Table 2.
Recent Therapeutic HPV Vaccine Clinical Trials Using Different Forms of Vaccines
| Vaccine | Antigen(s) | Construct | Organization | Trial Design | Outcome | Side Effects | Reference |
|---|---|---|---|---|---|---|---|
| Bacterial Vector Based | |||||||
| Lm-LLo-E7 (ADXS11-001; ADXS-HPV) | HPV-16 E7 | prfA-defective Listeria monocytogenes strain transformed with plasmid encoding HPV-16 E7 antigen fused to a fragment of nonhemolytic listeriolysin O (LLO) | Advaxis, Inc. | Phase I in patients with metastatic, refractory or recurrent, advanced squamous cell carcinoma of the cervix (15 patients) | Increase in E7-specific T cells detected in PBMCs of three patients. Reduction in tumor size observed in 4 patients. |
Pyrexia, vomiting, chills, headache, anemia, nausea, tachycardia, muscle and skeletal pain. | [123] |
| GLBL101c | HPV16-E7 | Recombinant Lactobacillus Casei expressing modified version of HPV16-E7 | GENOLAC BL Corp | Phase I/IIa in HPV16+ CIN3 patients (17 patients) | Significant increase in E7-CMI in cervical vaginal tract. 9 patients experienced disease regression to CIN2, and 5 further regressed to LSIL |
No major side effects observed. | [125] |
| Viral Vector Based | |||||||
| TG4001 | HPV-16 E6/E7 | Recombinant Modified Vaccinia Ankara expressing HPV-16 E6, E7, and IL-2 | Transgene/Roche | Phase I in HPV16+ CIN2/3 Patients (21 patients) | 10 of 21 (48%) showed disease regression. HPV DNA clearance in 8 patients and mRNA clearance in 7 patients. | Inflammation, pruritus, edema, lymphadenopathy, fever, headache, asthenia, bone pain, vaginal discharge | [126] |
| MVA E2 | HPV-16 E2 | Recombinant Modified Vaccinia Ankara encoding E2 from BPV | Instituto Mexicano del Seguro Social | Phase I/II in CIN1/2/3 Patients (78 patients) | 50% vaccinated patients were free of lesions at the end of treatment, and 87% were lesion free by 3 weeks after treatment. | Headache, flu-like symptom, fever, chills, abdominal pain, joint pain. | [128] |
| Phase I/II in male patients with flat condyloma lesions (30 patients) | No lesions or HPV detected in 28 of 30 patients 4 weeks after treatment. | No local or systemic adverse effects reported. | [129] | ||||
| Phase III in patients with HPV-induced AGIN (1176 female patients and 180 male patients) | 90% lesion clearance in female treated patient and 100% lesion clearance in male treated patients. Antibody and T cell responses observed in all tested patients. | Headache, flu-like symptom, fever, chills, abdominal pain, joint pain. | [130] | ||||
| Peptide / Protein Based | |||||||
| HPV16-SLP | HPV-16 E6/E7 | Combination of nine HPV-16 E6 and four HPV-16 E7 synthetic peptides with incomplete Freund’s adjuvant | ISA Pharmaceuticals | Phase II in patients with HPV16+ VIN3 (20 patients) | 15 patients had objective clinical response at 12 months. 9 complete response and 6 partial response. 85% with circulating HPV-16 specific T cells. 83% had CMI against HPV-16. | Local swelling, redness, increased skin temperature, pain at vaccination site, fever, flu like symptoms, chills, and tiredness. | [131] |
| Phase II study in patients with HPV16+ HSIL (9 patients) | All vaccinated patients showed strong HPV-specific T cell response after vaccination. Change in patterns of immune infiltrate. | Itching, redness, swelling, and pain at injection site, headache, diarrhea, fatigue/dizziness, nausea, chills, myalgia, rash, fever, urticarial, edema. | [132] | ||||
| Phase II in patients HPV16+ advanced or recurrent gynecological carcinoma (20 patients) | 9 patients with HPV-16 specific immune response. Duration of survival correlates with magnitude of T cell response. | Injection site reaction, fever, chills, fatigue, nausea, flue-like symptom | [133] | ||||
| Phase II in patients with low-grade abnormalities of the cervix (50 patients) | 97% of vaccinated patients generated HPV 16-specific CMI | Flu-like symptom, injection site reaction. | [135] | ||||
| GL-0810 | HPV-16 antigen | HPV-16 immunomodulatory peptide with adjuvant Montanide and GM-CSF | Gliknik Inc. | Phase I in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (9 patients) | 80% of patients who received 4 vaccinated developed T cell and antibody response. Progression free and over all survival is 80 and 196 days respectively. | Erythema, itching, and pain at injection site | [136] |
| TA-CIN | HPV-16 E6/E7/L2 | HPV16 E6E7L2 fusion protein | Xenova Research Limited | Phase I in healthy patients (40 subjects) | TA-CIN specific IgG in 24 of 32 vaccinated patients. 25 of 32 vaccinated patients generated CMI. | Injection site reaction, tenderness. Headache and fatigue | [138] |
| Phase II with VIN2/3 patients (19 patients) | 63% lesion response 1 year after vaccination. Significant increase. Significant CMI observed in lesion responders. |
Local reaction associated with imiquimod. | [141] | ||||
| TA-CIN + TA-HPV | HPV-16/18 E6/E7/L2 | HPV16 E6E7L2 fusion protein and vaccinia virus with HPV16/18 E6/E7 | Celtic Pharma | Phase I with HPV16+ VIN patient (10 patients) | Partial or complete clinical response in 2 patients. All but 1 patient showed HPV-16 specific IgG and/or T cell responses. | Pain at injection site. | [139] |
| Phase II with HPV16+ high-grade AGIN Patients (29 patients) | 17 patients showed TA-CIN induced T cell responses. 11 generated HPV-16/18 E6 and/or E7 specific T cells. 14 with IgG response to HPV-16 E7. | N/A | [140] | ||||
| Nucleotide Based | |||||||
| pNGVL4a-sig/E7(detox)/HSP70 + TA-HPV | HPV-16/18 E6/E7 | Plasmid encoding mutated form of HPV16-E7 linked to sig and HSP70 and vaccinia virus with HPV16/18 E6/E7 | Sidney Kimmel Comprehensive Cancer Center | Phase I with HPV16+ CIN3 Patients (12 patients) | 58% vaccinated patients have generated HPV-16 E7-specific CMI. Increase CD8+ T cell infiltration to lesions. | Tenderness, local site reaction, blister, erythema, pruritus | [142] |
| GX-188E | HPV-16/18 E6/E7 | Plasmid encoding fusion protein of HPV 16/18 E6/E7 linked to Flt3L and tpa | Genexine, Inc | Phase I in patients with HPV 16/18+ CIN3 (9 patients) | All patients displayed enhanced HPV-specific CMI. 7 patients demonstrated complete lesion regression by the end of the trial. | Chills, injection site pain, swelling, hypoesthesia, headache, fatigue, rhinitis | [143] |
| VGX-3100 | HPV-16/18 E6/E7 | Mixture of two plasmids encoding optimized consensus of E6 and E7 antigen of HPV 16 and 18 | Inovio Pharmaceuticals | Phase I with HPV16/18 + CIN2/3 Patients (18 patients) | HPV-specific CMI observed in 78% patients and HPV-specific humoral response observed in all patients. | Injection site reaction, pain, fever, tenderness. | [146] |
| Phase IIb with HPV16/18 + CIN2/3 Patients (167 patients) | 49.5% vaccinated patient demonstrated regression compared to 30.6% in placebo group. Vaccinations enhance T cell and humoral response. | Injection site reaction, fatigues, headache, lyalgia, nausea, arthralgia, erythema | [147] | ||||
| Whole Cell Based | |||||||
| DC + KLH | HPV-16 and HPV-18 E7 | Dendritic Cells pulsed with HPV-16 and HPV-18 E7 and keyhole limpet hemocyanin | National Institute of Health | Phase I in patients with stage Ib or IIa cervical cancer (10 patients) | Increase in HPV-specific humoral and CD4+ T cell responses observed, but not CD8+ T cell responses. | Local site reaction, erythema, swelling, pruritus | [148] |
| DC | HPV antigens | DC pulsed with HPV+ tumor lysate | Department of Biotechnology (DBT, Govt. of India) | Phase I in in patients with HPV+ advanced, recurrent cervical cancer (14 patients) | No significant increase in lymphocyte proliferation observed. Lack of biopsy sample and small sample size prevent definite conclusions. | Local site reaction, fever, chills, abdominal discomfort, vomiting. | [149] |
CIN - Cervical intraepithelial neoplasia; AGIN - Ano Genital Intraepithelial Neoplasia; HSIL - High-grade squamous intraepithelial lesion; VIN - vulvar intraepithelial neoplasia