Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1997-12-12
2002-04-16
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S197110, C424S201100, C424S218100, C424S239100, C424S281100, C424S093300, C424S093600
Reexamination Certificate
active
06372221
ABSTRACT:
The present invention relates to an immunogenic construct, a process for its preparation as well as its use as a vaccine.
The basis for the recognition of foreign immunogens by the immune system is still the subject of intense research. Each individual is exposed time and again to exogenous substances and it is often the case that only a weak immune response is induced against the corresponding substances.
Many vaccines are based on the use of attenuated microorganisms, for example attenuated viruses, which have the disadvantage however that they include virulent material, even if in a weakened form. These can then lead to an infection when using the corresponding attenuated microorganism to immunize humans and animals with an impaired and/or actively suppressed immune system. Disadvantages can also arise by reversion or—in the case of retroviruses—through recombination.
For these reasons, inactivated microorganisms and/or specially selected, highly purified proteins derived from the corresponding microorganism, polysaccharides or other immunogenic parts of the microorganism are more frequently being administered as vaccines instead of attenuated microorganisms. However, many of the proteins or polysaccharides and/or their epitopes known and used for this are only weakly immunogenic and the corresponding immune response, for example the formation of antibodies, is extremely weak.
Therefore, it is desirable to increase the immune response against weakly immunogenic substances and various methods for this are known in the art.
The use of adjuvants is an example of this. An adjuvant is an auxiliary agent which when administered together or parallel with an antigen increases its immunogenicity and/or influences the quality of the immune response. Hence, the adjuvant can considerably influence the extent of the humoral or cellular immune response for example. Customary adjuvants are aluminum compounds, lipid-containing compounds or inactivated mycobacteria for example. The use of particular carrier substances such as KLH (keyhole Limpet Hemocyanin) is also among the latest current methods to increase immune responses.
Aside from the bacterial products often used for increasing the immunogenicity of weakly immunogenic substances, the use of hepatitis B antigens as a carrier substance is also described in the art.
Hence, an immunogenic hybrid polypeptide consisting of hepatitis B surface antigen (HBsAg) or a fragment thereof which was bound to a further polypeptide component over a native sulfur atom is described in WO 92/11291 for example.
An immunogenic polypeptide conjugate is known from EP 0 271 302 which comprises hepatitis B core antigen (HBcAg) coupled with a further immunogenic polypeptide over an amino acid side-chain group.
A frequently described disadvantage of the hepatitis B antigens used as carrier substances is the immunodominace of these antigens when they are administered together with other immunogens. The immune response against an immunogen bound to hepatitis B antigen is only weakly pronounced by this.
Recombinant flaviviruses are known from WO 93/06214 which contain nucleic acids derived from at least two flaviviruses. These chimeric viruses contain, for example, the region of a nucleic acid which codes for a structural protein of TBEV and is combined with the region of a nucleic acid which codes for a structural protein of a flavivirus differing from TBEV, for example, Dengue virus. These chimeric viruses are described, among others, for use as live vaccines.
An object of the present invention is to provide a new immunogenic construct that enhances the immune response of a weak immunogen and simultaneously avoids the disadvantages known in the art. Additionally, a method for the production of said construct as well as the use as a vaccine are provided according to the invention.
The above problem is solved according to the invention by providing an immunogenic construct comprising as components (i) an inactive flavivirus or a derivative thereof, and (ii) at least one immunogenic component which is bound to the flavivirus and/or to the derivative.
It was surprisingly found that in binding small amounts of an immunogen to a flavivirus and/or a derivative thereof, the immune response against this immunogen is particularly enhanced. This behavior also indicates that an immune response against weak immunogens is generally enhanced through binding to a flavivirus and/or to a derivative thereof.
In the following, the inactive flavivirus is understood as a virus which no longer has the capacity to replicate in a suitable host and is therewith non-infectious.
The flavivirus is preferably an inactivated virus. For example, it can be a yellow fever virus, hepatitis C virus, Dengue virus or a Japanese Encephalitis virus. An inactive or inactivated TBE virus is particularly preferred, a TBE virus of the western subtype (FSME virus) is most preferred.
The flavivirus can be inactivated by a chemical or physical treatment. For example, a chemical treatment of the flavivirus can consist of a treatment with formaldehyde. A physical treatment can be conducted, for example, by heating and/or by a treatment with radiation (UV-irradiation, radioactive irradiation) and/or by ultrasound treatment. It can also be an attenuated virus which has been attenuated, for example, preferably by at least two mutations, by multiple passages in suitable cells or by targeted mutagenesis. The flavivirus can also be a recombinantly produced virus or a sub-viral and/or virus-like particle.
An inactivated whole virus or corresponding flavivirus antigens and/or derivatives of flavivirus are to be understood within the meaning of the invention under the term ‘inactive flavivirus or a derivative thereof’.
For example, derivatives of a flavivirus can be viral fragments. Within the meaning of the invention, such fragments of a flavivirus are polypeptides, proteins, polysaccharides, nucleic acids or combinations thereof.
For example, the fragment can be a structural protein of a flavivirus or a part of a structural protein. The size of the fragments can strongly vary; a size of 10 kDa can be seen as a minimum size of the fragment.
For example, a derivative of a flavivirus can also be a chemically modified virus fragment, a synthetically produced polypeptide with analogy to a part of the flavivirus or a synthetically produced structure which increases the adjuvant property of the derivative.
The immunogenic component, which is enhanced in its immune response by the inactive flavivirus or a derivative thereof, is a protein, a polypeptide, a polysaccharide or a nucleic acid and/or a combination of two or more of the above mentioned components or an inactive microorganism. In particular embodiments, the protein, polypeptide, polysaccharide or nucleic acid is derived or originates from a virus, bacterium, fungus or parasite or is derived or originates from an allergen.
Should the immunogenic component be derived from a virus, then the virus is preferably selected from the family of the Hepadnaviridae, Herpesviridae, Poxviridae, Adenoviridae, Papovaviridae, Parvoviridae, Retroviridae, Togaviridae or Flaviviridae. For example, the virus can be HIV, herpes simplex virus, influenza virus hepatitis A, B, C, D, G, E or X.
The immunogenic component can be a protein of a virus, for example, gp160, gp120or p24 of HIV, but can also represent a different subunit of the virus, for example, a regulatory protein such as nef or rev of HIV.
The immunogen can be a so-called subunit vaccine, a recombinant vaccine, an inactive whole virus or a virus-like particle.
Should the immunogenic component be derived from a bacterium, this bacterium is preferably selected from the group Bordetella, Haemophilus, Borrelia, Pseudomonas, Corynebacteria, Mycobacteria, Streptococci, Salmonella, Pneumococci, Staphylococci, Clostridia or Helicobacter.
Should the immunogenic component originate from a parasite, then the parasite is preferably selected from the group Amaebida, Trypanosoma or Plasmodium.
Preferably, the immunogenic component differs f
Leibl Heinz
Leibl Martha
Mannhalter Josef W.
Baker & Botts L.L.P.
Bio-Products & Bio-Engineering Aktiengesellschaft
Wortman Donna C.
LandOfFree
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