HPV-16 L1 genes with inactivated negative RNA elements induce potent immune responses

ABSTRACT Recombinant adenovirus or DNA vaccines encoding herpes simplex virus type 1 (HSV-1) glycoprotein D (gD) genetically fused to human papillomavirus type 16 (HPV-16) oncoproteins (E5, E6, and E7) induce antigen-specific CD8+ T-cell responses and confer preventive resistance to transplantable murine tumor cells (TC-1 cells). In the present report, we characterized some previously uncovered aspects concerning the induction of CD8+ T-cell responses and the therapeutic anticancer effects achieved in C57BL/6 mice immunized with pgD-E7E6E5 previously challenged with TC-1 cells. Concerning the characterization of the immune responses elicited in mice vaccinated with pgD-E7E6E5, we determined the effect of the CD4+ T-cell requirement, longevity, and dose-dependent activation on the E7-specific CD8+ T-cell responses. In addition, we determined the priming/boosting properties of pgD-E7E6E5 when used in combination with a recombinant serotype 68 adenovirus (AdC68) vector encoding the same chimeric antigen. Mice challenged with TC-1 cells and then immunized with three doses of pgD-E7E6E5 elicited CD8+ T-cell responses, measured by intracellular gamma interferon (IFN-γ) and CD107a accumulation, to the three HPV-16 oncoproteins and displayed in vivo antigen-specific cytolytic activity, as demonstrated with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled target cells pulsed with oligopeptides corresponding to the H-2Db -restricted immunodominant epitopes of the E7, E6, or E5 oncoprotein. Up to 70% of the mice challenged with 5 × 105 TC-1 cells and immunized with pgD-E7E6E5 controlled tumor development even after 3 days of tumor cell challenge. In addition, coadministration of pgD-E7E6E5 with DNA vectors encoding pGM-CSF or interleukin-12 (IL-12) enhanced the therapeutic antitumor effects for all mice challenged with TC-1 cells. In conclusion, the present results expand our previous knowledge on the immune modulation properties of the pgD-E7E6E5 vector and demonstrate, for the first time, the strong antitumor effects of the DNA vaccine, raising promising perspectives regarding the development of immunotherapeutic reagents for the control of HPV-16-associated tumors.

Download Full-text

Persistence of immune responses to the HPV ‐16/18 AS 04‐adjuvanted vaccine in women aged 15–55 years and first‐time modelling of antibody responses in mature women: results from an open‐label 6–year follow‐up study

BJOG An International Journal of Obstetrics & Gynaecology ◽

10.1111/1471-0528.13070 ◽

2014 ◽

Vol 122 (1) ◽

pp. 107-118 ◽

Cited By ~ 25

Author(s):

T Schwarz ◽

M Spaczynski ◽

A Kaufmann ◽

J Wysocki ◽

A Gałaj ◽

...

Keyword(s):

Immune Responses ◽

Antibody Responses ◽

Open Label ◽

Hpv 16 ◽

Adjuvanted Vaccine ◽

Follow Up Study ◽

Mature Women ◽

First Time

Download Full-text

Immune Responses to HPV 16 E7

Immunology of Human Papillomaviruses ◽

10.1007/978-1-4615-2449-6_45 ◽

1994 ◽

pp. 291-297 ◽

Cited By ~ 2

Author(s):

Merilyn H. Hibma ◽

M. Tommasino ◽

G. Van Nest ◽

S. J. Ely ◽

M. Contorni ◽

...

Keyword(s):

Immune Responses ◽

Hpv 16

Download Full-text

Time Course of Humoral and Cell-Mediated Immune Responses to Human Papillomavirus Type 16 in Infected Women

Clinical and Vaccine Immunology ◽

10.1128/cdli.9.4.877-882.2002 ◽

2002 ◽

Vol 9 (4) ◽

pp. 877-882 ◽

Cited By ~ 1

Author(s):

Mayumi Nakagawa ◽

Raphael Viscidi ◽

Ian Deshmukh ◽

Maria Da Costa ◽

Joel M. Palefsky ◽

...

Keyword(s):

Human Papillomavirus ◽

Immune Responses ◽

Time Course ◽

Cytotoxic T Lymphocyte ◽

Dna Detection ◽

Protective Role ◽

Hpv 16 ◽

Humoral Immune ◽

Human Papillomavirus Type 16 ◽

E6 And E7

ABSTRACT The time course of cell-mediated and humoral immune responses was elucidated in eight women with human papillomavirus type 16 (HPV-16) infection by performing serial HPV-16 E6 and E7 cytotoxic T-lymphocyte (CTL) assays and HPV-16 virus-like particle (VLP) antibody analyses. Four subjects had a single incident of HPV-16 DNA detection, and four subjects had two periods of HPV-16 DNA detection. In two of the women in the latter group, the second episode of HPV-16 detection occurred in the presence of high titers of HPV-16 VLP antibody, bringing into question the protective role of humoral immunity in preventing repeated infection. However, all four subjects rapidly became HPV-16 DNA negative following the second detection of HPV-16 DNA, suggesting the presence of immunological memory. In addition, one subject rapidly became negative for HPV-16 DNA despite having no evidence of CTL or VLP antibody response prior to the second HPV-16 DNA detection, suggesting the presence of immunological responses at an undetectable level. Overall, seven of eight subjects (88%) had detectable HPV-16 E6 and/or E7 CTL responses and seven of eight women (88%) had detectable HPV-16 VLP antibody responses.

Download Full-text

Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women

Vaccine ◽

10.1016/j.vaccine.2012.09.037 ◽

2012 ◽

Vol 31 (1) ◽

pp. 234-241 ◽

Cited By ~ 22

Author(s):

A.-B. Moscicki ◽

C.M. Wheeler ◽

B. Romanowski ◽

J. Hedrick ◽

S. Gall ◽

...

Keyword(s):

Immune Responses ◽

Adult Women ◽

Hpv 16 ◽

Adjuvanted Vaccine ◽

Fourth Dose

Download Full-text

Abstract A138: Vaccination with HPV 16 L2E6E7 with GPI-0100 adjuvant elicits protective humoral as well as cell-mediated immune responses

10.1158/1940-6207.prev-08-a138 ◽

2008 ◽

Author(s):

Balasubramanyam Karanam ◽

Richard Roden ◽

Ratish Gambhira ◽

Subhashini Jagu

Keyword(s):

Immune Responses ◽

Hpv 16

Download Full-text

Development of a DNA Vaccine Targeting Human Papillomavirus Type 16 Oncoprotein E6

Journal of Virology ◽

10.1128/jvi.78.16.8468-8476.2004 ◽

2004 ◽

Vol 78 (16) ◽

pp. 8468-8476 ◽

Cited By ~ 85

Author(s):

Shiwen Peng ◽

Hongxiu Ji ◽

Cornelia Trimble ◽

Liangmei He ◽

Ya-Chea Tsai ◽

...

Keyword(s):

Human Papillomavirus ◽

T Cell ◽

Immune Responses ◽

Dna Vaccine ◽

Vaccine Development ◽

Immunodominant Epitope ◽

Antitumor Effects ◽

Hpv 16 ◽

Associated Lesions ◽

T Cell Immune Responses

ABSTRACT Human papillomavirus (HPV), particularly type 16 (HPV-16), is present in more than 99% of cervical cancers. The HPV oncoproteins E6 and E7 are constantly expressed and therefore represent ideal targets for HPV vaccine development. We previously developed DNA vaccines encoding calreticulin (CRT) linked to HPV-16 E7 and generated potent E7-specific CD8+ T-cell immune responses and antitumor effects against an E7-expressing tumor. Since vaccines targeting E6 also represent an important strategy for controlling HPV-associated lesions, we developed a DNA vaccine encoding CRT linked to E6 (CRT/E6). Our results indicated that the CRT/E6 DNA vaccine, but not a wild-type E6 DNA vaccine, generated significant E6-specific CD8+ T-cell immune responses in vaccinated mice. Mapping of the immunodominant epitope of E6 revealed that an E6 peptide comprising amino acids (aa) 48 to 57 (E6 aa48-57), presented by H-2Kb, is the optimal peptide and that the region of E6 comprising aa 50 to 57 represents the minimal core sequence required for activating E6-specific CD8+ T lymphocytes. We also demonstrated that E6 aa48-57 contains cytotoxic T-lymphocyte epitopes naturally presented by E6-expressing TC-1 cells. Vaccination with a CRT/E6 but not a CRT/mtE6 (lacking aa 50 to 57 of E6) DNA vaccine could protect vaccinated mice from challenge with E6-expressing TC-1 tumors. Thus, our data indicate that E6 aa48-57 contains the immunodominant epitope and that a CRT/E6 DNA vaccine may be useful for control of HPV infection and HPV-associated lesions.

Download Full-text

Characterization of HLA-A2-restricted HPV-16 E7-specific CD8+ T-cell immune responses induced by DNA vaccines in HLA-A2 transgenic mice

Gene Therapy ◽

10.1038/sj.gt.3302607 ◽

2005 ◽

Vol 13 (1) ◽

pp. 67-77 ◽

Cited By ~ 27

Author(s):

S Peng ◽

C Trimble ◽

L He ◽

Y-C Tsai ◽

C-T Lin ◽

...

Keyword(s):

T Cell ◽

Transgenic Mice ◽

Immune Responses ◽

Dna Vaccines ◽

Cd8 T Cell ◽

Hpv 16 ◽

T Cell Immune Responses

Download Full-text

Cellular immune responses to HPV-18, -31, and -53 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles

Virology ◽

10.1016/j.virol.2006.06.021 ◽

2006 ◽

Vol 353 (2) ◽

pp. 451-462 ◽

Cited By ~ 39

Author(s):

Ligia A. Pinto ◽

Raphael Viscidi ◽

Clayton D. Harro ◽

Troy J. Kemp ◽

Alfonso J. García-Piñeres ◽

...

Keyword(s):

Immune Responses ◽

Healthy Volunteers ◽

Hpv 16 ◽

Virus Like Particles ◽

Cellular Immune Responses ◽

Cellular Immune ◽

Hpv 18

Download Full-text

Evaluation of therapeutic potency of human papillomavirus-16 E7 DNA vaccine alone and with interleukin-18 as a genetic adjuvant

Scientia Medica ◽

10.15448/1980-6108.2018.3.30555 ◽

2018 ◽

Vol 28 (3) ◽

pp. 30555

Author(s):

Behzad Pourhossein ◽

Amir Ghaemi ◽

Maryam Fazeli ◽

Kayhan Azadmanesh ◽

Mahmood Mahmoodi ◽

...

Keyword(s):

Human Papillomavirus ◽

Immune Responses ◽

Dna Vaccine ◽

Mtt Assay ◽

Tumor Size ◽

Lymphocyte Proliferation ◽

Model Systems ◽

Hpv 16 ◽

Significant Difference ◽

Ifn Γ

AIMS: Despite the existence of effective preventive vaccines for human papillomavirus (HPV), therapeutic vaccines that trigger cell-mediated immune responses are required to treat established infections and malignancies. The aim of this study was to evaluate the therapeutic potency of HPV-16 E7 deoxyribonucleic acid (DNA) vaccine alone and with interleukin (IL)-18. METHODS: In vitro expressions of IL-18 were performed on human embryonic kidney 293 cells and confirmed it by Western blotting methods. DNA vaccine was available from a previous study. A total of 45 female C57BL/6 mice divided into five groups (DNA vaccine, DNA vaccine adjuvanted with IL-18, pcDNA3.1, and phosphate buffer saline) were inoculated with murine tissue culture-1 cell line of HPV related carcinoma, expressing HPV-16 E6/E7 antigens. They were then immunized subcutaneously twice at a seven-day interval. The antitumor and antigen specific-cellular immunity were assessed by lymphocyte proliferation (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide: MTT) assay, lactate dehydrogenase release assay, IL-4 assay and interferon-gamma (IFN-γ) assay. Tumor size was followed for 62 days.RESULTS: MTT assay, which measures the lymphocyte proliferation in response to the specific antigen, increased in the co-administration and the DNA vaccine groups as compared to control and genetic adjuvant groups (p<0.001). The mice immunized with the co-administration generated significantly more IFN-γ and IL-4 than other immunized mice (p<0.001). Reduction of the tumor size in the co-administration and the DNA vaccine groups was significantly more pronounced than in the control and genetic adjuvant groups (p<0.001), but no statistically significant difference between DNA vaccine and co-administration groups (p=0.15) occurred.CONCLUSIONS: IL-18 as a genetic adjuvant and E7 DNA vaccine alone enhanced immune responses in mouse model systems against cervical cancer. However, using of IL-18 as a genetic adjuvant with E7 DNA vaccine had no significant synergistic effect on the immune responses in vivo.

Download Full-text