Peptide Vaccines for HPV: Beyond Gardasil

Peptide Vaccines for Infectious Disease

33%

response rate when ISA101 synthetic long peptide vaccine was combined with nivolumab in patients with incurable HPV-16+ cancer.

Sousa et al., J Immunother Cancer, 2022

Sousa et al., J Immunother Cancer, 2022

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Gardasil and Cervarix prevent HPV infection by generating neutralizing antibodies against the viral capsid protein L1. They are among the most successful vaccines in history, preventing an estimated 90% of HPV-related cancers when given before exposure. But they cannot treat existing infections. Once HPV integrates into cervical or oropharyngeal cells and begins expressing the E6 and E7 oncoproteins that drive malignant transformation, the immune system needs a fundamentally different tool: T-cell immunity that recognizes and kills infected cells from the inside. This is where therapeutic peptide vaccines enter the picture. For a broader overview of how peptide vaccines work across diseases, see Peptide-Based COVID Vaccine Candidates: What Made It to Trials and How Peptide Vaccines Are Designed: From Epitope to Injection.

Why Gardasil Cannot Treat Existing HPV Infections

Gardasil 9 contains virus-like particles (VLPs) made from the HPV L1 capsid protein of nine HPV types. These VLPs trigger B cells to produce neutralizing antibodies that block viral entry into epithelial cells. The immune response is humoral: antibodies circulate in the blood and mucosal surfaces, intercepting virus particles before they infect cells.

Once HPV has already infected a cell, the virus sheds its capsid. The L1 protein that Gardasil targets is no longer present. Instead, the infected cell expresses the early proteins E6 and E7, which are the actual drivers of cancer. E6 degrades the tumor suppressor p53. E7 inactivates the retinoblastoma protein (pRb). Together, they push the cell toward uncontrolled proliferation.

These oncoproteins are intracellular. Antibodies cannot reach them. Clearing the infection requires cytotoxic CD8+ T cells that recognize E6 and E7 fragments (epitopes) displayed on the cell surface via MHC class I molecules. Therapeutic HPV vaccines are designed to generate exactly this response. For more on how this antigen presentation works, see How Peptide-MHC Complexes Present Cancer Targets to T-Cells.

The Synthetic Long Peptide Approach: ISA101

ISA101 (peltopepimut-S), developed by ISA Pharmaceuticals, represents the most clinically advanced peptide-based therapeutic HPV vaccine. It consists of 13 synthetic long peptides (SLPs) ranging from 25 to 35 amino acids in length, collectively covering the entire amino acid sequence of both HPV-16 E6 and E7 oncoproteins.

The "long peptide" design is deliberate. Short peptides (8-10 amino acids) bind directly to MHC class I molecules on any cell surface, which can induce T-cell tolerance rather than activation. Long peptides require uptake and processing by professional antigen-presenting cells (dendritic cells), which present the processed epitopes in the context of proper co-stimulatory signals. This generates functional, cytotoxic T-cell responses rather than tolerogenic ones.

ISA101 Clinical Trial Results

In a phase 2 trial combining ISA101 with nivolumab (an anti-PD-1 checkpoint inhibitor), patients with incurable HPV-16+ cancers (primarily oropharyngeal) who had failed prior therapies achieved a 33% objective response rate. Median overall survival was 17.5 months, and three-year overall survival was reported. Patients were treated with ISA101 (100 micrograms per peptide) on days 1, 22, and 50, and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to one year.^[1]

Immune correlates of response showed that patients who responded had higher baseline infiltration by PD-1+ T cells and macrophages. Gene set enrichment analysis found that interferon-gamma response pathways and immune infiltration signatures strongly predicted therapeutic benefit.

A phase 2 study of ISA101b combined with cemiplimab (another anti-PD-1 antibody) in HPV-16+ oropharyngeal cancer patients who had already failed anti-PD-1 therapy showed more modest results, reflecting the difficulty of re-engaging immune responses in checkpoint-refractory disease.

Why Combination Matters

ISA101 alone showed limited clinical activity in earlier trials. The vaccine generates HPV-specific T cells, but these T cells are suppressed by the PD-1/PD-L1 immune checkpoint pathway that tumors exploit to evade immune attack. Adding a checkpoint inhibitor releases the brakes on the vaccine-induced T cells. This combination principle now guides nearly all therapeutic cancer vaccine development, not just HPV. See Peptide-Based Immune Checkpoint Inhibitors: Smaller Alternatives to Antibodies for how peptides are being developed as the checkpoint-blocking agents themselves.

Other Therapeutic HPV Vaccine Approaches

VGX-3100: DNA Vaccine Encoding E6/E7

VGX-3100 is not a peptide vaccine but a DNA vaccine that encodes the E6 and E7 proteins of HPV-16 and HPV-18. The DNA plasmids are delivered via electroporation, which uses brief electrical pulses to drive the DNA into cells that then produce the E6/E7 proteins and present them to the immune system. In a phase 2b randomized, double-blind trial, VGX-3100 achieved 49.5% histopathological regression of CIN2/3 lesions compared to 30.6% in the placebo group, with robust HPV-specific CD8+ T-cell responses. VGX-3100 reached phase 3 clinical trials, making it the most advanced therapeutic HPV vaccine as of 2025.

VGX-3100's relevance to peptide vaccine research is that it validates E6/E7 as therapeutic targets and demonstrates that T-cell immunity against these oncoproteins can produce clinical regression of precancerous lesions. The question is whether peptide-based delivery can achieve similar or better results.

PepCan: Peptide Vaccine with Candida Adjuvant

PepCan consists of four synthetic peptides derived from HPV-16 E6, formulated with Candida skin test reagent as a novel adjuvant. The Candida adjuvant was chosen because most adults have pre-existing memory T-cell responses to Candida antigens, which can provide bystander immune activation to boost the HPV-specific response.

Phase 2 results presented at ASCO 2024 showed that PepCan achieved 30.8% efficacy in the intention-to-treat population (12/39 patients), while the Candida adjuvant alone achieved 47.6% (20/42). In per-protocol analysis, PepCan showed 45.8% regression and Candida alone showed 62.1%. The unexpected finding that the adjuvant alone outperformed the vaccine-plus-adjuvant combination raised questions about whether the peptide component was adding value or potentially interfering with the Candida-induced immune activation.

Nanofiber and Nanoparticle Peptide Delivery

Li et al. (2019) demonstrated that self-assembled peptide nanofibers carrying an HPV16 E7 epitope (RAHYNIVTF) generated potent CD8+ T-cell responses and abolished established tumors in 100% of treated mice, without requiring an external adjuvant.^[2] The nanofiber structure itself provided the danger signals needed to activate dendritic cells, eliminating the need for traditional adjuvants like Montanide or polyIC. This approach has not yet entered human clinical trials.

Liu et al. (2018) showed that combining synthetic long peptides with toll-like receptor agonists (polyIC and CpG) enhanced HPV-specific immune responses significantly compared to peptide alone.^[3] The choice of adjuvant appears to be as important as the peptide design itself.

Epitope Selection: The Core Challenge

The effectiveness of any peptide vaccine depends on selecting the right epitopes. For HPV, the E6 and E7 oncoproteins are ideal targets because they are consistently expressed in all HPV-transformed cells and are essential for maintaining the malignant phenotype. Tumor cells cannot simply downregulate these proteins to escape immune attack without losing their proliferative advantage.

Jabbar et al. (2018) used immunoinformatics to predict antigenic peptides from E6 and E7 of HPV types 16 and 18, identifying epitopes with high binding affinity to both MHC class I and class II molecules.^[4] The computational approach screens thousands of possible peptide fragments for predicted MHC binding, proteasomal processing efficiency, and T-cell receptor recognition. Molecular dynamics simulations then evaluate the stability of predicted epitope-MHC complexes.

Santegoets et al. (2023) characterized the actual T-cell responses found in HPV-16+ tumors and identified common HLA class I-restricted epitopes that consistently attracted tumor-infiltrating T cells across patients.^[5] This real-world validation of which epitopes naturally generate anti-tumor immunity is critical for designing vaccines that work with the immune responses patients are already attempting to mount.

Dai et al. (2026) took this further with a precision-designed HLA-I-targeted multiepitope vaccine against HPV-16, using population-level HLA frequency data to select epitopes that would cover the broadest possible patient population.^[6] HLA diversity is the reason a single short peptide vaccine cannot work for everyone: the peptide must fit the patient's specific MHC molecules. Multi-epitope designs address this by including peptides that bind to multiple common HLA types.

Beyond Vaccines: Peptides That Directly Target E6

Emanuelson et al. (2025) took a non-vaccine approach, designing stapled peptides that covalently bind to the HPV E6 oncoprotein and block its interaction with p53.^[7] Unlike vaccines, which rely on generating an immune response, these peptides act as direct molecular inhibitors. Stapled peptides use hydrocarbon bridges to lock the peptide into an alpha-helical shape that resists protease degradation and penetrates cell membranes. If E6 is blocked, p53 accumulates and triggers apoptosis in the infected cell.

This represents a conceptually different approach: therapeutic peptides as drugs rather than as immunogens. The two strategies are not mutually exclusive and could be combined.

What Limits Therapeutic HPV Peptide Vaccines

Several challenges explain why therapeutic HPV vaccines have not yet achieved FDA approval despite decades of research.

Immune evasion: HPV-infected cells and HPV-driven tumors actively suppress local immune responses by downregulating MHC class I expression, secreting immunosuppressive cytokines (TGF-beta, IL-10), and recruiting regulatory T cells. The vaccine may generate E6/E7-specific T cells in the blood, but those T cells face a hostile microenvironment at the tumor site.

HLA restriction: Short peptide epitopes only work in patients with the matching HLA type. A peptide that binds HLA-A*02:01 (the most common HLA-A allele in Caucasians) will not generate responses in patients with different HLA types. Long peptide and multi-epitope designs partially address this, but HLA diversity remains a barrier to universal efficacy.

Adjuvant optimization: The PepCan results illustrate the challenge. The immune adjuvant may be doing more work than the antigen itself, and finding the optimal combination of antigen, adjuvant, and delivery system requires extensive empirical testing. Ma et al. (2020) reviewed the evolution of tumor peptide vaccines from universal to personalized approaches, noting that adjuvant selection and delivery format are often more important than peptide sequence for clinical outcomes.^[8]

Stage of disease: Therapeutic vaccines show the most promise in early-stage disease (CIN2/3, early cervical cancer) where immune function is relatively intact. In advanced, metastatic HPV-driven cancers, the immune system is often too suppressed for a vaccine alone to restore anti-tumor immunity. This is why combination with checkpoint inhibitors has become standard in late-stage trials.

Where the Field Stands

As of 2026, no therapeutic HPV vaccine has received FDA approval. At least 17 candidates have reached clinical trials across peptide, DNA, viral vector, and cell-based platforms. The most clinically advanced results come from:

• ISA101 + nivolumab: 33% response rate in advanced HPV-16+ cancer
• VGX-3100: 49.5% CIN2/3 regression (DNA vaccine, not peptide, but validates E6/E7 targeting)
• PepCan: Phase 2 completed, results complicated by adjuvant-alone activity

The peptide vaccine field for HPV is converging on several principles: long peptides over short ones, multi-epitope designs over single epitopes, combination with checkpoint inhibitors for advanced disease, and computational epitope selection guided by real-world HLA distribution data. For how these same principles apply to cancer vaccines more broadly, see Multi-Epitope Peptide Vaccines: Attacking Cancer on Multiple Fronts and Personalized Cancer Vaccines: How Neoantigen Peptides Target Your Tumor. The HIV peptide vaccine experience offers parallel lessons: Peptide Vaccines for HIV: Decades of Research, What We've Learned. For another virus-specific peptide vaccine application, see CMV Peptide Vaccines: Protecting Transplant Patients.

The Bottom Line

Therapeutic HPV peptide vaccines aim to generate cytotoxic T-cell responses against the E6 and E7 oncoproteins that prophylactic vaccines like Gardasil cannot target. Clinical results are mixed: ISA101 combined with checkpoint inhibitors achieved a 33% response rate in advanced HPV-16+ cancer, while the peptide vaccine PepCan showed comparable results to its adjuvant alone. The field is moving toward long peptide designs, multi-epitope coverage across HLA types, and mandatory combination with immune checkpoint inhibitors. No therapeutic HPV vaccine has yet reached FDA approval, but the validation of E6/E7 as targets by DNA vaccine VGX-3100 and the consistent immunogenicity of peptide approaches across trials suggest the approach is viable if the right combination of antigen, adjuvant, and immunomodulation is found.

Frequently Asked Questions

Is there a therapeutic vaccine for HPV?

No therapeutic HPV vaccine has received FDA approval as of 2026. Multiple candidates are in clinical trials. The most advanced peptide-based approach, ISA101, combined with the checkpoint inhibitor nivolumab, achieved a 33% response rate in patients with incurable HPV-16+ cancers. VGX-3100, a DNA vaccine targeting HPV E6 and E7 proteins, showed 49.5% regression of precancerous cervical lesions in phase 2b and has reached phase 3. Current prophylactic vaccines (Gardasil, Cervarix) prevent new infections but cannot treat existing ones.

How do therapeutic HPV vaccines differ from Gardasil?

Gardasil generates antibodies against the HPV L1 capsid protein to prevent new infections. Therapeutic HPV vaccines target the E6 and E7 oncoproteins that are expressed inside already-infected cells and drive cancer development. Because E6 and E7 are intracellular, antibodies cannot reach them. Therapeutic vaccines instead activate cytotoxic CD8+ T cells that recognize E6/E7 fragments on the cell surface and kill the infected cells directly. This requires a fundamentally different vaccine design focused on T-cell immunity rather than antibody production.

What is ISA101 HPV vaccine?

ISA101 (peltopepimut-S) is a therapeutic vaccine consisting of 13 synthetic long peptides, each 25-35 amino acids in length, that collectively cover the entire sequence of HPV-16 E6 and E7 oncoproteins. It is administered subcutaneously on days 1, 22, and 50. In a phase 2 trial combined with the checkpoint inhibitor nivolumab, ISA101 produced a 33% objective response rate in patients with advanced HPV-16+ cancers. The long peptide design ensures proper processing by dendritic cells, generating functional T-cell responses rather than immune tolerance.

Why do peptide vaccines for HPV need checkpoint inhibitors?

Peptide vaccines can generate HPV-specific T cells, but tumors suppress these T cells using the PD-1/PD-L1 immune checkpoint pathway. Cancer cells display PD-L1 on their surface, which binds to PD-1 on T cells and effectively shuts them down. Adding a checkpoint inhibitor like nivolumab blocks this interaction, allowing vaccine-induced T cells to remain active and attack the tumor. ISA101 alone showed limited clinical activity in earlier trials; the combination with nivolumab produced the 33% response rate that made headlines.

Can a peptide vaccine cure cervical cancer?

No peptide vaccine has demonstrated the ability to cure cervical cancer in clinical trials. The strongest evidence supports their use in precancerous stages (CIN2/3), where the immune system is still relatively functional. VGX-3100, a DNA vaccine targeting HPV E6/E7, achieved regression of CIN2/3 lesions in about half of treated patients. For advanced cervical cancer, combination with checkpoint inhibitors shows a 33% response rate, which is meaningful but not curative for most patients. The peptide vaccine approach is most promising when used early, before immune suppression becomes severe.

What HPV proteins do therapeutic vaccines target?

Nearly all therapeutic HPV vaccines target the E6 and E7 oncoproteins. These are ideal targets for three reasons: they are expressed in every HPV-transformed cell, they are essential for maintaining the cancerous state (E6 degrades p53, E7 inactivates pRb), and tumor cells cannot stop expressing them without losing their proliferative advantage. Some next-generation designs also include E5 or L2 epitopes. The key challenge is that E6 and E7 are small proteins with limited numbers of T-cell epitopes, and HLA diversity means different patients recognize different fragments.