For nearly two decades, preventive vaccines have been our primary shield against human papillomavirus (HPV), drastically reducing new infections. Now, a new frontier in medicine is opening: therapeutic DNA vaccines.
Unlike their preventive predecessors, therapeutic DNA vaccines are designed to battle existing HPV infections and even reverse the precancerous lesions they can cause, offering hope to countless individuals worldwide.
People in the US with existing HPV infections
Clinical regression rate in Vvax001 trial
Therapeutic vaccines in Phase III trials
To understand the breakthrough of therapeutic vaccines, it's essential to first grasp how HPV operates. HPV is a simple but formidable virus. Its circular DNA genome contains a small set of genes, including the early genes E6 and E7. These are not just ordinary viral genes; they are oncogenic drivers that hijack our cells' natural anti-cancer safeguards. The E6 protein disables the p53 tumor suppressor, while E7 neutralizes another, pRb. This one-two punch allows infected cells to proliferate uncontrollably, paving the road to cancer 2 .
Preventive vaccines use virus-like particles (VLPs) made from the HPV capsid protein L1 to train the immune system to recognize and block the virus before it enters cells. However, these VLPs are not present in an already infected cell. Once HPV has integrated its DNA into a host cell and begun producing E6 and E7, the preventive vaccine can no longer touch it 2 6 .
This gap in our arsenal is significant. Millions of people live with persistent HPV infections that can lead to high-grade squamous intraepithelial lesions (HSIL) and cancers of the cervix, anus, and oropharynx 1 . Therapeutic vaccines are engineered to close this gap. They are not designed to prevent infection, but to orchestrate a targeted immune attack on cells that are already harboring the virus and producing its cancer-causing proteins 2 .
Therapeutic HPV vaccines represent a sophisticated application of immunology. Their goal is to correct the immune system's failure to detect HPV-infected cells. These cells are, in essence, "foreign" because they are continuously producing the viral E6 and E7 proteins.
Scientists create a circular piece of DNA (a plasmid) that contains the gene for one or more of HPV's early proteins, most commonly E6 and/or E7 1 .
This plasmid is injected into the patient, often with specialized devices or formulations that help it get inside the patient's cells.
Once inside the body's cells, the plasmid uses the cell's own machinery to read the viral gene and produce the E6/E7 proteins.
| Advantage | Explanation |
|---|---|
| Safety | DNA plasmids are non-infectious and cannot cause disease. They do not contain the full viral genome, only specific genes 2 . |
| Stability & Simplicity | DNA is highly stable and easier to manufacture at high purity compared to other biologic drugs, simplifying storage and transport 2 . |
| Focus on Cell-Mediated Immunity | They are uniquely suited to induce potent T-cell responses, which are essential for attacking already-infected cells 1 . |
| Potential for Repeated Dosing | Unlike some vaccine platforms, DNA vaccines can be administered multiple times without losing efficacy 2 . |
A recent clinical trial exemplifies the remarkable potential of this approach. Published in 2024, researchers tested a therapeutic vaccine called Vvax001 on patients with CIN3, the most severe form of cervical precancerous lesion, which is typically treated with surgery 5 .
Vvax001 is not a DNA vaccine but uses a similar principle of directing the body to produce HPV antigens. It employs a modified, non-replicating virus to deliver the genes for the HPV16 E6 and E7 proteins. In this trial, 18 patients with HPV16-positive CIN3 received the vaccine 5 .
The outcomes were striking. Lesions shrank in 17 out of 18 patients. Most importantly, half of the participants experienced clinical regression of their disease, with three showing no signs of precancer at all. The vaccine also prompted the immune system to clear the underlying HPV16 infection in 10 out of the 16 patients evaluated. Researchers noted that patients whose lesions regressed often had T-cells already waiting at the edges of the lesions before vaccination, suggesting the vaccine effectively mobilized a pre-existing but stalled immune response 5 .
This trial demonstrated that a therapeutic vaccine could offer a potent alternative to invasive surgery, potentially allowing at least half of CIN3 patients to avoid surgical procedures and their associated risks and complications 5 .
The journey of therapeutic HPV vaccines from the lab to the clinic has been one of steady progress. Two DNA vaccine candidates, MAV E2 and VGX-3100, have completed Phase III clinical trials 1 .
Designed to target the E6 and E7 proteins of HPV16 and 18. In trials, it demonstrated the ability to clear both the virus and the associated high-grade lesions in a significant portion of patients 1 .
Takes a slightly different approach, using the E2 protein as its antigen. It also showed efficacy in eliminating HPV infection and causing lesion regression 1 .
While these vaccines have proven to be well-tolerated, their clinical efficacy in achieving HSIL regression has been described as modest when compared to placebo or standard surgery. However, their high effectiveness in clearing the underlying HPV infection is a major breakthrough, providing a clear path for future optimization 1 .
| Vaccine Name/Platform | Target Antigen(s) | Proposed Mechanism | Development Stage |
|---|---|---|---|
| VGX-3100 (DNA Vaccine) | HPV16/18 E6 & E7 | Electroporation-enhanced DNA plasmid delivery to activate T-cells | Phase III Completed 1 |
| MAV E2 (DNA Vaccine) | HPV E2 | Uses E2 protein to induce cell-mediated immunity and apoptosis | Phase III Completed 1 |
| PDS0101 (Liposomal) | HPV16 E6 & E7 peptides | Synthetic peptides delivered with a lipid-based immune activator | Phase I/II Trials |
| Hespecta (Peptide) | HPV16 E6 peptide | Peptide conjugated to a synthetic TLR2 ligand to boost immune response | Phase I |
Advancing these vaccines relies on a suite of specialized biological tools and reagents. Scientists use these to study the virus, design vaccine candidates, and test immune responses.
| Research Tool | Function in Vaccine R&D | Real-World Example |
|---|---|---|
| Recombinant L1 Protein (VLP) | Serves as the antigen for prophylactic vaccine development and immunogenicity testing. | Insect cell-derived HPV16 L1 VLP used in immunogenicity studies 9 . |
| Recombinant E6 & E7 Proteins | Key targets for therapeutic vaccines; used to test and validate T-cell immune responses. | His-tagged HPV16 E7 protein used in binding assays to measure antibody affinity 9 . |
| HPV Pseudotype Neutralisation Assay | Measures the potency of neutralizing antibodies induced by vaccines without using live virus. | Monoclonal antibodies characterized for their ability to block viral entry 7 9 . |
| International Standard Reagents | Provides a global benchmark to ensure the accuracy and comparability of HPV tests across labs. | WHO International Standards for HPV DNA and antibodies help calibrate lab equipment worldwide 7 . |
Despite promising leads, no therapeutic HPV vaccine has yet reached the market. The path forward involves overcoming several key challenges 1 :
"Researchers are exploring combination therapies, pairing therapeutic vaccines with other agents like immune checkpoint inhibitors, which can 'release the brakes' on the immune system and allow the vaccine-induced T-cells to attack tumors more effectively."
The development of therapeutic HPV vaccines marks a paradigm shift in our fight against HPV-related diseases. They move us from a strategy of pure prevention to one of active intervention, offering hope for those already affected.
Protect future generations from HPV infection
Rescue those already infected with the virus
While there is still a way to go, the progress in clinical trials is a powerful testament to the potential of harnessing the body's own immune system to fight disease. As research continues to refine these vaccines, we move closer to a comprehensive arsenal against HPV—one where preventive vaccines protect future generations, and therapeutic vaccines rescue those already in the crosshairs of the virus, ultimately making deaths from HPV-related cancers a rarity of the past.