A report shared by WHO in July 2024 presents the importance of designing therapeutic human papillomavirus (HPV) vaccines for use in lower resource settings to ensure “maximum public health benefits”. WHO preferred product characteristics for therapeutic HPV vaccines provides guidance to encourage innovation and development of therapeutic vaccines to “clear or treat” HPV infections or HPV-associated precancers or cancers. The report outlines ideal “parameters” such as vaccine indications, target populations, safety and efficacy considerations, and immunisation strategies.  

Another tool against HPV-related cancers 

The report states that the development of therapeutic vaccines for human papillomavirus (HPV) could provide an “important addition” to current methods for the prevention and treatment of HPV-related cancers. This includes cervical cancer, which is caused “almost exclusively” by sexual transmission of oncogenic types of HPV and represents an “important public health problem globally”. In 2022, an estimated 662,000 women were diagnosed with cervical cancer, and approximately 349,000 women died from the disease. 

WHO states that “over 90%” of cervical cancer-associated deaths were among women in low- and middle-income countries (LMICs), which is attributed to “inequitable access to effective cervical cancer prevention and management measures”.  Efforts to eliminate cervical cancer as a public health problem will involve three key targets: 

• Vaccination of 90% of girls with prophylactic HPV vaccines 
• Screening of 70% of women for cervical cancer with a high-performance test twice in their lifetime 
• Provision of treatment to 90% of women with cervical precancers and invasive cancers 

However, progress towards elimination is lagging, with issues such as the “cost and complexity” of screening and treatment programmes and “persistent inequities in access”. Therefore, therapeutic HPV vaccines, currently in early clinical development, could offer an “additional tool” to address gaps in cervical cancer programmes.  

Considerations for vaccine development 

A group of experts explored the “feasibility, pipeline, and clinical development considerations” for future therapeutic HPV vaccines to meet public health needs. They focused on vaccines that “primarily clear high-risk HPV infection and/or cause regression of high-grade cervical precancers”.  

Feasibility 

The report states that all HPV types encode “early” proteins (E-proteins: E1, E2, E4-E7) and “late” virion structural proteins (L-proteins: L1, L2). Infection is caused when HPV virions bind to basal cells in the epithelium using the viral capsid protein L1, so current prophylactic HPV vaccines target L1. In infected cells, E1 and E2 proteins facilitate viral replication and transcription, while E6 and E7 proteins drive cell proliferation. E6 and E7 are the main targets of “most” therapeutic vaccine candidates to date. However, to target early stages of pathogenesis, including proteins like E1 and E2 could be “critical for successful termination of HPV infection and the prevention of precancer”.  

There are several challenges for therapeutic HPV vaccine development. For example, it has a “relatively slow life cycle that is non-cytolytic, actively evades the innate and adaptive immune response, and does not induce a high level of inflammation that would alert the host to infection”. As antibodies are “insufficient to clear persistent HPV infection” or reduce precancerous lesions, post-exposure therapeutic vaccines will likely need to induce cell-mediated immunity with effective T cell responses against early viral proteins across genetically diverse populations.  

Furthermore, advanced cervical lesions have often undergone immune selection and present a highly immunosuppressive local environment that poses “scientific and immunological challenges”. Thus, WHO suggests that it could be easier to develop efficacious therapeutic HPV vaccines that target HPV infection or low-grade precancerous lesions than vaccines that target high-grade precancers or invasive cervical cancer. The experts considered an effective single-dose vaccine “unlikely” for targeting persistent high-risk HPV infection or more advanced cervical disease.  

“Mucosal delivery, such as oral or intravaginal, for either initial or booster dosing might improve the immune response and could allow self-administration. Intravaginal administration may have the added benefit of recruiting T cells into the relevant tissue site.”  

Pipeline 

Although there are no licensed therapeutic HPV vaccines, the pipeline is “active”, with a “wide variety of approaches” deployed, including peptide, protein, DNA, RNA, and bacterial- and viral-vectored vaccine platforms. Development has primarily focused on candidates targeting the regression of CIN2/3 lesions and invasive cervical cancer, but a few candidates target clearance of high-risk HPV infection. All candidates have been multiple-dose products administered at set intervals over several months, and the most common route of administration has been parenteral (subcutaneous and intramuscular) delivery. Other methods include oral delivery and direct injection at the site of the cervix.  

Clinical development 

Vaccine candidates designed primarily to clear HPV infection have not yet progressed to late-stage clinical development, with no specific regulatory pathways identified. Vaccine candidates designed primarily to cause regression of CIN2/3 lesions should be “carefully designed” to ensure they are “ethically and methodologically sound”. For both approaches, some outcomes could be evaluated post-licensure.  

Preferred characteristics 

WHO outlines several preferred characteristics in the report, divided into characteristics for vaccines used to clear oncogenic HPV infections, characteristics for vaccines used to treat cervical precancers, and characteristics common to both types of vaccines.  

A catalytic innovation 

Dr Sami Gottlieb, medical doctor and epidemiologist in WHO’s Department of Sexual and Reproductive Health and Research, commented on the importance of expanding access to existing interventions to eliminate cervical cancer as we advance the development of this tool. 

“Therapeutic HPV vaccines could be a catalytic innovation to complement these efforts, increasing options for the millions of women who have already acquired HPV and reducing their risks of developing life-threatening cancer in the future.”  

To read the report click here. For more on vaccine innovation and development, don’t forget to subscribe to our weekly newsletters here.  

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