Perspectives for preventive and therapeutic HPV vaccines

Abstract

Human Papillomavirus (HPV) has been associated with several human cancers, including cervical cancer, vulvar cancer, vaginal and anal cancer, and a subset of head and neck cancers. Thus effective vaccination against HPV provides an opportunity to reduce the morbidity and mortality associated with HPV. The Food and Drug Administration of the United States has approved two preventive vaccines to limit the spread of HPV. However, these are unlikely to impact upon HPV prevalence and cervical cancer rates for many years. Furthermore, preventive vaccines do not exert therapeutic effects on pre-existing HPV infections and HPV-associated lesions. In order to further impact upon the burden of HPV infections worldwide, therapeutic vaccines are being developed. These vaccines aim to generate a cell-mediated immune response to infected cells. This review discusses current preventive and therapeutic HPV vaccines and their future directions.

Figure 1

HPV-16 genome and protein function. HPV-16 has a 7904 base pair, double-stranded circular DNA genome. The transcriptional promoter is designated P₉₇. A_E and A_L are the early and late polyadenylation sites, respectively. The viral long control region (LCR) contains transcriptional and replication regulatory elements. The HPV-16 genome contains six early genes (E1, E2, E4, E5, E6, E7) and two late genes (L1, L2). The late genes comprise the viral capsid while the early genes are involved in viral replication. E1 regulates episomal viral DNA replication. E2 is a transcriptional regulator of E6 and E7. E4 is involved in cytoskeletal reorganization. E5 is involved in cellular transformation. E6 and E7 are responsible for the induction of malignant transformation by binding to p53 and retinoblastoma (Rb) protein, respectively.

Figure 2

Therapeutic HPV vaccines. A number of therapeutic vaccines have been developed targeting HPV E6 and/or E7 antigen(s), including live vector-based vaccines, peptide/protein-based vaccines, nucleic acid-based vaccines and cell-based vaccines. These vaccines likely control HPV infection through cell-mediated immunity. Dendritic cells (DCs) prime naïve T cells through MHC:Antigen (Ag) complex with the help of costimulatory molecules (B7 on the DC and CD28 on the T cell). Antigens are processed and presented to CD4+ T cells via MHC class II pathway and presented to CD8+ T cells via MHC class I pathway. The primed effector T cells are subsequently HPV-antigen-specific T cells. Activated CD8+ T cells kill tumor cells by inducing apoptosis in the target cells. Induction of CD4+ T cell help can augment the CD8+ T cell immune response, supplementing tumor killing.

Figure 3

Strategies to improve DC-T cell interaction in enhancing therapeutic DNA vaccine potency. (A) Prolonging DC survival. Once DCs have primed naïve T cells, they can become the target of these effector T cells. The use of short interfering RNA (siRNA) targeting key pro-apoptotic proteins such as Bak and Bax can transiently silence expression of Bak and Bax, improving DNA-transfected DC resistance to apoptosis and improving DC-T cell interaction. (B) Prevention of activated CD8+ T cell apoptosis. The Fas ligand (FasL) found on the surface of DCs is a pro-apoptotic signalling protein that binds to the Fas receptor on T cells, causing them to undergo apoptosis. Creation of DNA encoding small hairpin RNA (shRNA) to block FasL can prevent apoptosis of activated T cells and improve DC-T cell interaction.

Figure 3

Strategies to improve DC-T cell interaction in enhancing therapeutic DNA vaccine potency. (A) Prolonging DC survival. Once DCs have primed naïve T cells, they can become the target of these effector T cells. The use of short interfering RNA (siRNA) targeting key pro-apoptotic proteins such as Bak and Bax can transiently silence expression of Bak and Bax, improving DNA-transfected DC resistance to apoptosis and improving DC-T cell interaction. (B) Prevention of activated CD8+ T cell apoptosis. The Fas ligand (FasL) found on the surface of DCs is a pro-apoptotic signalling protein that binds to the Fas receptor on T cells, causing them to undergo apoptosis. Creation of DNA encoding small hairpin RNA (shRNA) to block FasL can prevent apoptosis of activated T cells and improve DC-T cell interaction.