Chimeric HBcAg virus-like particles presenting a HPV 16 E7 epitope significantly suppressed tumor progression through preventive or therapeutic immunization in a TC-1-grafted mouse model

Abstract

Background Therapeutic human papillomavirus (HPV) vaccines are currently being developed. However, no therapeutic efficacy has been achieved in clinical trials for the treatment of cervical intraepithelial neoplasia or cancer. One of the important issues in increasing vaccine efficacy is determining the best way to enhance tumor antigen-specific cellular immune responses. This study aimed to explore the virus-like particles (VLPs) of hepatitis B core antigen (HBcAg) as potential therapeutic vaccine carriers and to assess its immunological characteristics. Methods Chimeric VLPs presenting a HPV 16 cytotoxic T lymphocytes epitope E7 49–57 (amino acid 49–57 of the E7 protein) were prepared using recombinant genes. C57BL/6 mice were immunized with VLPs and grafted with tumor cells TC-1 which is an E7-expressing tumorigenic cell line. The dynamic tumor growth was monitored and anti-tumor immune responses were investigated. Results Using a preventive strategy, immunization with VLPs resulted in nearly complete suppression of tumor growth. In treatment studies, VLP immunization significantly suppressed the tumor progression in mice carrying 2–3 mm tumors and in those bearing even larger tumors with diameters up to 8–9 mm. The VLP structure was shown to be important to induce vigorous antitumor immunity and effects. In immunized mice, enhanced E7 49–57 -specific cellular immune responses were evidenced by increased interferon (IFN)-γ expression and decreased interleukin (IL)-4 expression in splenic lymphocytes, as well as an elevated number of effector cells expressing IFN-γ in response to the in vitro stimulation of the specific peptide E7 49–57 . In addition, effective immune memory after VLP immunization was maintained for at least 16 weeks, preventing significant tumor growth after subsequent TC-1 challenge. Conclusion While VLPs were highly immunogenic in stimulating humoral immunity, our results strongly indicated that VLPs, such as HBcAg particles, might also be potent therapeutic vaccine carriers to elicit robust cellular immune responses, even in the immunosuppressive microenvironment of a tumor.

Virus-like particles that display Zika virus envelope protein domain III induce potent neutralizing immune responses in mice

“…While it would be intriguing to investigate the extend of HBcAg carrier-specific responses elicited by HBcAg-zDIII VLPs in the future, extensive studies have shown that carrier-specific antibody responses to HBcAg are often mild and do not have significant negative influences on the immunogenicity of the foreign epitopes displayed by HBcAg VLPs 34 , 35 . For example, carrier-specific anti-HBcAg antibodies were found to have minimal effect on the antigen presentation, the induction of antigen-specific antibody and cytotoxic T-cell responses, and the protective immunity of antigens that are displayed by HBcAg VLPs 34 – 36 . The induction of carrier-specific antibodies may also prevent the use of the vaccine in populations that have pre-exposure to hepatitis B virus.…”

Application of built-in adjuvants for epitope-based vaccines

“…In addition, the nanoscale structure of HBcAg can be more effectively identified and processed by APCs (Lee et al, 2009; Ong, Tan & Ho, 2017). Therefore, HBcAg has been used as an vaccine carrier for several exogenous pathogens (e.g., hepatitis B, C, and E virus, influenza virus, foot-and-mouth disease virus, Human enterovirus 71, coxsackievirus A16, and C. trachomatis ), and the immunogenicity of recombinant HBc-based VLP vaccines against pathogens has also been verified in animal models (Dai et al, 2016; Su et al, 2013; Zheng et al, 2016; Chu et al, 2016; Zhu et al, 2016; Wu et al, 2017; Jiang et al, 2017). VLPs are the self-assembled structural proteins of most viruses and can stimulate the immune response in the absence of an adjuvant by exposing pathogen epitopes and simulating the structure of natural viruses (Plummer & Manchester, 2011; Yang et al, 2016).…”

Peer Review #3 of "Application of built-in adjuvants for epitope-based vaccines (v0.1)"

“…In addition, the nanoscale structure of HBcAg can be more effectively identified and processed by APCs (Lee et al, 2009;Ong et al, 2017). Therefore, HBcAg has been used as an vaccine carrier for several exogenous pathogens (e.g., hepatitis B, C, and E virus, influenza virus, foot-and-mouth disease virus, Human enterovirus 71, coxsackievirus A16, and Chlamydia trachomatis), and the immunogenicity of recombinant HBc-based virus like particle (VLP) vaccines against pathogens has also been verified in animal models (Dai et al, 2016;Su et al, 2013;Zheng et al, 2016;Chu et al, 2016;Zhu et al, 2016;Wu et al, 2017;Jiang et al, 2017). VLPs are the self-assembled structural proteins of most viruses and can stimulate the immune response in the absence of an adjuvant by exposing pathogen epitopes and simulating the structure of natural viruses (Plummer & Manchester, 2011;Yang et al, 2016).…”