Emerging human papillomavirus vaccines

Abstract

Introduction: Identification of human papillomavirus (HPV) as the etiologic factor of cervical, anogenital, and a subset of head and neck cancers has stimulated the development of preventive and therapeutic HPV vaccines to control HPV-associated malignancies. Excitement has been generated by the commercialization of two preventive L1-based vaccines, which use HPV virus-like particles (VLPs) to generate capsid-specific neutralizing antibodies. However, factors such as high cost and requirement for cold chain have prevented widespread implementation where they are needed most.

Areas covered: Next generation preventive HPV vaccine candidates have focused on cost-effective stable alternatives and generating broader protection via targeting multivalent L1 VLPs, L2 capsid protein, and chimeric L1/L2 VLPs. Therapeutic HPV vaccine candidates have focused on enhancing T cell-mediated killing of HPV-transformed tumor cells, which constitutively express HPV-encoded proteins, E6 and E7. Several therapeutic HPV vaccines are in clinical trials.

Expert opinion: Although progress is being made, cost remains an issue inhibiting the use of preventive HPV vaccines in countries that carry the majority of the cervical cancer burden. In addition, progression of therapeutic HPV vaccines through clinical trials may require combination strategies employing different therapeutic modalities. As research in the development of HPV vaccines continues, we may generate effective strategies to control HPV-associated malignancies.

Figure 1. Preventive HPV vaccination focuses on generating neutralizing antibodies for prevention of infection

Humoral immunity involves the interaction between an HPV capsid antigen (L1 and/or L2) and an antigen-specific B-cell receptor. The B cell internalizes the antigen, processes it, and presents it on an MHC class II molecule. The MHC II: L1/L2 antigen complex is recognized by a specific T_H2-cell receptor. This T_H2 cell has been activated by a dendritic cell presenting the L1/L2 antigen, causing it to mature and specifically recognize the MHC II: L1/L2 complex. The T_H2 cell activates the B cell to proliferate and differentiate into memory B cells and plasma B cells, which produce HPV-specific antibodies. The HPV antigen-specific antibodies prevent HPV infection by binding the viruses and thus preventing their entry into host cells.

Figure 2. Therapeutic HPV vaccination focuses on generating cell-mediated immunity for clearance of infection

Cell-mediated immunity involves the interaction between professional antigen-presenting cells (particularly dendritic cells) and T cells. Dendritic cells present the MHC:peptide complex to prime naïve T cells to become effector T cells. Effector T cells mediate therapeutic effects; effector CD8+ T cells, also known as cytotoxic T lymphocytes (CTL), mediate antigen-specific killing of tumor cells, and effector CD4+ T cells differentiate into T helper (T_H) cells to augment CTL immune responses through the production of IFN-γ. Regulatory T cells (T_reg) regulate immune responses by suppressing CTL and T_H cells. Strategies to inhibit the Foxp3+ CD4+ CD25+ Treg cells, such as the use of anti-CD25 monoclonal antibody, may improve CTL immune responses.

Figure 3. Schematic diagram to depict the next generation of preventive HPV vaccines based on HPV capsid proteins (L1 and/or L2)

A. Cervarix composed of HPV-16 and HPV-18 VLPs. B. Gardasil composed of HPV-6, HPV-11, HPV-16 and HPV-18 VLPs. C. Multivalent VLP vaccines composed of HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52 and HPV-58 VLPs (V503 Merck). D. L1 capsomer vaccine. E. Chimeric L1-L2 VLP vaccine with L2 on the surface. F. L2 peptide vaccine. G. Concatenated L2 peptide vaccine. H. L2 peptides displayed on the surface of bacteriophage VLP.