Current state in the development of candidate therapeutic HPV vaccines

Abstract

The identification of human papillomavirus (HPV) as an etiological factor for HPV-associated malignancies creates the opportunity to control these cancers through vaccination. Currently, available preventive HPV vaccines have not yet demonstrated strong evidences for therapeutic effects against established HPV infections and lesions. Furthermore, HPV infections remain extremely common. Thus, there is urgent need for therapeutic vaccines to treat existing HPV infections and HPV-associated diseases. Therapeutic vaccines differ from preventive vaccines in that they are aimed at generating cell-mediated immunity rather than neutralizing antibodies. The HPV-encoded early proteins, especially oncoproteins E6 and E7, form ideal targets for therapeutic HPV vaccines since they are consistently expressed in HPV-associated malignancies and precancerous lesions, playing crucial roles in the generation and maintenance of HPV-associated disease. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we review strategies to enhance vaccine efficacy and the latest clinical trials on therapeutic HPV vaccines.

Keywords: HPV; HPV E6; HPV E7; adjuvant; cervical cancer; clinical trials; combinatorial approach; human papillomavirus; immunotherapy; therapeutic vaccines.

Figure 1. Immune activation by therapeutic HPV vaccination

Administration of various types of therapeutic HPV vaccines leads to introduction of antigen into the body in different forms. DNA plasmids encoding antigens (HPV oncoprotein E6 and E7) can be transfected into dendritic cells through DNA vaccination or infection of modified live vector vaccine. The DNA encoding antigens will be transcribed into RNA, which can also be introduced into the cell through RNA vaccination. The transcribed RNA will be further translated into antigen proteins, or long peptides, which can also be taken up by the dendritic cells through phagocytosis following protein-based vaccination or peptide-based vaccination. The antigen proteins or long peptides are then processed by the proteasomes into short peptides, loaded onto class one major histocompatibility complex (MHC I) inside the endoplasmic reticulum (ER) to be presented to T cell receptors (TCR) of CD8+ T cells. Alternatively, dendritic cells or tumor cells can be prepared ex vivo to express target antigen on MHC I molecules as well as the necessary co-stimulatory molecules and be vaccinated back to the body (a process called adoptive transfer) as whole cell-based vaccines for the priming of T cells. (ER – Endoplasmic Reticulum; MHC – Major Histocompatibility Complex; TCR – T Cell Receptor; E6/E7 – Human Papillomavirus E6 and E7 Protein.)