Reengineered HPV Nanovaccine Trains T Cells to Destroy Cancer in Preclinical Study

What Is the New HPV Cancer Vaccine and How Does It Work?

The therapeutic vaccine, developed by researchers at Northwestern University and published in Science Advances, is built on a platform called spherical nucleic acids (SNAs). Each vaccine particle consists of a nanoscale lipid core surrounded by a shell of immune-activating DNA strands. Attached to this structure is a short fragment (peptide) of an HPV oncoprotein — a viral protein that is present in HPV-positive tumor cells but absent from healthy tissue, making it an ideal target for the immune system.

The critical breakthrough was the discovery that the physical arrangement of these components matters enormously. When the HPV peptide was attached to the particle's surface via its N-terminus (one end of the protein fragment), the vaccine triggered a dramatically stronger immune response compared to when the same peptide was attached via its C-terminus or embedded within the particle. This seemingly subtle structural change produced up to eight times more interferon-gamma — a key anti-tumor signaling molecule — from killer T cells.

Unlike existing preventive HPV vaccines such as Gardasil 9, which prevent viral infection and must be given before HPV exposure, this therapeutic vaccine is designed to treat patients who already have HPV-positive cancers. The vaccine essentially trains the immune system to recognize and attack cells displaying HPV proteins, turning the patient's own T cells into targeted cancer-killing agents. In laboratory tests using tumor samples from HPV-positive cancer patients, the optimized vaccine killed two to three times more cancer cells than the suboptimal configuration.

What Were the Preclinical Results?

The research team tested the vaccine in humanized mouse models — mice engineered to have a human-like immune system — bearing HPV-positive tumors. Animals receiving the optimized vaccine (N-terminus surface display) showed significantly slower tumor growth compared to untreated controls, animals receiving the suboptimal vaccine configuration, or those receiving the individual vaccine components alone.

The survival data were equally striking. Mice treated with the optimized vaccine lived significantly longer than all control groups. Detailed analysis of the tumor microenvironment revealed that the optimized vaccine produced a dramatic increase in tumor-infiltrating CD8+ T cells — the specific immune cells responsible for directly killing cancer cells. These T cells were not only more numerous but also more functionally active, producing higher levels of cytotoxic molecules including granzyme B and perforin.

The findings underscore an important principle in vaccine design: the same molecular ingredients can produce vastly different immune responses depending on how they are physically arranged. This insight has implications beyond HPV cancers, suggesting that the SNA nanovaccine platform could be optimized for other cancer types by displaying different tumor-associated antigens on the particle surface.

Who Could Benefit from This Therapeutic Vaccine?

Human papillomavirus is responsible for approximately 5% of all cancers worldwide, including virtually all cervical cancers, approximately 70% of oropharyngeal (throat) cancers, and significant proportions of anal, vulvar, vaginal, and penile cancers. The WHO estimates that cervical cancer alone kills more than 340,000 women annually, predominantly in low- and middle-income countries with limited access to screening and prevention programs.

While preventive HPV vaccination has been transformative — and could eventually eliminate cervical cancer in countries with high vaccination coverage — it offers no benefit to the hundreds of millions of people already infected with HPV or the approximately 660,000 people diagnosed with HPV-related cancers each year. Therapeutic vaccines that can treat existing disease represent a critical unmet need.

The Northwestern vaccine could be particularly valuable for patients with recurrent or metastatic HPV-positive cancers, where treatment options are limited. Current standard treatments include surgery, radiation, chemotherapy, and the immune checkpoint inhibitor pembrolizumab (Keytruda), but many patients eventually progress despite these therapies. A therapeutic vaccine that can specifically activate anti-HPV immune responses could potentially be combined with existing immunotherapies to improve outcomes. The research team is now working toward clinical trials, though the timeline for human testing has not yet been announced.