Therapeutic human papillomavirus vaccines: current clinical trials and future directions

Abstract

Background-Cervical cancer is the second largest cause of cancer deaths in women worldwide. It is now evident that persistent infection with high-risk human papillomavirus (HPV) is necessary for the development and maintenance of cervical cancer. Thus, effective vaccination against HPV represents an opportunity to restrain cervical cancer and other important cancers. The FDA recently approved the HPV vaccine Gardasil for the preventive control of HPV, using HPV virus-like particles (VLP) to generate neutralizing antibodies against major capsid protein, L1. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and HPV-associated lesions. Furthermore, due to the considerable burden of HPV infections worldwide, it would take decades for preventive vaccines to affect the prevalence of cervical cancer. Thus, in order to speed up the control of cervical cancer and treat current infections, the continued development of therapeutic vaccines against HPV is critical. Therapeutic HPV vaccines can potentially eliminate pre-existing lesions and malignant tumors by generating cellular immunity against HPV-infected cells that express early viral proteins such as E6 and E7. Objective-This review discusses the future directions of therapeutic HPV vaccine approaches for the treatment of established HPV-associated malignancies, with emphasis on current progress of HPV vaccine clinical trials. Methods-Relevant literature is discussed. Results/conclusion-Though their development has been challenging, many therapeutic HPV vaccines have been shown to induce HPV-specific antitumor immune responses in preclinical animal models and several promising strategies have been applied in clinical trials. With continued progress in the field of vaccine development, HPV therapeutic vaccines may provide a potentially promising approach for the control of lethal HPV-associated malignancies.

HPV vaccine: Current status and future directions

“…The challenge however is to present these antigens to the immune system to induce cell mediated immunity against HPV infected cells. 27 Do we actually need a therapeutic vaccine?…”

“…The strategies being tried include use of bacterial and viral vectors for introduction of HPV antigen into host, direct introduction of viral peptides, proteins or even DNA into the host and a dendritic cell based strategy for antigen presentation and T cell activation. 27 …”

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

“…This often results in the deletion or inactivation of some early (E2, E4 and E5) and late (L1 and L2) genes, while the E6 and E7 genes are consistently expressed within infected cells [13,14]. The viral E2 gene is a negative regulator of E6 and E7 expression.…”

“…After four vaccinations, neither adverse side effects nor clinical responses were observed in patients [126]. Phase I/II trials have also tested two HPV-16 peptides, E7 [11][12][13][14][15][16][17][18][19][20] and E7 [86][87][88][89][90][91][92][93] , and a PADRE emulsion in the Montanide ISA 51 adjuvant in patients with recurrent or refractory cervical cancer [105,106]. This therapeutic vaccine showed no significant adverse effects in both trials.…”

“…Despite the successful prophylactic effects of these vaccines, the high *Address correspondence to this author at the School of Chemistry & Molecular Biosciences, University of Queensland, Chemistry Blg #68, St. Lucia, Qld 4072; Tel: (617) 33469892; Fax: (617) 3365 4273; E-mail: i.toth@uq.edu.au cost, cold storage requirement, and availability of the existing prophylactic HPV vaccines are important limitations to the widespread delivery of these vaccines in developing countries. Thus, the prevalence and associated morbidity of cervical cancer may not be significantly reduced worldwide [12][13][14]. Prophylactic HPV vaccines that target the L1 capsid have no therapeutic effect on established HPV infection.…”