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  • 1
    Keywords: CANCER ; human ; CT ; EPIDEMIOLOGY ; INFECTION ; SKIN ; papillomavirus ; VARIANTS ; virus ; carcinogenicity ; PROGRESSION ; WOMEN ; etiology ; smoking ; cervical cancer ; CERVICAL-CANCER ; CERVIX ; PATHOGENESIS ; human papillomavirus ; HPV ; HUMAN-PAPILLOMAVIRUS ; DIETARY ; TOBACCO ; UTERINE CERVIX ; HERPES-SIMPLEX-VIRUS ; TYPE-2 ; INVASIVE CERVICAL-CANCER ; SKIN-CANCER ; INTEGRATION ; WORLDWIDE ; VARIANT ; HUMAN CANCER ; HIV ; COLLABORATIVE REANALYSIS ; CANCERS ; PERSPECTIVE ; HERPES-SIMPLEX ; nonmelanoma skin cancer ; LONG-TERM USE ; CONTRACEPTIVES ; herpes simplex virus ; HUMAN-PAPILLOMAVIRUS TYPES ; INDIVIDUAL DATA
    Abstract: The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of the vagina and anus are likewise caused by HPV, as are a fraction of cancers of the vulva, penis, and oropharynx. HPV-16 and -18 account for about 70% of cancers of the cervix, vagina, and anus and for about 30-40% of cancers of the vulva, penis, and oropharynx. Other cancers causally linked to HPV are non-melanoma skin cancer and cancer of the conjunctiva. Although HPV is a necessary cause of cervical cancer, it is not a sufficient cause. Thus, other cofactors are necessary for progression from cervical HPV infection to cancer. Long-term use of hormonal contraceptives, high parity, tobacco smoking, and co-infection with HIV have been identified as established cofactors; co-infection with Chlamydia trachomatis (CT) and herpes simplex virus type-2 (HSV-2), immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified. (c) 2006 Published by Elsevier Ltd
    Type of Publication: Journal article published
    PubMed ID: 16949995
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  • 2
    Keywords: CANCER ; IN-VITRO ; human ; VITRO ; CLASSIFICATION ; screening ; DIFFERENTIATION ; DNA ; papillomavirus ; antibodies ; antibody ; prevention ; ASSAY ; CERVICAL-CANCER ; human papillomavirus ; VIRUS-LIKE PARTICLES ; HPV ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; ESTABLISHMENT ; FEASIBILITY ; YOUNG-WOMEN ; IMPLEMENTATION ; WORLDWIDE ; PRODUCTS ; SWITZERLAND ; ASSAYS ; CANDIDATE ; serological ; serology ; CONTROLLED-TRIAL ; DNA evaluation ; HUMAN-PAPILLOMAVIRUS-16
    Abstract: International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16950007
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  • 3
    Keywords: CANCER ; Germany ; human ; GENE ; GENES ; PROTEIN ; EFFICIENCY ; MONOCLONAL-ANTIBODY ; GENE-TRANSFER ; RESPONSES ; DNA ; INFECTION ; INDUCTION ; E7 ; papillomavirus ; SEQUENCE ; ACIDS ; antibodies ; NEUTRALIZING ANTIBODIES ; PARTICLES ; WOMEN ; CAPSID PROTEIN ; VIRUS-LIKE PARTICLES ; LOCALIZATION ; VACCINE ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; L1 ; AMINO-ACIDS ; PLASMID DNA ; CYTOTOXIC T-LYMPHOCYTES ; IMMUNIZATION ; RE ; assembly ; LONG-TERM PERSISTENCE ; CONTROLLED-TRIAL ; DNA immunization ; INTRAMUSCULAR INJECTION
    Abstract: Infections by human papillomaviruses (HPV) are the major cause of uterine cancer in women worldwide. Aiming to develop a combined prophylactic and therapeutic vaccine we have previously demonstrated immunogenicity of chimeric virus-like particles consisting of a C-terminally truncated HPV 16 L1 capsid protein fused to an E7 portion. Here we show that genetic vaccination with a corresponding DNA was inefficient in the induction of a L1-specific prophylactic immune response. DNA immunization with C-terminally truncated HPV 16 L1 genes of different lengths revealed that only short deletions (L1(1-498)) were tolerated for eliciting a humoral immune response against viral capsids. This correlates with the observation that the C-terminal sequences are critical for nuclear localization, capsomere and capsid assembly. However, only the ability of L1 protein to form capsomeres or capsids showed a direct influence on the outcome of the immune response. C-terminal insertion of 60 amino acids of E7 was tolerated in fusion constructs, whereas insertion of full-length E7(1-98) or shuffled E7 (149 aa) completely abolished the humoral immune response. The L1(1-498)/E7(1-60) fusion construct not only induced L1-specific antibodies but also L1- and E7-specific CTL responses after DNA vaccination. (c) 2005 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16414157
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  • 4
    Keywords: Germany ; EXPOSURE ; SITE ; PROTEIN ; PROTEINS ; MOLECULES ; MONOCLONAL-ANTIBODY ; RESPONSES ; BINDING ; MOLECULE ; IMMUNE-RESPONSES ; antibodies ; antibody ; GLYCOPROTEIN ; NEUTRALIZING ANTIBODIES ; MEMBRANE ; FUSION ; REGION ; MONOCLONAL-ANTIBODIES ; VACCINE ; ANTIBODY-RESPONSES ; EPITOPE ; EPITOPES ; IMMUNE-RESPONSE ; HUMAN-IMMUNODEFICIENCY-VIRUS ; HIV ; analysis ; monoclonal antibodies ; BINDING-SITE ; function ; ENVELOPE GLYCOPROTEIN ; immunology ; MEMBRANE-FUSION ; immune responses ; CXCR4 ; GP41 ; CD4 RECEPTOR ; EXPRESSION SYSTEM ; HIV pseudovirions ; HIV vaccine ; HIV-Env induced epitopes ; HUMAN MONOCLONAL-ANTIBODY ; SOLUBLE CD4 ; TYPE-1 GP120
    Abstract: Functionally conserved HIV-Env epitopes, which are induced during the process of Env-mediated membrane fusion, represent interesting immunogens, which may elicit broad neutralising antibody responses. In this report, we analyse a pseudovirion (PV)-based HIV vaccine preparation, potentially enriched in such induced Env-conformations. The vaccine has been prepared by mixing and incubating Env-PVs, with incorporated fusion-defective Env, with PVs, which have incorporated functional CD4 and CXCR4 proteins. Here, we demonstrate that three different monoclonal antibodies (CG 10, 17b and 48d), recognising a region of gp 120 overlapping with the coreceptor binding site, and a further antibody, 8F101, recognising a CD4-induced epitope outside of the coreceptor site, bind to Env molecules in the putative PV vaccine mixture but not at all, or less strongly, to native Env-PVs. In all cases, antibody binding required an interaction of the Env-PVs with CD4 whereas CXCR4 was dispensible. These results confirm that in the PV vaccine preparation, CD4-induced Env epitopes are accessible and that these, as well as other induced epitopes "downstream" from CD4 binding, may function as immunogens to elicit potentially cross-neutralising Immoral immune responses. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17241712
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  • 5
    Keywords: PEPTIDE ; CANCER ; GROWTH ; tumor ; CELL ; CLINICAL-TRIAL ; INHIBITION ; MODEL ; PROSTATE ; REDUCTION ; RAT ; RATS ; T cell ; T-CELL ; SEQUENCE ; SUPPRESSION ; MOLECULE ; TRIAL ; TRIALS ; hormone ; CLINICAL-TRIALS ; prostate cancer ; PROSTATE-CANCER ; GROWTH-INHIBITION ; VACCINES ; VACCINE ; IMMUNOTHERAPY ; FUTURE ; PLASMODIUM-FALCIPARUM ; IMMUNIZATION ; CANCER VACCINES ; TUMOR-GROWTH ; END ; MURINE MODEL ; CARRIER ; TESTOSTERONE ; CANDIDATE ; immunology ; ANDROGEN ; HORMONE-RELEASING-HORMONE ; MEDICINE ; clinical trial ; ACTIVE IMMUNIZATION ; FERTILITY ; hormone-sensitive prostate cancer ; LHRH VACCINE ; REPRODUCTIVE-ORGANS
    Abstract: Previous studies with gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate cancer. To this end, we have generated a completely synthetic peptide modified at position 6 and attached to the 830-844 tetanic toxoid (TT) helper T cell sequence. Through this work we have demonstrated that the GnRHm1-TT molecule was highly immunogenic when it is formulated as an oil-based emulsion adjuvated with Montanide ISA 51. That results correlated directly with testosterone reduction and tumor growth inhibition of the Dunning R3327-H androgen responsive prostate tumor model in rats. GnRHm1-TT, proved to be safe and useful for future clinical trials. (c) 2007 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18022737
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  • 6
    Keywords: CANCER ; Germany ; PROTEIN ; MICE ; RESPONSES ; ANTIGEN ; papillomavirus ; ACID ; antibody ; FORM ; NEUTRALIZING ANTIBODIES ; virus ; cervical cancer ; CERVICAL-CANCER ; VIRUS-LIKE PARTICLES ; HPV ; PEPTIDES ; MONOCLONAL-ANTIBODIES ; VACCINE ; immune response ; AMINO-ACIDS ; IMMUNOGENICITY ; human papilloma virus ; POTENT ; AMINO-ACID ; N-TERMINUS ; MINOR CAPSID PROTEIN ; FORMULATION ; CANDIDATES ; thioredoxin ; PAPILLOMAVIRUS TYPES ; B-CELL EPITOPE ; CROSS-NEUTRALIZATION EPITOPE ; LINEAR EPITOPES ; Minor capsid protein L2
    Abstract: The minor capsid protein L2 is a promising candidate for the construction of an anti-human papillomavirus (HPV) broadly protective vaccine for the prophylaxis of cervical cancer. However, L2-derived peptides are usually poorly immunogenic and extensive knowledge on the most relevant(cross)neutralizing epitope(s) is still needed. We systematically examined the immunogenicity and Virus neutralization potential of six peptides encompassing the N-terminal (amino acids 1-120) region of HPV16 L2 (20-38; 28-42; 56-75: 64-81; 96-115; 108-120) using bacterial thioredoxin (Trx) as a novel peptide scaffold. Mice antisera generated by 19 different Trx-L2 peptide fusions hearing one or multiple copies of each peptide were analyzed. Internal fusion to thioredoxin conferred strong immunogenicity to all the tested peptides, with a trend toward art increased immunogenicity for the multipeptide vs. the monopeptide forms of the various antigens. All Trx-L2 peptides induced HPV16 neutralizing antibodies in some of the immunized mice, but neutralization titers differed by more than two orders of magnitude. Trx-L2(20-38) antisera were by far the most effective in HPV16 neutralization and did not differ significantly from those induced by a reference polypeptide covering the entire L2 (1-120) region. The same antisera were also the most effective when challenged against the non-cognate HPV 18, 58, 45 and 31 pseudovirions. The data identify L2(20-38) as the best (cross)neutralizing epitope among the six that were examined, and point to thioredoxin fusion derivatives of this peptide as excellent candidates for the formulation of a low-cost, broadly protective HPV vaccine. (C) 2009 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19368776
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  • 7
    Keywords: CD8(+) T-CELLS ; innate immunity ; NATURAL-KILLER-CELLS ; NK cells ; PROGNOSTIC-SIGNIFICANCE ; I INTERFERON ; INTERFERON-ALPHA ; VIRAL-INFECTION ; IFN-alpha ; Newcastle disease virus ; SUPPRESSOR-CELLS ; anti-tumor ; FUNCTIONAL-SIGNIFICANCE ; Hemagglutinin-Neuraminidase
    Abstract: A plasmid encoding the Hemagglutinin-Neuraminidase (HN) protein of Newcastle Disease Virus (pHN) was tested for its capacity to stimulate innate anti-tumor activity in tumor-bearing mice. We observed that application of the pHN plasmid at the ear pinna site (i.e.) of mice induces higher levels of systemic interferon-alpha and reduced tumor growth in the prophylactic mammary carcinoma DA3 tumor model in comparison to application of a control plasmid not encoding the HN protein. Analysis of the tumor microenvironment revealed a significant increase in NK cell infiltration and decrease in infiltration of CD11b(+)Gr-1(high) myeloid cells bearing the myeloid-derived suppressor cell (MDSC) phenotype after vaccination with the pHN DNA compared to a control DNA. Finally, innate immunity and partially type I IFN responses were proved important for the reduction of s.c. RMA-S tumor growth after pHN vaccination, as shown with the use of RAG2(-/-) and RAG2(-/-)IFNAR1(-/-) mice. These data demonstrate that triggering innate immunity by pHN application at the ear pinna of mice modulates the immune cell compartment in the tumor microenvironment and reduces tumor growth. This highlights thus the potential adjuvant activity of the HN gene in tumor therapy.
    Type of Publication: Journal article published
    PubMed ID: 21172381
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  • 8
    Abstract: Ninety-one HIV-infected individuals (61 men and 30 women) were randomized to vaccination either with quadrivalent (Gardasil) or bivalent (Cervarix) HPV vaccine. Neutralizing and specific HPV-binding serum antibodies were measured at baseline and 12 months after the first vaccine dose. Presence of neutralizing and binding antibodies had good agreement (average Kappa for HPV types 6, 11, 16, 18, 31, 33 and 45 was 0.65). At baseline, 88% of subjects had antibodies against at least one genital HPV. Following vaccination with Cervarix, all subjects became seropositive for HPV16 and 18. After Gardasil vaccination, 96% of subjects seroconverted for HPV16 and 73% for HPV18. Levels of HPV16-specific antibodies were 〈1 international unit (IU) in 87% of study subjects before vaccination but 〉10IU in 85% of study subjects after vaccination. Antibodies against non-vaccine HPV types appeared after Gardasil vaccination for 〉50% of vaccinated females for HPV 31, 35 and 73 and for 〉50% of Cervarix-vaccinated females for HPV 31, 33, 35, 45, 56 and 58. Cross-reactivity with non-genital HPV types was also detected. In conclusion, HIV-infected subjects responded to HPV vaccination with induction of neutralizing antibodies against both vaccine and non-vaccine types.
    Type of Publication: Journal article published
    PubMed ID: 26896686
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  • 9
    Keywords: CANCER ; CELLS ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; CELL-PROLIFERATION ; Germany ; human ; DISEASE ; ADHESION MOLECULES ; MOLECULES ; RELEASE ; PATIENT ; ACTIVATION ; RESPONSES ; ANTIGEN ; T-CELL ; T-CELLS ; MOLECULE ; cytokines ; IMMUNE-RESPONSES ; antibodies ; antibody ; virus ; UP-REGULATION ; MONOCLONAL-ANTIBODIES ; VACCINE ; SAFETY ; IMMUNE-RESPONSE ; INTERFERON ; INTERFERON-ALPHA ; NEWCASTLE-DISEASE VIRUS ; CANCER PATIENTS ; chemokine ; EFFECTOR ; IMMUNOLOGICAL SYNAPSE ; bispecific antibody ; CYTOTOXICITY ; tumor vaccine ; RE ; NEWCASTLE-DISEASE-VIRUS ; SINGLE-CHAIN ANTIBODY ; bispecific ; Newcastle disease virus ; CD28 COSTIMULATION ; bispecific single chain antibody ; CD3 and CD28 cross-linking
    Abstract: The aim was to develop T cell costimulatory molecules that are broadly applicable to augment anti-tumor immune responses upon application of a virus-modified tumor vaccine to cancer patients. We generated recombinant bispecific single-chain antibodies with one specificity directed against the CD3 or the CD28 antigen on human T cells and the other against the viral target molecule hemagglutinin-neuraminidase (HN) of Newcastle Disease Virus (NDV). By re-directing unstimulated primary human T cells against HN-expressing NDV-infected tumor cells, the bispecific molecule bsHN-CD3 cross-linked effector and target cells and rapidly induced cytotoxicity at nanomolar concentrations. The bsHN-CD28 molecule exerted T cell co-stimulatory function. Maximal T cell activation was achieved with tumor cells infected by NDV and modified with both new stimulatory molecules. This was revealed by T cell proliferation, upregulation of CD69 and CD25 and by release of cytokines, interferons and chemokines. The new molecules combine high-effectivity with specificity and safety. (c) 2004 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15752830
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  • 10
    Keywords: IN-VITRO ; Germany ; human ; GENERATION ; PROTEIN ; PROTEINS ; MICE ; RESPONSES ; ANTIGEN ; ANTIGENS ; LYMPH-NODES ; papillomavirus ; antibodies ; antibody ; NEUTRALIZING ANTIBODIES ; PARTICLES ; virus ; CERVICAL-CANCER ; CAPSID PROTEIN ; human papillomavirus ; TYPE-16 ; VIRUS-LIKE PARTICLES ; HPV ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; L1 ; NASAL IMMUNIZATION ; FUSION PROTEIN ; CHOLERA-TOXIN ; CYTOTOXIC T-LYMPHOCYTES ; SERUM ; IMMUNIZATION ; LEVEL ; immunology ; CTA1-D2D1 ; capsomeres ; CTA1-DD VACCINE ADJUVANT ; CTB ; HUMAN PAPILLOMAVIRUSES ; intranasal immunization ; MUCOSAL IMMUNIZATION
    Abstract: Prophylactic immunization against human papillomaviruses (HPVs) aims preferentially at the generation of antibodies, which are directed against the virus capsid proteins. DNA-free virus-like particles or their pentameric subunits, the capsomeres represent suitable antigens. Here we investigated if anti-HPV16 L1 specific antibodies and U-specific CTL induced by intranasal immunization with capsomeres in sera and vaginal washings of C57B16 mice can be enhanced by co-application of the non-toxic cholera toxin adjuvants CTA1-D2D1 or CTB. We found that CTA1-D2D1 elevated L1-specific serum IgG antibodies in a dose-dependent manner and both CTA1-D2D1 and CTB significantly increased L1-specific IgA antibody levels in the vaginal lumen. Furthermore, CTA1-D2D I and CTB enhanced L1-specific CTL responses. (c) 2005 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16455165
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