Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-11-18
1999-03-30
Knode, Marian C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 2372, 435 691, 435 697, 514 44, C07H 2102, C07H 2104, C12P 2106, A01N 4304
Patent
active
058891684
DESCRIPTION:
BRIEF SUMMARY
RELATED APPLICATIONS
This application claims priority under 35 U.S.C. .sctn.119 to GB9409962.9 filed May 18, 1994.
The present invention relates to recombinant cytomegalovirus proteins, more particularly to fusion proteins comprising a portion of a human cytomegalovirus (HCMV) protein and a portion of a protein from herpes simplex virus (HSV) and their expression in eukaryotic cells. The invention further relates to methods of constructing and expressing the said fusion proteins, intermediates for use therein and recombinant proteins which may be obtained from the intermediates. Recombinant proteins of the invention have potential utility in the development of vaccines for the prevention of HCMV infection and/or HSV infection.
HCMV is human DNA virus belonging to the family of herpes viruses. In common with other herpetic viruses (such as Herpes Simplex Virus (HSV) Varicella Zoster Virus (VZV)) HCMV is made up of a DNA core, an outer capsid and covered by a lipid membrane which incorporates virus specific glycoproteins.
Human cytomegalavirus is endemic in most parts of the world. Primary infection however normally results in subclinical disease after which the virus becomes latent retaining the capacity to reactivate at any time. Among two populations, HCMV is however responsible for serious medical conditions. HCMV is a major cause of congenital defects in new borns. Also associated with infection in such infants, are hearing loss, and poor intellectual performance. The second population at risk are immunocompromised patients such as those suffering from HIV infection and those patients undergoing transplantations. In this situation the virus becomes an opportunistic pathogen and causes severe disease with high morbidity and mortality. The clinical disease causes a variety of symptoms including fever, hepatitis, pneumonitis, and infectious mononucleosis.
This therefore explains the extensive efforts of those skilled in the art and the importance of studies dedicated to the biology of these viruses. However no efficient vaccine against HCMV is currently available.
Therefore there still exists a need for antigens which will effectively protect against challenge with the HCMV virus.
According to a first aspect of the present invention there is provided a fusion protein or an immunogenic derivative thereof comprising a portion of an HCMV glycoprotein fused to a portion of a glycoprotein of HSV.
By a portion of an HCMV glycoprotein is meant a part of the protein which contains at least one antigenic determinant capable of raising an immune response specific to HCMV. A preferred HCMV glycoprotein is gB.
By a portion of a glycoprotein of HSV is meant a part of the protein which contains at least the signal sequence of the glycoprotein and optionally additional parts of the protein which contain at least one antigenic determinant capable of raising an immune response specific to HSV and/or contain a sequence enhancing the secretion of the protein when suitably expressed. A preferred HSV glycoprotein is gD, in particular HSV type 2gD.
The gB protein of HCMV strain AD 169 contains 906 amino acid residues; amino acids 1 to 24 correspond to the signal peptide and residues 712 to 776 the membrane anchor domain. The molecule presents 19 potential sites for glycosylation. Used alone for immunization, the gB protein generates an immune response which is insufficient to confer protection against a challenge with the virus.
The protein gD from herpes simplex virus (HSV) is composed of 394 amino acids; its membrane anchor domain occurs in the C-terminal end of the molecule, between amino acid residues 339 and 365.
Preferably the fusion is between an amino acid in the N-terminal part of a portion of the HCMV gB protein and an amino acid at the C terminus of a portion of the HSV gD protein.
Preferably both the HCMV gB protein and the HSV gD protein components of the fusion protein of the invention lack a membrane anchor domain.
Preferably the portion of the HCMV gB protein comprises a non-cleaveable form of HCMV gB. Suitably
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Sambrook et al. In: Molecular Cloning, A Laboratory Manual, 2nd edition, pp. 11.7-11.8, 1989.
Forrester, et al., "Construction and Properties of a Mutant of Herpes Simplex Virus Type 1 with Glycoprotein H Coding Sequences Deleted", Journal of Virology, 66 No. 1, pp. 341-348 (1992).
Cranage, et al., "Identification of the human cytomegalovirus glycoprotein B gene and induction of neutralizing antibodies via its expression in recombinant vaccinia virus", The EMBO Journal, 5 No. 11, pp. 3057-3063 (1986).
Flexner, et al., "Successful vaccination with a polyvalent live vector despite existing immunity to an expressed antigen", Nature, 335 No. 6187, pp. 259-262 (1988).
Eagle Alissa M.
King William T.
Knode Marian C.
SmithKline Beecham s.a.
Venetianer Stephen
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