(adapted from Michelle Giles and Suzanne M. Garland in Papillomaviruses) Papillomavirus Vaccines: There are potentially three stages of oncogenic anogenital HPV infection in which vaccine mediated immune intervention strategies could be implemented. The first is a prophylactic vaccine which aims to elicit a neutralizing antibody mediated inhibition of HPV binding to the cell surface receptor or a subsequent step in the cell invasion pathway. The second potential role of HPV vaccination is after infection when the virus is replicating in the basal cells of the epithelium. A therapeutic vaccine directed toward early viral proteins would aim to eliminate infection. Finally, if the virus has integrated into the host and transformed the cell, another therapeutic vaccine would be aimed at controlling growth of invasive tumors.
Currently, there are two different types of vaccines: prophylactic vaccine that would elicit an antibody response and prevent infection, and therapeutic vaccine which would induce a specific T cell mediated response leading to regression of already existing lesions. Antibodies to the viral capsid proteins L1 and L2 can neutralize extracellular virus and, in animal models, not only protect against primary infection, but also provide resistance to challenge with high dose of homologous virus. Neutralizing antibodies are also long lasting with passive transfer offering protection against experimental challenge. HPV E6 and E7 gene products are attractive candidates for a therapeutic vaccine as these are expressed in all HPV induced lesions and are required to maintain the proliferative state. Because HPV is difficult to obtain in sufficient quantities from in vitro culture systems, an attenuated virus vaccine is unlikely. Development of an HPV vaccine relies on expression of recombinant viral antigen in cell systems or the use of overlapping synthetic peptides corresponding to individual gene products.
Virus-like particles (VLPs) are DNA free and can be produced in yeasts, for example, Saccharomyces cerevisiae or higher eukaryotic cells via vaccinia virus or Semliki Forest virus vectors. The VLPs are morphologically indistinguishable from the complete native virion, yet provide a source of epitopes in a conformational correct format, typically genotype specific, and elicit an antibody response (see Chapter 18 for a full description of the properties of VLPs). VLPs are attractive candidates for a prophylactic vaccine.
A therapeutic vaccine needs to be able to prime cytotoxic T lymphocytes directed to epitopes derived from intracellularly processed viral proteins presented by MHC class I complexes. The target proteins should be ones expressed in the suprabasal epithelium rather than in the differentiated layer of HPV infected epithelium, as this would not eliminate the underlying self-renewing stem cells. E1 and E2 proteins are the major antigens expressed in the suprabasal epithelium; however these are expressed in very small quantities and may escape specific CTL attack. Ideally a therapeutic vaccine would be combined with a means of up-regulating E1 and E2 expression.
HPV16 E6 and E7 proteins are potential targets for cytotoxic T cell responses and for stimulating immunity with a therapeutic vaccine as they are constitutively expressed in high-grade squamous intraepithelial lesions (HSIL) and cancer of the cervix and never deleted in HPV transformed cells. Continued expression of the oncogenes E6 and E7 is essential for progression to and maintenance of the malignant phenotype, so these are potential targets for a vaccine aimed at controlling HPV induced tumors. HPV induced tumor cells have devised ways of evading the hosts immune system; for example by point mutations in the CTL epitopes, loss of expression of MHC class I alleles or by down regulating endogenous peptide processing for MHC presentation. Strategies to overcome these problems include development of a vaccine which is engineered ex vivo to secrete cytokines or combining the target protein for example, E7 to the lysosomal and endosomal components of the MHC class II pathway using a lysosomal-associated membrane protein (LAMP) sorting signal. This last method has been used in mice with vaccinia virus containing a chimeric E7/LAMP-1 gene, which generated greater antibody response than E7 alone.
An authoritative reference on Papillomavirus Vaccines is provided by the new book Papillomaviruses.
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