Variants of human papilloma virus antigens

#This invention relates generally to variants of human papilloma virus (HPV) antigens, and in particular it relates to non-transforming variants of HPV antigens which are suitable for use in vaccines. The invention also extends to vaccine compositions which include these variants of HPV antigens as active immunogens, as well as to methods of use of these variants to elicit an immune response against HPV.

#Papillomaviruses are small DNA viruses that infect a variety of animal species. Some are associated with the development of malignancies in their natural hosts. Over 60 types of human papillomavirus (HPV) have been identified. These infect humans at a variety of body locations and are responsible for common skin warts, laryngeal papillomas, genital warts and other wart-like lesions. Genital HPV infections are particularly common and a number of HPV types, but most frequently types 6, 11, 16 and 18, infect the genital tract in both men and women. In women, HPVs infect various portions of the genital tract including the cervix.

#Genital HPVs are a significant clinical problem. HPV infection of the ano-genital region is now regarded as the most common form of viral sexually-transmitted disease (STD). The viruses cause genital infections which become manifest in one of three ways:

#FIGS. 1(a)-(d) show domain maps for the different proteins referenced herein.

#FIG. 2 shows amounts of fusion protein produced in transformed cells following IPTG induction in Example 1.

#FIG. 3 shows a Western blot of a protein described in Example 2.

#As used herein, references to the variant of this invention as being “not cell-transforming in the host animal” mean that the cell-transforming property of the “parent” or wild-type HPV E6 or E7 protein has been reduced, and preferably effectively eliminated, in the variant. In particular, these references indicate that this cell-transforming property has been significantly reduced in comparison with wild-type E6 or E7 protein in appropriate test systems.

#It will be appreciated that where the non-transforming variant HPV E6 or E7 protein of this invention is produced by expression of an appropriate encoding recombinant DNA molecule, the nature of that encoding DNA, unlike the wild-type E6 or E7 genes, would not have the potential to initiate irreversible transformation events in the cells of the host animal.

#The variant HPV E6 or E7 proteins of the present invention include, but are not limited to, deletion mutants of the wild-type E6 or E7 proteins in the form of non-full length fragments of the wild-type proteins, as well as fusion proteins in which E6 and/or E7 moieties are fused, optionally with a linkage of from 1 to 50, preferably a short linkage of from 1 to 20, and more preferably from 1 to 5, amino acid residues between the E6 and/or E7 moieties. The E6 and/or E7 moieties in such a fusion protein may comprise the full wild-type E6 or E7 proteins, or alternatively they may comprise non-full length fragments of the wild-type proteins. The fusion proteins may also comprise other moieties fused or otherwise coupled thereto, for example moieties to assist in purification of the fusion protein (for example, a glutathione-S-transferase or GST moiety or hexa-His moiety) or to enhance the immunogenicity of the fusion protein (for example an adjuvant such as diphtheria or cholera toxin or a non-toxic derivative thereof such as the holotoxoid or B sub-unit of cholera toxin).