Cassidy Beeson

Background: Persistent high risk genital Human Papillomavirus (HPV) infections are the cause of 99.7% of cervical cancer cases.¹ While there has been a growing availability of the prophylactic HPV vaccine, this type of vaccine only prevents an initial infection from certain types of HPV.² Prophylactic vaccines provide little to no therapeutic properties for those who already have an HPV infection or those with cancerous lesions.² Since the development of cancerous or precancerous lesions occurs many years after the initial HPV infection, the effects of mass HPV vaccination may not become present for at least 20 years.² A therapeutic vaccine would be highly beneficial to treat those patients with preexisting HPV infections and cancerous lesions.²

Objective: The purpose of this literary review is to explore five therapeutic HPV vaccines and their potential as cervical cancer treatment.

Search Methods: The PubMed database was used for an online search using resources published from 2018-2024 and keywords such as “HPV”, “Therapeutic vaccines”, “HPV vaccination”, “Cervical Cancer”, and “HPV pathogenesis”.

Results: Five various vaccines and their therapeutic effects were studied. The first utilized a synthetic gene ‘5GHPV3’ that was crafted by pinpointing conserved segments within the six early proteins and creating consensus sequences to represent five high-risk HPV genotypes.³ Targeting 6 early proteins was advantageous over other regimens by creating a higher magnitude and more durable HPV specific T cell response. ³ HPV specific CD8+ T cells were detected in the cervix and continued to increase in number over time.³ The second study altered a previously developed vaccine, pBI-10, using codon optimization to create the pBI-11 vaccine.⁴ Mice that were vaccinated with the pBI-11 DNA vaccine induced the HPV antigen-specific CD8+ T cell immune responses, had improved fusion protein expression, and had stronger therapeutic responses to TC-1 tumors.⁴ The third vaccine sought to utilize human extra domain A (hEDA) combined with the E7 protein from HPV 16 and 18.⁵ It induced HPVE7-specific Cytotoxic T lymphocyte responses and eliminated established TC-1 tumors. ⁵ When given HPVE7-16/18+Poly ICLC there was a 100% tumor regression. ⁵ The fourth vaccine was a non-integrative Lentiviral vector vaccine.⁶ Intramuscular injection of a single dose of Lenti‐HPV‐07 resulted in 100% tumor eradication through CD8+ T‐cell induction and production of a pro-inflammatory microenvironment of the tumor.⁶ It was long lasting and prevented relapse after a late re-challenge.⁶ The final vaccine was a phase 2 human trial in patients with recurrent or advanced inoperable cervical cancer.⁷ The GX-188E vaccine and the Pembrolizumab vaccine were used together to see if they were synergistic. At 24 weeks after the first vaccination, 11 of the 26 patients had an overall response. ⁷

Conclusion: These studies show the wide array of targets that are possible in the creation of a therapeutic HPV vaccine. Current treatments for cervical lesions and cancer utilize physical procedures and do not utilize the body’s immune system.⁸ The development of a therapeutic vaccine will revolutionize the treatment of cervical cancer and in the future other HPV related cancers.

Works Cited:

1. Okunade KS. Human papillomavirus and cervical cancer [published correction appears in J Obstet Gynaecol. 2020 May;40(4):590]. J Obstet Gynaecol. 2020;40(5):602-608. doi:10.1080/01443615.2019.1634030
2. Hancock G, Hellner K, Dorrell L. Therapeutic HPV vaccines. Best Pract Res Clin Obstet Gynaecol. 2018;47:59-72. doi:10.1016/j.bpobgyn.2017.09.008
3. Hancock G, Blight J, Lopez-Camacho C, et al. A multi-genotype therapeutic human papillomavirus vaccine elicits potent T cell responses to conserved regions of early proteins. Sci Rep. 2019; 9:18713. doi:10.1038/s41598-019-55014-y.
4. Peng S, Ferrall L, Gaillard S, et al. Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody. mBio. 2021;12(1):e03224-20. Published 2021 Jan 19. doi:10.1128/mBio.03224-20
5. Arribillaga L, Echeverria I, Belsue V, et al. Bivalent therapeutic vaccine against HPV16/18 genotypes consisting of a fusion protein between the extra domain A from human fibronectin and HPV16/18 E7 viral antigens. J Immunother Cancer. 2020;8(1):e000704. doi:10.1136/jitc-2020-000704
6. Douguet L, Fert I, Lopez J, et al. Full eradication of pre-clinical human papilloma virus-induced tumors by a lentiviral vaccine. EMBO Mol Med. 2023;15(10):e17723. doi:10.15252/emmm.202317723
7. Youn JW, Hur SY, Woo JW, 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. Lancet Oncol. 2020;21(12):1653-1660. doi:10.1016/S1470-2045(20)30486-1
8. Johnson CA, James D, Marzan A, Armaos M. Cervical Cancer: An Overview of Pathophysiology and Management. Semin Oncol Nurs. 2019;35(2):166-174. doi:10.1016/j.soncn.2019.02.003