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Table 1 Different forms of therapeutic HPV vaccines recently used in clinical trials

From: Perspectives for therapeutic HPV vaccine development

Vaccine Antigen(s) Construct Organization Trial design Outcome Side effects Reference
Bacterial Vector Based
 (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. [30]
 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. [32]
Viral Vector Based
 TA-HPV HPV-16/18 E6/E7 Recombinant Vaccinia virus European Organization for Research and Treatment of Cancer (EORTC) Phase I/II in patients with advanced stage of cervical cancer (8 patients) Vaccination induced HPV-specific cytotoxic T lymphocyte immune response in 28 % of participants (3 out of 8). 2 patients showed tumor free condition at 15 and 21 months after vaccination. Single dose generated mild and tolerable toxicity [46]
Phase I in patients with clinical International Federation of Gynecology and Obstetrics (FIGO) stage Ib or IIa cervical cancer who will undergo radical hysterectomy (29 patients) After a single vaccination HPV-specific CTLs were found in 4 patients. 8 patients (28 %) developed HPV-specific serological responses. Mild to moderate local toxicity [54]
Phase II in patients ages 42–54 with high-grade HPV-positive vulval or vaginal intraepithelial neoplasia of up to 15 years duration (12 patients) 5 of 12 (42 %) patients showed at least 50 % reduction in total lesion diameter over 24 weeks with 1 patient showing complete regression of lesion. Overall, 83 % of women showed some average decrease in lesion size of 40 %. All patients showed an increased IgG titer and T-cell response to the vaccinia virus. A local reaction at the site of vaccination between day 7–10 was common and 2 patients had temporarily limited arm movement. [55]
 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) Ten of 21 (48 %) showed disease regression, HPV DNA clearance in eight patients and mRNA clearance in seven patients Inflammation, pruritus, edema, lymphadenopathy, fever, headache, asthenia, bone pain, vaginal discharge [47]
 MVA E2 HPV-16 E2 Recombinant Modified Vaccinia Ankara encoding E2 from BPV Instituto Mexicano del Seguro Social 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. [53]
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 responses 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. [60]
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. [59]
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 [61]
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. [63]
Observational study in patients with advanced, recurrent, or metastatic cervical cancer scheduled to receive standard Carboplatin/Paclitaxel chemotherapy (18 patients). 11 of 12 vaccinated patients induced proliferative T cell responses Chemotherapy related anemia, thrombocytopenia, leucopenia, neutropenia, and alopecia. Cancer related shortness of breath, pulmonary embolism, abdominal pain, gastroenteritis, erysipelas, hydronephrosis [64]
 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 (5 patients) 80 % of patients who received four vaccinated developed T cell and antibody response. Progression free and overall survival is 8- to 196 days respectively Erythema, itching, and pain at injection site [66]
 Pepcan + Candin HPV-16 E6 HPV16 E6 peptides combined with Candida skin testing reagent candin. University of Arkansas Phase I study in patients with biopsy-confirmed HSIL (31 patients) 45 % patients experienced histological disease regression. Mild to moderate injection site reaction. [65]
HPV-16 and HPV-18 Recombinant HPV16 and HPV18 E7 proteins fused to catalytically inactive Bordetella pertussis CyaA expressed in E. coli Genticel Phase I trial in patients positive for HPV-16 or HPV-18 infection but with normal cytology (47 patients) Patients in cohort 4 (n = 9) who received 600ug GTL001 powder + imiquimod experienced the highest HPV16/18 clearance rate. Injection site reactions including pain, swelling, induration, tenderness, and itching [73]
 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 [70]
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. [72]
 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. [69]
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 [71]
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 [79]
 pNGVL4a-CRT/E7(detox) HPV-16 E7 Plasmid encoding mutated form of HPV16-E7 linked to CRT Sidney Kimmel Comprehensive Cancer Center Phase I with HPV16+ CIN2/3 Patients (32 patients) 30 % vaccinated patients experienced histological regression to CIN1 or less. Increase in intraepithelial C8+ T cells infiltrate after vaccination. Injection site reaction. [81]
 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 [82]
 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. [85]
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 [86]
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 Institutes 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 [101]
 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. [102]
  1. CIN Cervical intraepithelial neoplasia, AGIN Ano Genital Intraepithelial Neoplasia, HSIL High-grade squamous intraepithelial lesion, VIN vulvar intraepithelial neoplasia