Prophylactic and Therapeutic HPV Vaccines: Current Scenario and Perspectives

Abstract

Persistent human papillomavirus (HPV) infection is recognized as the main cause of cervical cancer and other malignant cancers. Although early detection and treatment can be achieved by effective HPV screening methods and surgical procedures, the disease load has not been adequately mitigated yet, especially in the underdeveloped areas. Vaccine, being regarded as a more effective solution, is expected to prevent virus infection and the consequent diseases in the phases of both prevention and treatment. Currently, there are three licensed prophylactic vaccines for L1-VLPs, namely bivalent, quadrivalent and nonavalent vaccine. About 90% of HPV infections have been effectively prevented with the implementation of vaccines worldwide. However, no significant therapeutic effect has been observed on the already existed infections and lesions. Therapeutic vaccine designed for oncoprotein E6/E7 activates cellular immunity rather than focuses on neutralizing antibodies, which is considered as an ideal immune method to eliminate infection. In this review, we elaborate on the classification, mechanism, and clinical effects of HPV vaccines for disease prevention and treatment, in order to make improvements to the current situation of HPV vaccines by provoking new ideas.

Keywords: HPV; cervical cancer; pathogenic mechanism; prophylactic vaccines; therapeutic vaccines.

Figure 1

The incidence of cervical cancer in all regions of the world (Data come from WHO, 2020), the incidence of cervical cancer is lower in developed regions such as North America and Europe, and higher in backward regions such as Africa.

Figure 2

Schematic representation of the dsHPV16 genome (gray circles, other HPV subtypes are similar to it), with the ORFs of the virus indicated by colored arcs above the genome. The promoters are indicated by P (P97, P670, PE8) and the pAE and pALs (polyadenylation sites) stages are indicated by short straight lines.

Figure 3

Signal pathways in progression to cervical cancer. Oncogenes E6 and E7 are overexpressed as the HPV genome is integrated into the host genome. E6 combines with E6AP to degrade p53, and E6 activates the Wnt/β-catenin pathway which increases β-catenin and promotes cell proliferation. E7 acts on the Rb family and disrupts their connection with E2F transcription factors. The interaction of E7 with HDACs leads to chromosome remodeling and genome instability. E6 acts on PDZ protein to inactivate PTEN, resulting in an increase in pAkt and enhancing cell proliferation. E7 enhances the ability of Akt to bind and inactivate Rb, which proves that both E6 and E7 can activate the PI3K/Akt pathway. The interaction between the two oncoproteins and DNMTs leads to abnormal methylation and thus silences tumor suppressor genes. The combined effect of these mechanisms causes the occurrence of tumors.

Figure 4

(A) HPV genotypes contained in the three prophylactic vaccines. (B, C) Status and stage of prophylactic vaccines in clinical trials (data from ClinicalTrials.gov). In addition to the three common vaccines, the current status of other vaccines ranging from 1v to 11v is also sorted out, with the majority of clinical trials completed and many of the incomplete trials being geographic inter-rater effect analyses.

Figure 5

(A) Schematic diagram of several major types of therapeutic vaccines. (B, C) Status and phase of therapeutic vaccines (Data from ClinicalTrials.gov). Most of the clinical trials we found were in Phase I/II, and few of the completed clinical trials have progressed to the next phase, which has resulted in no therapeutic vaccines being available at this time.