Background: Human papillomavirus (HPV) causes cancer, cervical cancer being the most common. Almost all cases of cervical cancer can be attributed to the presence of High-risk Human Papillomavirus. High risk strains of HPV alter the DNA inside cervical epithelial cells, specifically due to the activation of the E6 and E7 oncogenes within the HPV virus.¹ Currently, there is an intramuscular vaccine against carcinogenic HPV strains. However worldwide availability and patient compliance necessitate other therapy options. Oral immunotherapy and vaccine clinical trials show promise for noninvasive, nonsurgical, cost-effective intervention for patients infected with HPV16 precancerous lesions, and those seeking protection against future infection.

Objective: In a literature review of studies focused on mechanisms associated with oral immunotherapy and vaccines for Human Papillomavirus, we explored the efficacy of an orally administered Lactobacillus vector for prophylactic and continued treatment against High-risk HPV.

Search Methods: An online search of PubMed database was conducted from 2019 to 2024 using keywords such as: “Human Papillomavirus”, “oral”, “vaccination”, “immunotherapy”, “Lactobacillus”.

Results: Studies indicate oral administration of recombinant or genetically altered Lactobacillus for HPV vaccination and immunotherapy is safe and efficacious. Specifically, Lactobacillus lactis serves as an sufficient host for HPV-16, allowing E6 and E7 proteins to be synthesized. Consequent enhancement of the secretion of these proteins allows the host’s immune system to be exposed to HPV proteins and build an immune response, leading to immunoprotection against future exposure.² Oral administration of the modified L. lactis induced E7-specific CD4+ T helper cells and CD8+ cytotoxic T cells, which secrete cytokines including IL-2 and IFN-gamma leading to inflammatory response.³ These immune responses decrease the potential for undetected proliferation and carcinogenesis of HPV and cervical cancer in infected individuals. In addition to administration of Lactobacillus lactis expressing HPV-16 E6 oncoprotein ((pNZ8123-HPV16-E7 or  pNZ8123-HPV16-optiE7) for vaccination, the genetically modified, NZ8123-HPV-16-optiE6 strain, orally administered vaccine, promoted presentation of the E6 oncoprotein to the host immune system, eliciting an inflammatory and protective response against HPV-16 E6 and E7 oncogenesis.⁴ As for immunotherapy for previously infected individuals with HPV-16, significant change in vaginal microbiota composition occurred at end of 90 day treatment with orally administered L. crispatus M247. 94% of the women showed microbiota change from CST IV to CST I (L. crispatus dominating), with approximately 70% decrease in HPV infection, in both high and low risk strains.⁵

Conclusion: Oral administration of various recombinant L. lactis acts as a delivery vector for the HPV-16 E7 antigen, stimulating the host’s immune system to generate antibodies and cytotoxic T cells which individually target the HPV E7 oncoprotein. These immune responses can potentially counteract the carcinogenic effects of HPV-16 E6 and E7 oncoproteins in infected or exposed individuals, stifling the infection rate of HPV and corresponding carcinogenesis of infected cervical epithelium.² Findings from investigation of vaginal microbial communities are suggestive that the Lactobacillus family represent a great potential for safe oral vectors of vaccine and immunotherapies for HPV.³ Oral administration has the potential to vaccinate and help millions of people worldwide as oral vaccines are generally cheaper and easier to store, transport and administer compared to IM vaccines.

Works Cited:

1. Nelson CW, Mirabello L. Human papillomavirus genomics: Understanding carcinogenicity. Tumour Virus Res. 2023;15:200258. doi:10.1016/j.tvr.2023.200258
2. Mohseni AH, Razavilar V, Keyvani H, Razavi MR, Khavari-Nejad RA. Oral immunization with recombinant Lactococcus lactis NZ9000 expressing human papillomavirus type 16 E7 antigen and evaluation of its immune effects in female C57BL/6 mice. J Med Virol. 2019;91(2):296-307. doi:10.1002/jmv.25303
3. Nicolò S, Antonelli A, Tanturli M, Baccani I, Bonaiuto C, Castronovo G, Rossolini GM, Mattiuz G, Torcia MG. Bacterial Species from Vaginal Microbiota Differently Affect the Production of the E6 and E7 Oncoproteins and of p53 and p-Rb Oncosuppressors in HPV16-Infected Cells. International Journal of Molecular Sciences. 2023; 24(8):7173. https://doi.org/10.3390/ijms24087173
4. Taghinezhad-S S, Mohseni AH, Keyvani H, Razavi MR. Phase 1 Safety and Immunogenicity Trial of Recombinant Lactococcus lactis Expressing Human Papillomavirus Type 16 E6 Oncoprotein Vaccine. Mol Ther Methods Clin Dev. 2019;15:40-51. Published 2019 Aug 29. doi:10.1016/j.omtm.2019.08.005
5. DI Pierro F, Criscuolo AA, Dei Giudici A, et al. Oral administration of Lactobacillus crispatus M247 to papillomavirus-infected women: results of a preliminary, uncontrolled, open trial. Minerva Obstet Gynecol. 2021;73(5):621-631. doi:10.23736/S2724-606X.21.04752-7