Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials
Abstract
:1. Introduction: The Need for Developing Therapeutic, Anti-HPV Vaccines
2. Key Advantages in Developing Therapeutic, Anti-HPV Vaccines
3. Factors That Hinder Efforts for Vaccine Development
4. Strategies for Enhancing Immunogenicity of Therapeutic DNA Vaccines
5. Bottlenecks in Preclinical Systems
6. Vaccine Candidates That Have Completed Phase III Clinical Trials
7. Promising Leads from Other Vaccine Candidates That Have Gone through Clinical Trials
8. Directions for Further Refinements
9. Ramifications of Recent Success in the Development of mRNA Vaccines
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Host | HPV Type | CTL Epitope | CTL Epitope Sequence | MHC Restriction | Reference(s) |
---|---|---|---|---|---|
Mouse | HPV-16 | E6 (aa 48–57) | EVYDFAFRDL (EVL10) | H-2K | PMC479075 [35] |
Mouse | HPV-16 | E7 (aa 49–57) | RAHYNIVTF (RAF9) | H-2D | PMID: 7,690,326 [36] |
Human | HPV-16 | E6 (aa 11–19) | KLPQLCTEV (KL9V) b | HLA-A*02 | PMC5444324 [37] |
Human | HPV-16 | E6 (aa 29–37) a | TIHDIILEC (TIC9) | HLA-B*48 | PMC1182184 [38] |
Human | HPV-16 | E6 (aa 29–38) a | TIHDIILECV (TIV10) | HLA-A*02 | PMC1797519 [39] |
Human | HPV-16 | E6 (aa 31–38) a | HDIILECV (HDV8) | HLA-B*40 | PMC1797519 [39] |
Human | HPV-16 | E6 (aa 52–61) | FAFRDLCIVY (FAY9) | HLA-B*35, -B*57 | PMID: 15,358,648 [40], PMC1182184 [38] |
Human | HPV-16 | E6 (aa 72–80) | KISEYRHYC (KIC9) | HLA-A*02 | PMC5444324 [37] |
Human | HPV-16 | E6 (aa 90–99) | QLYNKPLCDV (QLV10) b | HLA-A*02 | PMC5444324 [37] |
Human | HPV-16 | E7 (aa 11–19) | YMLDLQPET (YMT9) | HLA-A*02 | PMC5444324 [37] |
Human | HPV-16 | E7 (aa 11–20) | YMLDLQPETT (YMT10) | HLA-A*02 | PMID: 7,538,538 [41] |
Human | HPV-16 | E7 (aa 7–15) | TLHEYMLDL (YLL9) | HLA-A*02, -B*48 | PMID: 15,358,648 [40], PMC5444324 [37] |
Human | HPV-16 | E7 (aa 61–69) | CDSTLRLCV (CDV9) | HLA-A*24 | PMID: 21,918,960 [42] |
Human | HPV-16 | E7 (aa 67–76) | LCVQSTHVDI (LCI10) | HLA-A*24 | PMID: 21,918,960 [42] |
Human | HPV-16 | E7 (aa 77–86) | RTLEDLLMGV (RTV10) b | HLA-A*02 | PMC5444324 [37] |
Human | HPV-16 | E7 (aa 79–87) | LEDLLMGTL (LEL9) | HLA-B*60 | PMID: 15,358,648 [40] |
Human | HPV-16 | E7 (aa 82–90) | LLMGTLGIV (LLV9) | HLA-A*02 | PMID: 7,538,538 [41] |
Human | HPV-16 | E7 (aa 86–93) | TLGIVCPI (TLI8) | HLA-A*02 | PMID: 7,538,538 [41] |
Human | HPV-18 | E6 (aa 13–21) | KLPDLCTEL (KLL9) | HLA-A*02 | PMID: 11,300,474 [43] |
Human | HPV-18 | E6 (aa 36–44) | KTVLELTEV (KTV9) | HLA-A*02 | PMID: 11,300,474 [43] |
Human | HPV-18 | E6 (aa 50–58) | ELTEVFEFA (ELA9) | HLA-A*02 | PMID: 11,300,474 [43] |
Human | HPV-18 | E6 (aa 54–62) | VVYRDSIPH (VVH9) | HLA-A*11 | PMID: 19,738,415 [44] |
Human | HPV-18/45 | E6 (aa 67–75) | KCIDFYSRI (KCI9) | HLA-A*02 | PMID: 16,353,149 [40] |
Human | HPV-18 | E6 (aa 84–92) | SVYGDTLEK (SVK9) | HLA-A*11 | PMID: 19,738,415 [44] |
Human | HPV-18 | E7 (aa 7–15) | TLQDIVLHL (TLL9) | HLA-A*02 | PMID: 11,300,474 [43] |
Human | HPV-18 | E7 (aa 81–95) | DDLRAFQQLFLNTLS (DDS15) c | HLA-A*02, *11, *24 & 33 | PMC4145224 [45] |
Human | HPV-18 | E7 (aa 86–94) | FQQLFLNTL (FQI9) | HLA-A*02 | PMID: 12,569,558 [40] |
Human | HPV-18 | E7 (aa 88–97) | QLFLNTLSFV (QLV10) | HLA-A*02 | PMID: 11,426,965 [46] |
Human | HPV-18 | E7 (aa 89–103) | LFLNTLSFVCPWCAS (LFS15)c | HLA-A*02, *11, *24 & 33 | PMC4145224 [45] |
Attributes | Four Promising DNA Vaccine Candidates a as of October 2021 | |||
---|---|---|---|---|
Vaccine name | MVA E2 | VGX-3100 | GX-188E | pBI-11 |
Backbone | Vaccinia virus Ankara | Two synthetic plasmids/pVAX | Plasmid/pGX27 | pNGVL4a-Sig/E7(detox) |
Encoded antigen | Cross-reactive E2 (bovine papilloma virus) | E6 & E7 (HPV-16 & -18) | E6 & E7 (HPV-16 & -18) | E6 & E7 (HPV-16 & -18) |
Codon optimization | NA | Yes | Yes | Yes |
Other modification | NA | Domain deletions | NA | Various mutations (e.g., C24G & E26G) |
Vaccine adjuvant | NA | NA | NA | Mtb HSP70 d |
Companion vaccine b | NA | NA | NA | TA-HPV e (IM) |
Delivery | Injection, site-specific | IM, with electroporation | IM, with electroporation | IM |
Dosage | 6, weekly | 3 | 3 | 2 pBI-11 + 1 TA-HPV |
N in phase I trial | 36 women [79] | 18 women [80] | 9 women [81] | 30 women f [82] |
Phase I registration ID | Not applicable | NCT00685412 | NCT01634503 | NCT00788164 g |
Trial site(s) | Mexico | U.S. | South Korea | U.S. |
Target condition | CIN1-3 | CIN2/3 | CIN3 | CIN3 |
Trial end points | CIN resolution & HPV clearance | CIN regression & HPV clearance | CIN regression & HPV clearance | CIN regression & HPV clearance |
Phase III trial | Yes, in 1176 women & 180 men c | Yes, in 193 subjects (mITT) | NA | NA |
Latest report | PMC4270165 [83] | Website [84] | PMID: 31,727,676 [85] | PMC7845631 [75] and NCT00788164 g |
License | NA | NA | NA | NA |
R&D Staging | Bottleneck(s) | Directions for Improvement |
---|---|---|
Vaccine design | Limited choice of suitable CTL epitopes a | Testing fusion proteins that expand the coverage of CTL epitopes |
Delivery | Not always efficient, with few adjuvants | Using LNP and nanoplasmids; directing APC-specific gene expression d |
Preclinical system | Poor coverage (mostly HPV-16-related) b | Rendering TC-1 to also express HPV-18-derived E6 and E7; developing in vitro systems for rapid assessment of immunogenicity |
Clinical trials | Limited efficacy data for cancer patients c | Comparing monotherapy versus combination therapy for late-stage patients with poor prognosis |
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Tang, J.; Li, M.; Zhao, C.; Shen, D.; Liu, L.; Zhang, X.; Wei, L. Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials. Viruses 2022, 14, 239. https://doi.org/10.3390/v14020239
Tang J, Li M, Zhao C, Shen D, Liu L, Zhang X, Wei L. Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials. Viruses. 2022; 14(2):239. https://doi.org/10.3390/v14020239
Chicago/Turabian StyleTang, Jianming, Mingzhu Li, Chao Zhao, Danhua Shen, Lei Liu, Xiujun Zhang, and Lihui Wei. 2022. "Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials" Viruses 14, no. 2: 239. https://doi.org/10.3390/v14020239
APA StyleTang, J., Li, M., Zhao, C., Shen, D., Liu, L., Zhang, X., & Wei, L. (2022). Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials. Viruses, 14(2), 239. https://doi.org/10.3390/v14020239