Evaluation of immune responses induced by a novel human papillomavirus type 16 E7 peptide-based vaccine with Candida skin test reagent as an adjuvant in C57BL/6 mice.

Cell mediated immune (CMI) responses are crucial for the clearance of human papillomavirus (HPV) infection and HPV-associated lesions. Activated CD8 T cells are critical effector cells in recognizing and killing HPV-infected or HPV-transformed cells. CD4 T cells provide help for priming the generation and maintenance of CD8 T cells as well as for tumors immunity. An ideal therapeutic HPV peptide-based vaccine should induce both a robust CD8 T-cell response as well as a CD4 T-cell response for ensuring their efficiency. Candida skin test reagent was demonstrated to be able to induce the secretion of IL-12 by Langerhans cells and T-cell proliferation in vitro by our group, which indicated the potential of Candida to enhance CMI response. In this current study, we designed a novel HPV peptide-based vaccine which includes HPV16 E7 peptides and Candida as an adjuvant. The immune responses induced by the vaccine were comprehensively evaluated. The results showed that the vaccine induced significant HPV-specific CD8 T-cell and Th1 CD4 T-cell responses as well as humoral immune response. It is interesting that Candida alone induced a significant polarization of Th1 response an production of IFN-γ, which indicated Candida alone may be used as a potential immunotherapeutic reagent not only for HPV-associated lesions but also for other viral infection or even cancers.

Wang X ，Che Y ，Chen B ，Zhang Y ，Nakagawa M ，Wang X ... -  《-》

Prevention and treatment of cervical cancer by a single administration of human papillomavirus peptide vaccine with CpG oligodeoxynucleotides as an adjuvant in vivo.

No licensed therapeutic human papillomavirus (HPV) vaccine is currently available, so it remains a high priority to develop a therapeutic HPV vaccine or prophylactic/therapeutic HPV vaccine for cervical cancer. In this current study, we designed an HPV vaccine including CpG oligodeoxynucleotides 1826 as an adjuvant and HPV16 E7 43-77 peptide as antigen, which contains a CD8 T cell epitope (E7 49-57), and two CD4 T cell epitopes (E7 43-77 and E7 50-62). The prophylactic and therapeutic effect on cervical cancer induced by a single administration of vaccine, were comprehensively evaluated by examining the tumor size and the percentage of tumor-free/bearing mice. The cellular immunity and modulation of immunosuppressive cells induced by the vaccine were evaluated by examining intracellular cytokine staining (ICS) of splenocytes and FCM, respectively. Antigen-specific cytotoxic T-lymphocyte (CTL) responses were investigated using in vivo cytolytic assay. The results showed that the single administration of vaccine elicited significant prophylactic as well as therapeutic effect on cervical cancer. The increased cellular immunity mediated by CD4 + IFN-γ + T cells and CD8 + IFN-γ + T cells, and the decreased numbers of immunosuppressive cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were induced by the vaccine. Antigen-specific CTL response was also induced by vaccination. These findings suggested that significant anti-tumor effect of the vaccine may result from the induction of increased cellular immunity and decreased immunosuppressive cells.

Yang Y ，Che Y ，Zhao Y ，Wang X ... -  《-》

Candida skin test reagent as a novel adjuvant for a human papillomavirus peptide-based therapeutic vaccine.

A vaccine adjuvant that can effectively promote cell-mediated immunity is currently not available. Because of the ability of a Candida skin test reagent injection to induce common wart regression, our group is using it as a novel adjuvant in a clinical trial of a peptide-based human papillomavirus therapeutic vaccine. The goal of this current study was to investigate the mechanisms of how Candida enhances the vaccine immune responses. Maturation effects on Langerhans cells, capacity to proliferate T-cells, expression of cytokines and pattern recognition receptors by Langerhans cells, and ability to induce Th1, Th2, and Th17 responses were investigated in healthy subjects. The vaccine, human papillomavirus peptides with Candida, demonstrated partial maturation effects on Langerhans cells indicated by significantly up-regulated CD40 (p=0.00007) and CD80 (p<0.00001) levels, and showed T-cell proliferative capacity (p<0.00001) when presented by Langerhans cells in vitro. Interestingly, the maturation effects were due to the peptides while Candida was responsible for the T-cell proliferation. The cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-23Ap19, IFN-γ and TNF-α) of Langerhans cells treated with the vaccine or Candida alone showed that IL-12p40 mRNA was most frequently induced, and IL-12p70 protein was detected in the supernatants. The presence of pattern recognition receptors known to associate with Candida albicans (DC-SIGN, dectin-1, dectin-2, galectin-3, mincle, mannose receptor, Toll-like receptors-1, 2, 4, 6 and 9) were demonstrated in all subjects. On the other hand, the induction of Th1 response demonstrated by IFN-γ secretion by CD4 cells stimulated with the vaccine or Candida pulsed Langerhans cells was demonstrated only in one subject. In summary, the Langerhans cell maturation effects of the vaccine were due to the peptides while the T-cell proliferative capacity was derived from Candida, and the most frequently induced cytokine was IL-12.

Wang X ，Coleman HN ，Nagarajan U ，Spencer HJ ，Nakagawa M ... -  《-》

Design and evaluation of a multi-epitope DNA vaccine against HPV16.

Zhu L ，Cui X ，Yan Z ，Tao Y ，Shi L ，Zhang X ，Yao Y ，Shi L ... -  《-》

Enhancement of therapeutic DNA vaccine potency by melatonin through inhibiting VEGF expression and induction of antitumor immunity mediated by CD8+ T cells.

Baghban Rahimi S ，Mohebbi A ，Vakilzadeh G ，Biglari P ，Razeghi Jahromi S ，Mohebi SR ，Shirian S ，Gorji A ，Ghaemi A ... -  《-》