Eliminating HPV-related diseases requires not only preventive vaccines to prevent new infections, but also effective therapeutic strategies to clear persistent HPV infection and promote the regression of precancerous lesions. The World Health Organization (WHO) has released Preferred Product Characteristics (PPCs) for therapeutic HPV vaccines, identifying two major application scenarios: population-based approaches aimed at clearing persistent HPV infection, and screen-and-treat approaches aimed at promoting the regression or resolution of HPV-related precancerous lesions. These recommendations provide important guidance for the global development of therapeutic HPV products.
A central challenge in HPV treatment is identifying molecular targets for persistent infection. Extensive research has established that sustained expression of the high-risk HPV oncoproteins E6 and E7 plays a critical role in HPV persistence, cellular transformation, and lesion progression. E6/E7 have therefore become major therapeutic targets for HPV therapeutic vaccines and targeted drug development.
E6/E7 — Core Targets for HPV Treatment
At the 31st International Papillomavirus Conference (IPVC) in Cape Town in 2017, the role of E6/E7 in persistent high-risk HPV infection and cervical carcinogenesis was extensively discussed. E6 promotes degradation of the tumor suppressor p53, impairing DNA-damage responses and apoptosis, while E7 disrupts Rb-mediated cell-cycle regulation and promotes abnormal cellular proliferation.
Unlike preventive HPV vaccines, which primarily target the viral capsid protein L1 to prevent new infections, therapeutic approaches generally target viral proteins continuously expressed in infected or transformed cells, particularly E6/E7. Inhibiting these viral oncogenic pathways or inducing E6/E7-specific immune responses therefore represents an important strategy for controlling HPV-related disease.
At the 37th IPVC in 2025, E6/E7 continued to feature prominently in therapeutic HPV research. E6/E7-based strategies are being investigated across multiple platforms, including therapeutic vaccines, cellular immunotherapy, RNA-based approaches, and targeted therapies.
Major Approaches to HPV Therapeutic Vaccines
The conference highlighted several major technology platforms, most of which use high-risk HPV E6/E7 proteins as key target antigens:
DNA vaccines deliver plasmids encoding HPV antigens, particularly E6/E7, to induce antigen-specific cellular immunity. VGX-3100, encoding optimized HPV16/18 E6/E7 antigens, is among the most extensively studied candidates.
mRNA vaccines deliver mRNA encoding E6/E7 antigens for transient intracellular expression. Their advantages include efficient antigen expression, absence of genomic integration, and flexible manufacturing.
Viral vector vaccines use vectors such as adenoviruses or poxviruses to deliver HPV antigens and induce strong cellular immune responses.
Bacterial vector vaccines use attenuated bacteria or probiotics to express HPV antigens and stimulate mucosal and systemic immunity.
Recombinant protein vaccines directly deliver E6/E7-derived antigens, generally combined with adjuvants to enhance antigen presentation and immune responses.
Despite decades of research, therapeutic HPV vaccine development remains challenging because persistent HPV infection involves complex mechanisms including immune evasion, immune tolerance, and difficulties in eliminating infected cells. Although numerous candidates have demonstrated immunogenicity and varying degrees of clinical activity, therapeutic vaccine development remains an active area of investigation.
Challenges in Anti-HPV Drug Development
The biological characteristics of HPV also create significant barriers to conventional antiviral drug development.
First, HPV lacks many of the classic virus-specific enzymes commonly targeted by antiviral drugs. Although the viral E1 protein has ATPase/helicase activity, developing clinically suitable inhibitors has proved difficult.
Second, experimental models of productive HPV infection are technically challenging. HPV genome-carrying keratinocytes can be difficult to maintain, while three-dimensional epithelial models such as organotypic raft cultures are complex and costly, limiting their use in large-scale drug screening.
Third, HPV exhibits strict species and tissue specificity, making conventional animal infection models difficult to establish. Animal papillomavirus models provide useful information but do not fully reproduce human HPV infection.
Finally, HPV E6/E7 transgenic and tumor models can help evaluate therapeutic mechanisms but do not reproduce the complete natural history of persistent HPV infection.
Emerging Directions in Anti-HPV Drug Research
As conventional antiviral approaches face limitations, research is increasingly exploring HPV-dependent cellular mechanisms and host signaling pathways.
Nucleoside analogues represent one approach under investigation. Because HPV relies extensively on host-cell machinery for replication, compounds affecting cellular DNA synthesis may interfere indirectly with viral replication, although selectivity and safety remain important considerations.
Host signaling pathways are another emerging area. Studies suggest that the Ras/MAPK–MEK/ERK pathway can regulate the expression of HPV genes including E6/E7. Modulating these pathways may suppress HPV-related oncogenic signaling and potentially enhance responses to immunotherapy. Such strategies remain at an early stage and require further preclinical and clinical validation.
Conclusion
HPV therapeutic research is advancing across multiple technology platforms. E6/E7 remain central molecular targets for therapeutic vaccine development, while RNA-based technologies, cellular immunotherapy, targeted drugs, and host-directed approaches are expanding the therapeutic landscape.
Although substantial scientific and clinical challenges remain, advances in HPV biology, immunology, drug delivery, and therapeutic technologies are creating new opportunities for interventions aimed at persistent HPV infection and HPV-related precancerous lesions.
