Article Data

  • Views 429
  • Dowloads 168


Open Access

Progress in therapeutic HPV vaccines: observations from clinical trials

  • Tao Zhou1,†
  • Ran Liu1,†
  • Jian-hua Wu1,*,

1Department of Dermatology, Changhai Hospital, Naval Medical University, 200433 Shanghai, China

DOI: 10.22514/ejgo.2022.038 Vol.43,Issue 5,October 2022 pp.1-8

Submitted: 22 June 2022 Accepted: 19 July 2022

Published: 15 October 2022

*Corresponding Author(s): Jian-hua Wu E-mail:

† These authors contributed equally.


Human papillomavirus (HPV)-related cancer accounts for a large number of new-onset malignant tumors caused by infection annually. Exogenous genes integrated into the tumors, mainly HPV E6 and E7, are ideal targets for therapeutic vaccines. Although there are no officially approved therapeutic HPV vaccines, several breakthroughs have been made in peptide-based, vector and DNA vaccines against HPV-related tumors and precancerous lesions. Therapeutic HPV vaccines alone showed limited clinical efficacy against HPV-related tumors, but preliminary results with combination treatments have been encouraging. Thus, more studies should focus on the role of HPV in tumorigenesis and tumor microenvironment to overcome therapy resistance and improve clinical efficacy.


HPV; Peptide-based vaccine; Vector vaccine; DNA vaccine

Cite and Share

Tao Zhou,Ran Liu,Jian-hua Wu. Progress in therapeutic HPV vaccines: observations from clinical trials. European Journal of Gynaecological Oncology. 2022. 43(5);1-8.


[1] Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, et al. The landscape of viral associations in human cancers. Nature Genetics. 2020; 52: 320–330.

[2] De Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. The Lancet Global Health. 2020; 8: e180–e190.

[3] Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. Journal of Clinical Oncology. 2011; 29: 4294–4301.

[4] Li Y, Xu C. Human papillomavirus-related cancers. Advances in Experimental Medicine and Biology. 2017; 1018: 23–34.

[5] Lowy DR. HPV vaccination to prevent cervical cancer and other HPV-associated disease: from basic science to effective interventions. The Journal of Clinical Investigation. 2016; 126: 5–11.

[6] Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, et al. HPV vaccination and the risk of invasive cervical cancer. The New England Journal of Medicine. 2020; 383: 1340–1348.

[7] Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F. The HPV E6/E7 oncogenes: key factors for viral carcinogenesis and therapeutic targets. Trends in Microbiology. 2018; 26: 158–168.

[8] Tang J, Li M, Zhao C, Shen D, Liu L, Zhang X, et al. Therapeutic DNA vaccines against HPV-related malignancies: promising leads from clinical trials. Viruses. 2022; 14: 239.

[9] Zhang J, Fan J, Skwarczynski M, Stephenson RJ, Toth I, Hussein WM. Peptide-based nanovaccines in the treatment of cervical cancer: a review of recent advances. International Journal of Nanomedicine. 2022; 17: 869–900.

[10] Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. The New England Journal of Medicine. 2009; 361: 1838–1847.

[11] van Poelgeest MI, Welters MJ, Vermeij R, Stynenbosch LF, Loof NM, Berends-van der Meer DM, et al. Vaccination against oncoproteins of HPV16 for noninvasive vulvar/vaginal lesions: lesion clearance is related to the strength of the T-cell response. Clinical Cancer Research. 2016; 22: 2342–2350.

[12] Coleman HN, Greenfield WW, Stratton SL, Vaughn R, Kieber A, Moerman-Herzog AM, et al. Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination. Cancer Immunology, Immunotherapy. 2016; 65: 563–573.

[13] Zandberg DP, Rollins S, Goloubeva O, Morales RE, Tan M, Taylor R, et al. A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). Cancer Immunology, Immunotherapy. 2015; 64: 367–379.

[14] Massarelli E, William W, Johnson F, Kies M, Ferrarotto R, Guo M, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncology. 2019; 5: 67–73.

[15] Melief CJM, Welters MJP, Vergote I, Kroep JR, Kenter GG, Ottevanger PB, et al. Strong vaccine responses during chemotherapy are associated with prolonged cancer survival. Science Translational Medicine. 2020; 12: eaaz8235.

[16] Paston SJ, Brentville VA, Symonds P, Durrant LG. Cancer vaccines, adjuvants, and delivery systems. Frontiers in Immunology. 2021; 12: 627932.

[17] Borysiewicz LK, Fiander A, Nimako M, Man S, Wilkinson GW, Westmoreland D, et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. The Lancet. 1996; 347: 1523–1527.

[18] Harper DM, Nieminen P, Donders G, Einstein MH, Garcia F, Huh WK, et al. The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: randomized controlled phase II trial with 2.5 years of follow-up. Gynecologic Oncology. 2019; 153: 521–529.

[19] Basu P, Mehta A, Jain M, Gupta S, Nagarkar RV, John S, et al. A Randomized phase 2 study of ADXS11-001 listeria monocytogenes-listeriolysin O immunotherapy with or without cisplatin in treatment of advanced cervical cancer. International Journal of Gynecological Cancer. 2018; 28: 764–772.

[20] Hussain SF, Paterson Y. What is needed for effective anti-tumor immunotherapy? Lessons learned using Listeria monocytogenes as a live vector for HPV-associated tumors. Cancer Immunology, Immunotherapy. 2005; 54: 577–586.

[21] Safran H, Leonard KL, Perez K, Vrees M, Klipfel A, Schechter S, et al. Tolerability of ADXS11-001 Lm-LLO listeria-based immunotherapy with mitomycin, fluorouracil, and radiation for anal cancer. International Journal of Radiation Oncology, Biology, Physics. 2018; 100: 1175–1178.

[22] Huh WK, Brady WE, Fracasso PM, Dizon DS, Powell MA, Monk BJ, et al. Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: an NRG oncology/gynecologic oncology group study. Gynecologic Oncology. 2020; 158: 562–569.

[23] van der Gracht ET, Schoonderwoerd MJ, van Duikeren S, Yilmaz AN, Behr FM, Colston JM, et al. Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer. Journal for Immunotherapy of Cancer. 2020; 8: e001133.

[24] Komdeur FL, Singh A, van de Wall S, Meulenberg JJM, Boerma A, Hoogeboom BN, et al. First-in-human phase I clinical trial of an SFV-based RNA replicon cancer vaccine against HPV-induced cancers. Molecular Therapy. 2021; 29: 611–625.

[25] Atherton MJ, Stephenson KB, Pol J, Wang F, Lefebvre C, Stojdl DF, et al. Customized viral immunotherapy for HPV-associated cancer. Cancer Immunology Research. 2017; 5: 847–859.

[26] Trimble CL, Peng S, Kos F, Gravitt P, Viscidi R, Sugar E, et al. A phase I trial of a human papillomavirus DNA vaccine for HPV16+ cervical intraepithelial neoplasia 2/3. Clinical Cancer Research. 2009; 15: 361–367.

[27] Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. The Lancet. 2015; 386: 2078–2088.

[28] Morrow MP, Kraynyak KA, Sylvester AJ, Dallas M, Knoblock D, Boyer JD, et al. Clinical and immunologic biomarkers for histologic regression of high-grade cervical dysplasia and clearance of HPV16 and HPV18 after immunotherapy. Clinical Cancer Research. 2018; 24: 276–294.

[29] Aggarwal C, Cohen RB, Morrow MP, Kraynyak KA, Sylvester AJ, Knoblock DM, et al. Immunotherapy targeting HPV16/18 generates potent immune responses in HPV-associated head and neck cancer. Clinical Cancer Research. 2019; 25: 110–124.

[30] Kim TJ, Jin HT, Hur SY, Yang HG, Seo YB, Hong SR, et al. Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients. Nature Communications. 2014; 5: 5317.

[31] Choi YJ, Hur SY, Kim TJ, Hong SR, Lee JK, Cho CH, et al. A phase II, prospective, randomized, multicenter, open-label study of GX-188E, an HPV DNA vaccine, in patients with cervical intraepithelial neoplasia 3. Clinical Cancer Research. 2020; 26: 1616–1623.

[32] Youn JW, Hur SY, Woo JW, Kim YM, Lim MC, Park SY, et al. Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial. The Lancet Oncology. 2020; 21: 1653–1660.

[33] van den Berg JH, Oosterhuis K, Schumacher TN, Haanen JB, Bins AD. Intradermal vaccination by DNA tattooing. Methods in Molecular Biology. 2014; 1143: 131–140.

[34] Bakker NAM, Rotman J, van Beurden M, Zijlmans HJM, van Ruiten M, Samuels S, et al. HPV-16 E6/E7 DNA tattoo vaccination using genetically optimized vaccines elicit clinical and immunological responses in patients with usual vulvar intraepithelial neoplasia (uVIN): a phase I/II clinical trial. Journal for Immunotherapy of Cancer. 2021; 9: e002547.

[35] American Association for Cancer Research. Combo approaches for HPV16+ cancers. Cancer Discovery. 2021; 11: 1865–1866.

[36] Bhatt KH, Neller MA, Srihari S, Crooks P, Lekieffre L, Aftab BT, et al. Profiling HPV-16-specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients. The Journal of Experimental Medicine. 2020; 217: e20200389.

[37] Wieland A, Patel MR, Cardenas MA, Eberhardt CS, Hudson WH, Obeng RC, et al. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature. 2021; 597: 274–278.

[38] Gagliardi A, Porter VL, Zong Z, Bowlby R, Titmuss E, Namirembe C, et al. Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes. Nature Genetics. 2020; 52: 800–810.

[39] Rosales R, López-Contreras M, Rosales C, Magallanes-Molina JR, Gonzalez-Vergara R, Arroyo-Cazarez JM, et al. Regression of human papillomavirus intraepithelial lesions is induced by MVA E2 therapeutic vaccine. Human Gene Therapy. 2014; 25: 1035–1049.

[40] Nelson HH, Pawlita M, Michaud DS, McClean M, Langevin SM, Eliot MN, et al. Immune response to HPV16 E6 and E7 proteins and patient outcomes in head and neck cancer. JAMA Oncology. 2017; 3: 178–185.

[41] Lei J, Arroyo-Mühr LS, Lagheden C, Eklund C, Nordqvist Kleppe S, Elfström M, et al. Human papillomavirus infection determines prognosis in cervical cancer. Journal of Clinical Oncology. 2022; 40: 1522–1528.

[42] He J, Liu L, Tang F, Zhou Y, Liu H, Lu C, et al. Paradoxical effects of DNA tumor virus oncogenes on epithelium-derived tumor cell fate during tumor progression and chemotherapy response. Signal Transduction and Targeted Therapy. 2021; 6: 408.

[43] Bhat AA, Yousuf P, Wani NA, Rizwan A, Chauhan SS, Siddiqi MA, et al. Correction: tumor microenvironment: an evil nexus promoting aggressive head and neck squamous cell carcinoma and avenue for targeted therapy. Signal Transduction and Targeted Therapy. 2021; 6: 93.

[44] Arneth B. Tumor microenvironment. Medicina. 2020; 56: 15.

[45] Peltanova B, Raudenska M, Masarik M. Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Molecular Cancer. 2019; 18: 63.

[46] Chen YP, Wang YQ, Lv JW, Li YQ, Chua MLK, Le QT, et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Annals of Oncology. 2019; 30: 68–75.

[47] Abdulrahman Z, de Miranda N, van Esch EMG, de Vos van Steenwijk PJ, Nijman HW, J P Welters M, et al. Pre-existing inflammatory immune microenvironment predicts the clinical response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 vaccination. Journal for Immunotherapy of Cancer. 2020; 8: e000563.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,500 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Biological Abstracts Easily discover critical journal coverage of the life sciences with Biological Abstracts, produced by the Web of Science Group, with topics ranging from botany to microbiology to pharmacology. Including BIOSIS indexing and MeSH terms, specialized indexing in Biological Abstracts helps you to discover more accurate, context-sensitive results.

Google Scholar Google Scholar is a freely accessible web search engine that indexes the full text or metadata of scholarly literature across an array of publishing formats and disciplines.

JournalSeek Genamics JournalSeek is the largest completely categorized database of freely available journal information available on the internet. The database presently contains 39226 titles. Journal information includes the description (aims and scope), journal abbreviation, journal homepage link, subject category and ISSN.

Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.

BIOSIS Previews BIOSIS Previews is an English-language, bibliographic database service, with abstracts and citation indexing. It is part of Clarivate Analytics Web of Science suite. BIOSIS Previews indexes data from 1926 to the present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Submission Turnaround Time