Abstract
ObjectiveThis study aims to prepare candidate vaccines for cervical cancer immunotherapy by inserting the fused genes of human papillomavirus (HPV)16/18/58 mE6E7 lacking transforming activity into an adenovirus vector and to verify its efficiency in model mice with tumor expressing the associated HPV genes.MethodsThe E6/E7 genes of HPV16/18/58 were point-mutated to abolish their transforming activity, and adenovirus (AD)-HPV16/18/58 mE6E7 adenovirus vaccine was constructed. The immune effect of the adenovirus vaccine against HPV16/18/58-type tumors was analyzed by tumor morphology, enzyme linked immunosorbent assay, enzyme-linked immunospot and specific cytotoxic T lymphocyte (CTL) and T lymphocyte subsets.ResultsThe HPV16/18/58 mE6E7 plasmid containing point mutations was verified by quantitative real-time polymerase chain reaction (qRT-PCR), enzyme digestion and electrophoresis, and gene sequencing. qRT-PCR and Western blots verified that AD-HPV16/18/58 mE6E7 could express the HPV16 mE6E7, HPV18 mE6E7 and HPV58 mE6E7 fusion genes and proteins in cells. The results of animal experiments were as follows: In the vaccine group, the tumors formed later, the incubation period was longer, the growth was slower, growth was inhibited, and the survival period was significantly prolonged. The immunological results all showed that the vaccine could induce effective humoral and cellular immunity in mice with three types of tumors, compared with the phosphate buffered saline (PBS) group and the adenovirus-negative control (AD-NC) group, the differences were statistically significant (P < 0.05).ConclusionWe successfully constructed the HPV16/18/58 trivalent therapeutic adenovirus vaccine AD-HPV16/18/58 mE6E7. The AD-HPV16/18/58 mE6E7 adenovirus vaccine can protect immunized mice to a certain extent from TC-1, U14/LV-HPV18 E6E7 and U14/LV-HPV58 E6E7 cells, which contain HPV16, 18 and 58 E6 and/or E7 genes, respectively.
Highlights
Cervical cancer is one of the most common malignant tumors of the female reproductive system and seriously endangers women’s life and health [1]
Due to the genetic differences between the various types of Human papillomavirus (HPV), there is no or weak cross-protection between the various types of HPV vaccines [7], and the vaccines currently on the market are all preventive vaccines, which are not effective for cervical lesions or even cervical cancer patients who have been infected with HPV
There is an urgent demand for the development of a composite cervical cancer therapeutic vaccine including the HPV16/18/58 type to benefit Chinese patients with squamous intraepithelial lesion and cervical cancer patients suffering from high-risk HPV
Summary
Cervical cancer is one of the most common malignant tumors of the female reproductive system and seriously endangers women’s life and health [1]. Since almost all cervical cancer cells express HPV DNA and virus transforming protein, HPV protein can stimulate the body as an antigen to produce an immune response against HPV [4], suggesting that cervical cancer may be prevented and treated through vaccine immunotherapy. According to their selected antigen fragments and effects, HPV vaccines which have been put on the market or are being studied can be divided into preventive vaccines and therapeutic vaccines. There is an urgent demand for the development of a composite cervical cancer therapeutic vaccine including the HPV16/18/58 type to benefit Chinese patients with squamous intraepithelial lesion and cervical cancer patients suffering from high-risk HPV
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