Therapeutic vaccines for high-risk HPV-associated diseases

Abstract

Cancer is the second leading cause of death worldwide, and it is estimated that Human papillomavirus (HPV) related cancers account for 5% of all human cancers. Current HPV vaccines are extremely effective at preventing infection and neoplastic disease; however, they are prophylactic and do not clear established infections. Therapeutic vaccines which trigger cell-mediated immune responses for the treatment of established infections and malignancies are therefore required. The E6 and E7 early genes are ideal targets for vaccine therapy due to their role in disruption of the cell cycle and their constitutive expression in premalignant and malignant tissues. Several strategies have been investigated for the development of therapeutic vaccines, including live-vector, nucleic acid, peptide, protein-based and cell-based vaccines as well as combinatorial approaches, with several vaccine candidates progressing to clinical trials. With the current understanding of the HPV life cycle, molecular mechanisms of infection, carcinogenesis, tumour biology, the tumour microenvironment and immune response mechanisms, an approved HPV therapeutic vaccine seems to be a goal not far from being achieved. In this article, the status of therapeutic HPV vaccines in clinical trials are reviewed, and the potential for plant-based vaccine production platforms described.

Keywords: Cervical cancer; E6 and E7; HPV; Plant-based production; Therapeutic vaccine.

Fig. 1

The life-cycle of a typical hr-HPV. Infection occurs at basal epithelial cells through anatomically accessible points such as microlesions. The genomes of HPVs stay as episomes in the host's cell nuclei. Cells proliferate and differentiate. The expression of structural proteins, L1 and L2, viral assembly and release only occur at late stages of the cell life cycle. Integration of the viral genome into the host's genome leads to overexpression of E6 and E7 which disrupt the cell life cycle regulation which promotes prolonged cell life leading to genomic instability and cancer. At this stage no viral structural proteins are expressed. Adapted from Moody and Laimins .

Fig. 2

Ideal mechanism of a therapeutic vaccine against HPV-related malignancies. An ideal HPV therapeutic vaccine would elicit a strong cell-mediated immune response where CD4+ T-cells would provide support to CD8+ T-cells by secreting cytokines such as IFN-γ and IL2 labelling infected and malignant cells. Cytotoxic CD8+ T-cells would eliminate infected cells by secreting high amounts of granzyme B and perforin which lead to cell death. The response would be effective even in the presence of immunosuppressive cells .