-to-person infection can occur.
  • ORF of the PUUV (strain Kazan-E6) N protein gene was cloned and sequenced.
  • the N ORF encoding amino acids (aa) 1-433, was amplified from cDNA with primers 5' TTG CAT GCT TAT GAG TGA CTT GAC AGA CAT CCA.
  • the N ORF was cloned into the pQE-32 vector (Qiagen), containing a T5 promotor and encoding a polyhistidine tag to facilitate purification, according to the manufacturer's instructions.
  • Competent Ml 5 [pREP4_/ E. coli cells were transformed and spread on Luria-Bertani agar containing 100 ⁇ g/ml ampicillin and 25 ⁇ g/ml kanamyan. Selected colonies were grown in super broth medium containing antibiotics, as above, and induced with IPTG (1 mM). Induced mini cultures were screened for expression of N protein by immunoblotting with a pool of PUUV N- specific monoclonal antibodies (MAbs). Colonies containing a fusion protein of the expected size were selected for further amplification and purification. The rN protein was extracted and purified, using the polyhistidine tag, on a column containing nickel- agarose (Qiagen).
  • DHFR mouse dihydrofolate reductase
  • the sequence of the cloned S gene was confirmed by nucleotide sequence analysis using sequencing primers provided by the vector supplier (Qiagen).
  • the expressed rN protein gave a band of the expected size (about 54 kDa) by immunoblot with a pool of PUUV-specif ⁇ c MAbs or a polyhistidine-specif ⁇ c Mab.
  • the rN protein was also characterized with a panel of 13 N-specific MAbs which recognized all the epitopes earlier seen in E. cot ⁇ -expressed recombinant proteins.
  • T-helper cell recognition sites Localization of T-helper cell recognition sites. Immunizations were carried out on groups of five to six mice (each group of a different haplotype) intraperitoneally with 20 ⁇ g of rN protein emulsified in Freund's complete adjuvant (FCA). The mice were boosted 4 weeks later subcutaneously with 50 ⁇ g of rN protein emulsified in Freund's incomplete adjuvant and sera were collected by retroorbital bleedings at 2, 4 and 6 weeks.
  • FCA Freund's complete adjuvant
  • mice For proliferation assays and cytokine detection, groups of mice were immunized subcutaneously in the base of the tail with 50 ⁇ g of rN protein emulsified in FCA.
  • mice For peptide immunizations, mice were injected with 100 ⁇ g of peptide emulsified in FCA.
  • the rN protein raised PUUV-specific antibodies in inbred mice and all IgG subclasses were detected. Epitope mapping using peptides spanning the N protein reveal that the B-cell recognition sites were mainly located at the aminoterminal part of the protein. Proliferative T-helper (Th) lymphocyte responses were detected in all haplolypes after a single immunization with rN. Several Th-recognition sites, spanning amino acids 6-27, 96-117, 211-232 and 256-277, were identified using overlapping peptides. Peptides representing the identified sites could also prime Th-lymphocytes to proliferate in response to recall with rN protein, thereby confirming the authenticity of the identified sites. The rN-primed Th lymphocytes produced predominantly interleukin (IL)-2 and gamma interferon, together with lower levels of IL-4 and IL-6, indicating a mixed Thl/Th2 response.
  • IL interleukin
  • rN protects 100% of the voles which were vaccinated with the homologous N protein, determined as detectable antigen (Ag-ELISA) or RNA (RT-PCR) in the lung tissue of the challenged animal. Furthermore, 65 to 100% of the voles challenged with non-homologous strain were also protected.
  • the emulsion was produced by mixing the rN protein with 100 ⁇ l of soybean oil and 100 ⁇ l of a mixture of mono-olein and oleic acid (1:1). The amount of rN protein was adjusted so that a dose of 10 ⁇ g was given to the mice in 100 ⁇ l (parenteral) or in 10 ⁇ l (nasal). This mixture was sonicated briefly for a few seconds whereafter 1.0 ml of 0.1M TRISS buffer and 20 ⁇ l of 4 M NaOH was added. Sonication was performed for 2 minutes whereafter the vaccine formulation was used for immunization.
  • the voles were killed and the amount of virus was determined in the lung tissue by two different methods, either using a method which detects proteins from the virus (known as an antigen-ELISA) or using a PCR method for detection of virus RNA in the tissue.
  • a method which detects proteins from the virus known as an antigen-ELISA

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Abstract

L'invention concerne une formulation de vaccin contre un micro-organisme. Cette formulation comprend comme adjuvant une ou plusieurs substances sélectionnées entre : (a) des préparations de monoglycéride présentant une teneur de monoglycéride d'au moins 80 %, et (b) des acides gras de formule générale CH3-(CH2)n-COOH dans laquelle « n » peut varier entre 4 et 22 et la chaîne acyle contient une ou plusieurs liaisons non saturées, et comme composant immunisant un produit immunogène constitué d'une N protéine d'Hantavirus active sur le plan antigénique. Cette formulation peut comprendre comme adjuvant un mélange de mono-oléine et d'acide oléique, et éventuellement une huile de soja, et, comme agent immunisant, la N protéine d'un Hantavirus.
PCT/SE2001/002788 2001-01-03 2001-12-14 Vaccin contre l'hantavirus renfermant un adjuvant Ceased WO2002053183A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0100011A SE0100011D0 (sv) 2001-01-03 2001-01-03 Virus vaccine formulation
SE0100011-6 2001-01-03

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049764A1 (fr) * 2001-12-12 2003-06-19 Fh Faulding & Co Limited Composition de preservation virale
WO2004047861A1 (fr) * 2002-11-26 2004-06-10 Eurocine Ab Vaccins contre des virus a substances cationiques utilisees en tant qu'additifs
AU2002366653B2 (en) * 2001-12-12 2008-05-15 Commonwealth Scientific And Industrial Research Organisation Composition for the preservation of viruses
CN110548136A (zh) * 2018-05-30 2019-12-10 王美亮 汉坦病毒长肽疫苗

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183658A (en) * 1988-11-18 1993-02-02 Korea Green Cross Corporation Hantaan virus strain ROK84/105 and vaccine therefor
WO1997028819A1 (fr) * 1996-02-06 1997-08-14 Sbl Vaccin Ab Vaccin contre les hantavirus
WO1997047320A1 (fr) * 1996-06-10 1997-12-18 Pharmatrix Ab Formulation de lipides immunostimulants
US5916754A (en) * 1995-02-17 1999-06-29 The United States Of America As Represented By The Department Of Health And Human Services Bayou hantavirus and related methods

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183658A (en) * 1988-11-18 1993-02-02 Korea Green Cross Corporation Hantaan virus strain ROK84/105 and vaccine therefor
US5916754A (en) * 1995-02-17 1999-06-29 The United States Of America As Represented By The Department Of Health And Human Services Bayou hantavirus and related methods
WO1997028819A1 (fr) * 1996-02-06 1997-08-14 Sbl Vaccin Ab Vaccin contre les hantavirus
WO1997047320A1 (fr) * 1996-06-10 1997-12-18 Pharmatrix Ab Formulation de lipides immunostimulants

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUNG CHOON YOO ET AL.: "Adjuvant activity of muramyl dipeptide derivatives to enhance immunogenicity of a hanta-virus inactivated vaccine", VACCINE, vol. 16, no. 2/3, 1998, pages 216 - 224, XP004098626 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049764A1 (fr) * 2001-12-12 2003-06-19 Fh Faulding & Co Limited Composition de preservation virale
WO2003049763A1 (fr) * 2001-12-12 2003-06-19 Fh Faulding & Co Limited Composition pour la conservation de virus
US7091030B2 (en) 2001-12-12 2006-08-15 Kerrie Setiawan Composition for the preservation of viruses
AU2002366653B2 (en) * 2001-12-12 2008-05-15 Commonwealth Scientific And Industrial Research Organisation Composition for the preservation of viruses
WO2004047861A1 (fr) * 2002-11-26 2004-06-10 Eurocine Ab Vaccins contre des virus a substances cationiques utilisees en tant qu'additifs
CN110548136A (zh) * 2018-05-30 2019-12-10 王美亮 汉坦病毒长肽疫苗

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