Angelika Kurpan

Background: Human papillomavirus virus (HPV) is the most common sexually transmitted disease that can lead to the manifestation of cervical, head and neck squamous cell, and anal cancer.¹ Fortunately, 90% of HPV infections resolve on their own within 2 years which leaves a small percentage that can progress into cancer.² Out of over 40 HPV strains identified, only 12 are considered oncogenic, and HPV 16/18 alone account for 70% of cervical cancers.¹ The estimated worldwide prevalence of cancers due to HPV is 630,000 with the highest impact in the immunocompromised, older, and low income populations without access to HPV prophylactic vaccines.¹ Current approved prophylactic HPV vaccines in the market include Cervarix, Gardasil, and Gardasil 9 which are based on virus like particles that stimulate an adaptive immune system response.¹ Unfortunately, there are no approved treatments for HPV related cancers, so scientists are working on developing therapeutic vaccines to make our adaptive immune system destroy HPV infected cells.

Objective: In this narrative review, we explore the efficacy of various therapeutic vaccine vectors encoding nonpathogenic versions of the E6/E7 human papillomavirus oncoproteins to analyze lymphocyte and antibody response and potential in clearing infection to prevent manifestation of cancer.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “human papillomavirus”, “cervical cancer”, “treatment”, “oncoprotein E6”, “oncoprotein E7”.

Results: The first study utilized the major immune dominant region (MIR) of a hepatitis B virus core antigen (HBc) and inserts E5aa28-46, E6aa37-57 and E7aa26-57 peptides to form a novel multi-epitopes therapeutic vaccine (E765m). C57BL/6 mice were injected with HBc, HBc-E765m, E765m or PBS; HBc-E765m cVLPs elicited high E5/E6/E7 specific CD8+ T-cells and serum IgG antibody responses.³ The second paper used a therapeutic nanoparticle-conjugated E7 long-peptide vaccine adjuvanted with CpG (NP-E7LP). C57BL/6 wild-type mice were vaccinated with NP-E7LP, CpG, or PBS; NP-E7LP showed greatest E7 antigen and antibody induction, but vaccination did not prolong mice survival or decrease tumor growth, unless the tumor was resected.⁴ The third study chose an adenovirus vector to deliver the AD-HPV16/18/58 mE6E7 vaccine, AD-HPV16/18/58 mE6E7 adenovirus vaccine, or sterilized PBS solution. Vaccinated mice showed later tumor formation, longer incubation period and slower overall growth of tumors.⁵ The fourth study used a DNA plasmid vaccine vector with codon optimized sequences for HPV E6/E7 antigen recognition in humans. C57BL/6 mice were vaccinated with one of the four pBI-11 DNA vaccines; codon optimized pB-11 DNA vaccine showed highest T-cell response out of all the four vaccines.⁶ The last study used human subjects to test a DNA plasmid vaccine that combined non-oncogenic E6/E7 viral oncoproteins of HPV 16/18 with an IL-12 plasmid. When the MEDI0457 vaccine was given to patients after chemoradiation, it generated an immune response that resulted in clearance of HPV DNA and potential for suppressing future cancer growth.⁷

Conclusion: Comparing the efficacy of various vaccine vectors to each other can be challenging, so instead scientists should focus on combining promising experimental methods from the papers such as resecting tumors prior to vaccine injection, using codon optimized E6/E7 antigens, addition of an adjuvant such as CpG, and choosing a well-established vector in the community such as adenovirus. Experiments must also be performed within a longer time frame than 60 days to consider the recurrence of cervical cancer after clearance of the HPV DNA. In relation to the MEDI0457 vaccine, small sample size and long-term effects are areas of concern for further research.

Works Cited:

1. Markowitz LE, Schiller JT. Human Papillomavirus Vaccines. J Infect Dis. 2021;224(12 Suppl 2):S367-S378. doi:10.1093/infdis/jiaa621
2. Mo Y, Ma J, Zhang H, et al. Prophylactic and Therapeutic HPV Vaccines: Current Scenario and Perspectives. Front Cell Infect Microbiol. 2022;12:909223. Published 2022 Jul 4. doi:10.3389/fcimb.2022.909223
3. Qi W, Qingfeng L, Jing Z, et al. A novel multi-epitope vaccine of HPV16 E5E6E7 oncoprotein delivered by HBc VLPs induced efficient prophylactic and therapeutic antitumor immunity in tumor mice model. Vaccine. 2022;40(52):7693-7702. doi:10.1016/j.vaccine.2022.10.069
4. Domingos-Pereira S, Roh V, Hiou-Feige A, et al. Vaccination with a nanoparticle E7 vaccine can prevent tumor recurrence following surgery in a human papillomavirus head and neck cancer model. Oncoimmunology. 2021;10(1):1912473. Published 2021 Apr 13. doi:10.1080/2162402X.2021.1912473
5. Wan B, Qin L, Ma W, Wang H. Construction and immune effect of an HPV16/18/58 trivalent therapeutic adenovirus vector vaccine. Infect Agent Cancer. 2022;17(1):5. Published 2022 Feb 23. doi:10.1186/s13027-022-00417-3
6. 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
7. Hasan Y, Furtado L, Tergas A, et al. A Phase 1 Trial Assessing the Safety and Tolerability of a Therapeutic DNA Vaccination Against HPV16 and HPV18 E6/E7 Oncogenes After Chemoradiation for Cervical Cancer. Int J Radiat Oncol Biol Phys. 2020;107(3):487-498. doi:10.1016/j.ijrobp.2020.02.031