Recent progress in vaccination against human papillomavirus‐mediated cervical cancer

Abstract

It has been more than 7 years since the commercial introduction of highly successful vaccines protecting against highrisk human papillomavirus (HPV) subtypes and the development of cervical cancer. From an immune standpoint, the dependence of cervical cancer on viral infection has meant that HPV proteins can be targeted as strong tumour antigens leading to clearance of the infection and the subsequent protection from cancer. Commercially available vaccines consisting of the L1 capsid protein assembled as virus-like particles (VLPs) induce neutralising antibodies that deny access of the virus to cervical epithelial cells. While greater than 90% efficacy has been demonstrated at the completion of large phase III trials in young women, vaccine developers are now addressing broader issues such as efficacy in boys, longevity of the protection and inducing cross-reactive antibody for oncogenic, non-vaccine HPV strains. For women with existing HPV infection, the prophylactic vaccines provide little protection, and consequently, the need for therapeutic vaccines will continue into the future. Therapeutic vaccines targeting HPVE6 and E7 proteins are actively being pursued with new adjuvants and delivery vectors, combined with an improved knowledge of the tumour microenvironment, showing great promise. This review will focus on recent progress in prophylactic and therapeutic vaccine development and implementation since the publication of end of study data from phase III clinical trials between 2010 and 2012. Copyright © 2015 John Wiley & Sons, Ltd. INTRODUCTIONTargeting cancers for immunotherapy is often complicated by a lack of immunogenic tumour peptides. Mutated or overexpressed self-antigens are frequently the targets and invoke a generally low affinity/avidity T and B cell response. In contrast, the tight association between infection with HPV and cervical cancer means that foreign viral proteins encoded by HPV can provide the basis of either prophylactic or therapeutic cancer vaccines [1,2]. The natural course of anogenital HPV infection results in overwhelming clearance of the virus in 98% of individuals with an immune component suggested by the increased risk of HPV-associated cancers in immune-compromised organ transplant recipients [3,4]. However, HPV genotype-specific antibodies against the viral capsid proteins (L1 and L2) are produced at only low levels in about half the patients, can take close to a year to develop after natural infection and associate with higher viral loads in the cervix [5]. Thus, natural antibody may reflect the non-lytic, localised, intracellular nature of the infection leading to poor immunogenicity for immunoglobulin production and a greater emphasis on T-cell immunity for viral clearance. In contrast, prior immunization with HPV capsid proteins in animal studies induces high titres of antibody that are protective against challenge infection. Early studies in dogs demonstrated that prior immunization with L1 capsid protein could protect beagles from mucosal challenge with canine oral ...

Clinical significance of human papillomavirus genotyping

“…Vaccines that prevent HPV infection provide little protection in women with a pre-existing HPV infection [ 67 68 ]; therefore, therapeutic vaccines that might control an existing infection are currently under investigation. Moreover, therapeutic vaccines should not only manage HPV-related lesions, but also establish a systemic immunological memory to help prevent disease recurrence [ 69 ]. Many of the therapeutic vaccines currently being studied contain the E6/E7 oncogenes of specific high-risk HPV genotypes (particularly HPV 16 and 18), and work by inducing a robust cellular immune response that eradicates HPV-related lesions [ 65 70 71 72 ].…”

Cervical cancer screening of HPV vaccinated populations: Cytology, molecular testing, both or none

“…They are remarkably efficacious and safe [6–13]. Table 1 shows their characteristics and target population.…”

The U4 Antibody Epitope on Human Papillomavirus 16 Identified by Cryo-electron Microscopy

“…Although commercial vaccines targeting the viral capsid proteins have been applied successfully to protect against high-risk HPV, the efficacy of vaccines is genotype specific, and vaccines provide little therapeutic benefit against existing infections (3). Understanding the antigenic nature of the HPV capsid offers an opportunity to discover structural features that are crucial to capsid integrity and conserved across species.…”