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  • HPV  (2)
  • LYMPHOCYTES  (2)
  • ASSAY  (1)
  • 1
    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; Germany ; human ; PROTEIN ; PROTEINS ; TUMORS ; MICE ; RELEASE ; COMPLEX ; RESPONSES ; COMPLEXES ; SERA ; REDUCTION ; DENDRITIC CELLS ; BINDING ; SEQUENCE ; antibodies ; NEUTRALIZING ANTIBODIES ; PARTICLES ; ASSAY ; ESCHERICHIA-COLI ; GLUTATHIONE ; LYMPHOCYTES ; VIRUS-LIKE PARTICLES ; HPV ; HPV16 ; VACCINE ; IMMUNE-RESPONSE ; vaccination ; L1 ; SEQUENCE-ANALYSIS ; glutathione-S-transferase ; HPV PSEUDOVIRIONS ; NASAL IMMUNIZATION
    Abstract: We analyzed capsomeres of human papillomavirus type 16 (HPV16) consisting of the L1 major structural protein for their ability to trigger a cytotoxic T-cell (CTL) response. To this end, we immunized C57BL/6 mice and used the L1(165-173) peptide for ex vivo restimulation of splenocytes prior to analysis (Cr-51 release assay and enzyme-linked immunospot assay [ELISPOT]). This peptide was identified in this study as a D-b-restricted naturally processed CTL epitope by HPV16 L1 sequence analysis, major histocompatibility complex class I binding, and Cr-51 release assays following immunization of C57BL/6 mice with HPV16 L1 virus-like particles (VLPs). HPV16 L1 capsomeres were obtained by purification of HPV16 L1 lacking 10 N-terminal amino acids after expression in Escherichia coli as a glutathione S-transferase fusion protein (GST-HPV16 L1DeltaN10). Sedimentation analysis revealed that the majority of the purified protein consisted of pentameric capsomeres, and assembled particles were not observed in minor contaminating higher-molecular-weight material. Subcutaneous (s.c.) as well as intranasal immunization of C57BL/6 m ice with HPV16 L1 capsomeres triggered an L1-specific CTL response in a dose- dependent manner as measured by ELISPOT and Cr-51 release as say. Significant reduction of contaminating bacterial endotoxin (lipopolysaccharide) from the capsomere preparation did not diminish the immunogenicity. Antibody responses (serum and vaginal) were less robust under the experimental conditions employed. In addition, s.c. vaccination with HPV16 L1 capsomeres induced regression of established tumors expressing L1 determinants (C3 tumor cells). Our data demonstrate that capsomeres are potent inducers of CTL responses similar to completely assembled T=7 VLPs. This result is of potential relevance for the development of (combined prophylactic and therapeutic) HPV-specific vaccines, since capsomeres can be produced easily and also can be modified to incorporate heterologous sequences such as early HPV proteins
    Type of Publication: Journal article published
    PubMed ID: 12663770
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  • 2
    Keywords: CANCER ; EXPRESSION ; CLINICAL-TRIAL ; Germany ; human ; INFORMATION ; PROTEIN ; PROTEINS ; PATIENT ; RESPONSES ; INFECTION ; T cell ; T-CELLS ; E7 ; IMMUNE-RESPONSES ; antibodies ; antibody ; PARTICLES ; TRIAL ; NEOPLASIA ; HUMANS ; WOMEN ; cervical cancer ; cervical intraepithelial neoplasia ; CERVICAL-CANCER ; EFFICACY ; FUSION ; LYMPHOCYTES ; VIRUS-LIKE PARTICLES ; HPV ; VACCINE ; SAFETY ; immune response ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; intraepithelial neoplasia ; T-LYMPHOCYTES ; vaccination ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; L1 ; T lymphocyte ; DOUBLE-BLIND ; PREVALENCE ; T lymphocytes ; glutathione-S-transferase ; YOUNG-WOMEN ; IMMUNIZATION ; ONCOLOGY ; PERSISTENT ; RECOMBINANT ; END ; GRADE ; RECIPIENTS ; development ; EVENTS ; PERSISTENCE ; USA ; HUMAN PAPILLOMAVIRUSES ; IMPROVEMENT ; immune responses ; clinical trial ; CIN
    Abstract: Persistent infection with human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. Vaccination with virus-like particles (VLP) has demonstrated efficacy in prophylaxis but lacks therapeutic potential. HPV16 L1E7 chimeric virus-like particles (CVLP) consist of a carboxy-terminally truncated HPV16L1 protein fused to the amino-terminal part of the HPV16 E7 protein and self-assemble by recombinant expression of the fusion protein. The CVLP are able to induce L1- and E7-specific cytotoxic T lymphocytes. We have performed a first clinical trial to gain information about the safety and to generate preliminary data on the therapeutic potential of the CVLP in humans. A randomized, double blind, placebo-controlled clinical trial has been conducted in 39 HPV16 mono-infected high grade cervical intraepithelial neoplasia (CIN) patients (CIN 2/3). Two doses (75 mu g or 250 mu g) of CVLP were applied. The duration of the study was 24 weeks with 2 optional visits after another 12 and 24 weeks. The vaccine showed a very good safety profile with only minor adverse events attributable to the immunization. Antibodies with high titers against HPV16 L1 and low titers against HPV16 E7 as well as cellular immune responses against both proteins were induced. Responses were equivalent for both vaccine concentrations. A trend for histological improvement to CIN I or normal was seen in 39% of the patients receiving the vaccine and only 25% of the placebo recipients. Fifty-six percent of the responders were also HPV16 DNA-negative by the end of the study. Therefore, we demonstrated evidence for safety and a nonsignificant trend for the clinical efficacy of the HPV16 L1E7 CVLP vaccine. (c) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17721997
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