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1.
J Microbiol ; 57(9): 821-827, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31452045

RESUMO

Most commercialized virus-like particle (VLP) vaccines use aluminum salt as adjuvant, even though VLPs provoke adequate antibody responses without adjuvant. We do not have detailed knowledge of how adjuvant affects the profile of anti-VLP antibodies. Meanwhile, there is evidence that differences between vaccination protocols influence the glycosylation of antibodies, which may alter their effector functions. In the present study a murine model was used to investigate the effects of dosing schedule and adjuvant on the antibody profiles and glycosylation levels of antigen-specific antibody responses to human papillomavirus type 16 L1 (HPV16 L1) VLPs. Mice received subcutaneously 2,000 ng of antigen divided into 4 or 7 doses. The HPV16 L1 VLPs elicited > 4 log10 anti-HPV16 L1 IgG titers without adjuvant, and aluminum hydroxide as adjuvant increased IgG titers 1.3- to 4-fold and reduced the anti-HPV16 L1 IgG2a / anti-HPV16 L1 IgG1 ratio value (use of aluminum hydroxide reduced the ratio of the IgG2a). Immunization with HPV16 L1 VLPs in combination with Freund's adjuvant enhanced IgG titers 5- to 12-fold. Seven-dose immunization markedly increased anti-HPV16 L1 IgM titers compared to four-dose immunization, as well as increasing the proportion of glycosylated antibodies. Our results suggest that antibody glycosylation can be controlled immunologically, and IgG and IgM profiles and glycosylation profiles of the vaccine-induced antibodies can be used as indicators reflecting the vaccine characteristics. These results indicate that the HPV16 L1 VLP dosing schedule can affect the quality of antigen-specific antibody responses. We suggest that dosing schedules should be noted in vaccination protocols for VLP-based vaccines.


Assuntos
Papillomavirus Humano 16/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antivirais/imunologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Papillomavirus Humano 16/genética , Humanos , Esquemas de Imunização , Camundongos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia
2.
BMC Infect Dis ; 19(1): 552, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234784

RESUMO

BACKGROUND: Human papillomavirus (HPV) is the most widespread sexually transmitted infection worldwide. It causes several health consequences, in particular accounting for the majority of cervical cancer cases in women. In the United Kingdom, a vaccination campaign targeting 12-year-old girls started in 2008; this campaign has been successful, with high uptake and reduced HPV prevalence observed in vaccinated cohorts. Recently, attention has focused on vaccinating both sexes, due to HPV-related diseases in males (particularly for high-risk men who have sex with men) and an equity argument over equalising levels of protection. METHODS: We constructed an epidemiological model for HPV transmission in the UK, accounting for nine of the most common HPV strains. We complemented this with an economic model to determine the likely health outcomes (healthcare costs and quality-adjusted life years) for individuals from the epidemiological model. We then tested vaccination with the three HPV vaccines currently available, vaccinating either girls alone or both sexes. For each strategy we calculated the threshold price per vaccine dose, i.e. the maximum amount paid for the added health benefits of vaccination to be worth the cost of each vaccine dose. We calculated results at 3.5% discounting, and also 1.5%, to consider the long-term health effects of HPV infection. RESULTS: At 3.5% discounting, continuing to vaccinate girls remains highly cost-effective compared to halting vaccination, with threshold dose prices of £56-£108. Vaccination of girls and boys is less cost-effective (£25-£53). Compared to vaccinating girls only, adding boys to the programme is not cost-effective, with negative threshold prices (-£6 to -£3) due to the costs of administration. All threshold prices increase when using 1.5% discounting, and adding boys becomes cost-effective (£36-£47). These results are contingent on the UK's high vaccine uptake; for lower uptake rates, adding boys (at the same uptake rate) becomes more cost effective. CONCLUSIONS: Vaccinating girls is extremely cost-effective compared with no vaccination, vaccinating both sexes is less so. Adding boys to an already successful girls-only programme has a low cost-effectiveness, as males have high protection through herd immunity. If future health effects are weighted more heavily, threshold prices increase and vaccination becomes cost-effective.


Assuntos
Análise Custo-Benefício , Modelos Econômicos , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Vacinação/economia , Adolescente , Feminino , Custos de Cuidados de Saúde , Humanos , Imunidade Coletiva , Masculino , Papillomaviridae/imunologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Anos de Vida Ajustados por Qualidade de Vida , Reino Unido/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle
3.
Eur J Pharm Biopharm ; 141: 221-231, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154067

RESUMO

Thimerosal has been widely used as a preservative in human vaccines for decades. Thimerosal, a thiol capping agent with ethyl mercury being the active degradant, could have impacts on the vaccine potency due to potential thiol modification. The effects on the antigenicity and immunogenicity of human papillomavirus (HPV) virus-like particles (VLPs) in the presence of thimerosal was studied. In general, reduced binding activity was observed between HPV antigens and monoclonal antibodies (mAbs) upon thimerosal treatment, accompanied by reduced protein conformational stability. The immunogenicity of a pentavalent vaccine formulation (HPV6, HPV11, HPV16, HPV18 and hepatitis E virus) with or without thimerosal was studied in mice. The functional antibody titres, as well as the binding titres, were determined, showing a substantial decrease for vaccine formulations containing thimerosal for HPV16/18. Similarly, epitope-specific competition assays using specific and functional mAbs as tracers also showed a significant reduction in immunogenicity for HPV16/18 in the presence of thimerosal. Structural alterations in the capsid protein for HPV18 were observed with cryo-electron microscopy and 3-dimensional reconstruction in the comparative structural analysis. The results should alert scientists in formulation development field on the choice for vaccine preservatives, in particular for thiol-containing antigens.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Antígenos Virais/imunologia , Papillomaviridae/imunologia , Timerosal/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Proteínas do Capsídeo/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Vacinação/métodos
4.
Biomed Res Int ; 2019: 8163591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31111067

RESUMO

Retrospective analysis has already shown correlation between severe Chronic Periodontitis (CP) cases with human papiloma virus (HPV). Hence, we aimed to explore deep-seated infected granulation tissue removed during periodontal flap surgery procedures for residential bacterial species between HPV+ and HVP- CP cases, which may serve as good predisposition marker for oral cancer. All CP-granulation samples showed the prominence of Firmicutes, Proteobacteria, and Bacteroidetes phyla with an abundance of gram negative anaerobes, except Streptococcus. In Beta diversity nonmetric multidimensional scaling plot, the random distribution of species was observed between HPV+ and HPV- CP granulation-samples. However, an abundance of Capnocytophaga ochracea was observed in HPV+ CP samples (p<0.05), while Porphyromonas endodontalis, Macellibacteroides fermentas, Treponema phagedenis, and Campylobacter rectus species were highly abundant in HPV- CP samples (p<0.05). The differential species richness leads altered functions related to mismatch-repair and nucleotide excision-repair and cytoskeleton-proteins. Hence, differential abundance of gram negative bacterial species between HPV+ and HPV- granulation-samples under anaerobic conditions may release virulence factors which may alter pathways favouring carcinogenesis. Hence, these species may serve as good predisposition marker for oral-cancer.


Assuntos
Bactérias/classificação , Periodontite Crônica/microbiologia , Disbiose , Tecido de Granulação/microbiologia , Microbiota , Infecções por Papillomavirus/complicações , Adolescente , Adulto , Idoso , Bactérias/genética , Biodiversidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/imunologia , Índice Periodontal , Bolsa Periodontal , RNA Ribossômico 16S , Estudos Retrospectivos , Adulto Jovem
5.
Virol J ; 16(1): 72, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138240

RESUMO

BACKGROUND: Human papillomavirus (HPV) E6 and E7 oncoproteins play a crucial role in HPV-related diseases, such as cervical cancer, and can be used as ideal targets for therapeutic vaccines. Human leukocyte antigen (HLA) participates in the immune response to block HPV infection and invasion by its target/recognition function. HPV-33 and HPV-58 are highly prevalent among Chinese women. Therefore, it is of great significance to study the E6 and E7 region-specific gene polymorphisms of HPV-33 and HPV-58 in Southwest China and to identify ideal epitopes for vaccine design. Both HPV-33 and HPV-58 belong to α-9 genus HPV and are highly homologous, so their correlations are included in our research. METHODS: To study the E6 and E7 variations and polymorphisms of HPV-33 and HPV-58 in Southwest China, we collected samples, extracted and sequenced DNA, and identified variants. Nucleotide sequences were translated into amino acids by Mega 6.0 software. The physical/chemical properties, amino acid-conserved sequences and secondary structure of protein sequences were analysed by the Protparam server, ConSurf server and PSIPRED software. The T and B cell epitopes of the E6/E7 reference and variant sequences in HPV-33 and HPV-58 were predicted by the Immune Epitope Database (IEDB) analysis server and the ABCpred server, respectively. RESULTS: Five and seven optimal HLA-I restricted T cell epitopes were selected from HPV-33 and HPV-58 E6, respectively, and these optimal epitopes are mainly located in 41-58EVYDFAFADLTVVYREGN of HPV-33 E6 and 40-60SEVYDFVFADLRIVYRDGNPF of HPV-58 E6. Six optimal HLA-I-restricted T cell epitopes were selected from HPV-33 and HPV-58 E7, and these epitopes are mainly located in 77-90RTIQQLLMGTVNIV of HPV-33 E7 and 78-91RTLQQLLMGTCTIV of HPV-58 E7. CONCLUSIONS: HPV-33/HPV-58 E6/E7 gene polymorphisms and T/B cell epitopes of their reference and variant sequences were studied, and candidate epitopes were selected by bioinformatics techniques for therapeutic vaccine design for people in Southwest China. This study was the first to investigate the correlation of epitopes between HPV-33 and HPV-58. After experimental validation, these selected epitopes will be employed to induce a wide range of immune responses in heterogeneous HLA populations.


Assuntos
Epitopos/imunologia , Variação Genética , Papillomaviridae/imunologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Epitopos/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Infecções por Papillomavirus/epidemiologia , Filogenia , Neoplasias do Colo do Útero/virologia
6.
Neoplasia ; 21(6): 591-601, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31055200

RESUMO

Substantial heterogeneity exists within cervical cancer that is generally infected by human papillomavirus (HPV). However, the most common histological subtype of cervical cancer, cervical squamous cell carcinoma (CSCC), is poorly characterized regarding the association between its heterogeneity and HPV oncoprotein expression. We filtered out 138 CSCC samples with infection of HPV16 only as the first step; then we compressed HPV16 E6/E7 expression as HPVpca and correlated HPVpca with the immunological profiling of CSCC based on supervised clustering to discover subtypes and to characterize the differences between subgroups in terms of the HPVpca level, pathway activity, epigenetic dysregulation, somatic mutation frequencies, and likelihood of responding to chemo/immunotherapies. Supervised clustering of immune signatures revealed two HPV16 subtypes (namely, HPV16-IMM and HPV16-KRT) that correlated with HPVpca and clinical outcomes. HPV16-KRT is characterized by elevated expression of genes in keratinization, biological oxidation, and Wnt signaling, whereas HPV16-IMM has a strong immune response and mesenchymal features. HPV16-IMM exhibited much more epigenetic silencing and significant mutation at FBXW7, while MUC4 and PIK3CA were mutated frequently for HPV16-KRT. We also imputed that HPV16-IMM is much more sensitive to chemo/immunotherapy than is HPV16-KRT. Our characterization tightly links the expression of HPV16 E6/E7 with biological and clinical outcomes of CSCC, providing valuable molecular-level information that points to decoding heterogeneity. Together, these results shed light on stratifications of CSCC infected by HPV16 and shall help to guide personalized management and treatment of patients.


Assuntos
Carcinoma de Células Escamosas/genética , Papillomavirus Humano 16/genética , Neoplasias do Colo do Útero/genética , Adulto , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Metilação de DNA/genética , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Queratina-1/genética , Pessoa de Meia-Idade , Mucina-4/genética , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Intervalo Livre de Progressão , Proteínas Repressoras/genética , Transdução de Sinais/genética , Neoplasias do Colo do Útero/classificação , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
7.
BMC Cancer ; 19(1): 290, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935375

RESUMO

BACKGROUND: Human papillomavirus (HPV) vaccines are indicated for the prevention of cancers and genital warts caused by vaccine-covered HPV types. Although the standard regimen requires a two or three-dose vaccine series, there is emerging data suggesting that a single dose of the bivalent or quadrivalent HPV vaccine generates persistently positive antibody titers. No similar data is yet available for the nonavalent HPV vaccine, currently the only HPV vaccine available in the United States. The overall objective of our study is to assess the stability and kinetics of antibody titers for 24 months following a single dose of the nonavalent HPV vaccine among preteen girls and boys. METHODS: This is a prospective, single-arm, open-label, non-randomized, Phase IIa trial among 9-11 year-old girls and boys to determine the immunogenicity after a single dose of the nonavalent HPV vaccine (GARDASIL® 9) over 24 months, with a deferred booster dose at 24 months and an optional booster at 30 months after the first dose. Participants provide blood specimens at 6, 12, 18, 24, and 30 months after the first dose. Serologic geometric mean titers (GMT) of the nine vaccine types (HPV 16/18/ 6/11/31/33/45/52/58) will be measured at each time point. The primary objective is to determine the stability of type-specific serologic GMT of HPV16 and HPV18 between the 6- vs. 12-month, 12- vs. 18-month, and 18- vs. 24-month visits. Secondary objectives are to determine the stability of type-specific serologic GMT of the other HPV types (HPV 6/11/31/33/45/52/58) between the visits and to assess safety and reactogenicity after each vaccine dose. DISCUSSION: Single dose HPV vaccination could simplify the logistics and reduce costs of HPV vaccination in the US and across the world. This study will contribute important immunogenicity data on the stability and kinetics of type-specific antibody titers and inform feasibility of the single dose HPV vaccination paradigm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02568566 . Registered on October 6, 2015.


Assuntos
Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Anticorpos Antivirais , Criança , Feminino , Humanos , Esquemas de Imunização , Imunogenicidade da Vacina , Masculino , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento
8.
Vet J ; 244: 112-115, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30825886

RESUMO

Papillomaviruses are among the most widespread animal viruses, with many hosts harbouring multiple virus types. The present study aimed to evaluate the haematological and immunophenotypic profile of cattle infected with bovine papillomavirus (BPV). Blood samples were collected from 10 animals with clinical cutaneous BPV and without clinical papillomatosis (control). Haematological analysis demonstrated a significant reduction in haemoglobin and haematocrit for BPV-infected animals. The results also showed an increase of natural killer cells and a decrease of γδ+ T-cells and the CD4+/CD8+ ratio for the BPV group when compared to the control group. The infection was also found to stimulate a pro-inflammatory profile with the participation of CD8+T cells producing elevated IFN-γ and IL-17. These findings, although preliminary, provide a better understanding of the immune response of cattle infected with BPV.


Assuntos
Papillomavirus Bovino 1/isolamento & purificação , Doenças dos Bovinos/imunologia , Infecções por Papillomavirus/veterinária , Animais , Papillomavirus Bovino 1/patogenicidade , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Estudos de Casos e Controles , Bovinos , Doenças dos Bovinos/sangue , Doenças dos Bovinos/virologia , Feminino , Imunofenotipagem/veterinária , Células Matadoras Naturais , Masculino , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia
9.
Acta Cytol ; 63(2): 159-168, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870844

RESUMO

HPV is the most common sexually transmitted biological agent and is the cause of many conditions in men and women, including precancer lesions and cancer. Three prophylactic HPV vaccines targeting high-risk HPV types are available in many countries worldwide: 2-, 4- and 9-valent vaccines. All the 3 vaccines use recombinant DNA technology and are prepared from the purified L1 protein that self-assembles to form HPV type-specific empty shells. This non-systematic review aims to summarize the HPV epidemiology and the vaccine development to review the landmark trials of HPV vaccine, to present to most remarkable results from clinical trials and the real world, and to stress the challenges and the barriers for HPV vaccine implementation.


Assuntos
Vacinas contra Papillomavirus/imunologia , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Feminino , Humanos , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia
10.
Acta Cytol ; 63(2): 85-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921789

RESUMO

BACKGROUND: Massive strides have been made with respect to primary and secondary prevention of human papillomavirus (HPV)-associated disease as a result of prophylactic vaccination and cervical screening based on molecular HPV testing. However, cervical cancer continues to be an important clinical and societal burden. Additionally, other HPV-associated cancers, for which there are no screening programmes, are rising. Finally, the optimal combination of vaccination and screening strategies will require careful thinking. Considering this unprecedented and important time, we were keen to solicit the views of the expert community to determine what they perceived were the key priorities for HPV research. Our objective was to identify consensus and key priorities for HPV-based research through provision of a questionnaire disseminated to a multidisciplinary group of key opinion leaders (KOLs). SUMMARY: A structured survey composed of 46 HPV research "categories" was sent to 73 KOLs who were invited to "rank" the categories according to priority. The invitees represented clinical and public health disciplines as well as basic scientists. Scores were weighted according to the number of responses. Invitees also had the opportunity to comment on barriers to the research and suggest other research areas that required attention not reflected in the survey. We received 29 responses in total; overall, the 3 highest-ranked categories were "optimal cervical screening in low and middle-income countries (LMICs)," "primary disease prevention in LMICs" and "impact of vaccine on HPV infection and associated disease." "HPV and the microbiome" and "mechanisms of transformation" were the highest-ranked categories with respect to basic research. Consistent barriers to research were around governance on the use of samples and data and funding, particularly in an era of vaccination. Key Messages: Research to support the management of disease in LMICs is clearly perceived as a priority in the international community in addition to other diverse areas which necessitate an improved basic understanding of viral mechanisms and interactions. International, multidisciplinary efforts which articulate the broader HPV research agenda will be important when seeking funding in addition to international endeavours to support the efficient use of existing samples and cohorts to facilitate such research.


Assuntos
Papillomaviridae/fisiologia , Pesquisa , Humanos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus , Inquéritos e Questionários , Bancos de Tecidos
11.
BMC Infect Dis ; 19(1): 142, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755156

RESUMO

BACKGROUND: Among different types of human papillomavirus (HPV), types 16 and 18 were known to be high-risk agents causing mainly cervical cancer. Up to now, the potential of HPV E7 protein has been proved as a diagnostic marker of cervical cancer. Moreover, the levels of anti-heat shock protein (Hsp) and anti-high mobility group box-1 (HMGB1) antibodies in cancer patients have been useful in tumor diagnosis. The goal of the present study was to determine the efficiency of the potential serologic markers including HPV E7, Hsp20, Hsp27 proteins and Hp91 peptide in Iranian HPV-exposed women, for the first time. METHODS: At first, the recombinant HPV E7, Hsp20 and Hsp27 proteins were expressed in E. coli system, and purified by affinity chromatography under native conditions. Then, antibody responses were detected against the recombinant proteins as well as Hp91 peptide as potential markers in 49 Iranian women who were seropositive for HPV-16 and 18 L1 capsids (i.e., HPV-exposed women) and 49 controls using indirect ELISA. RESULTS: Our data indicated that the seroreactivities of women exposed to HPV16, HPV18 and both of them against the recombinant E7, Hsp20, Hsp27 proteins and Hp91 peptide were significantly higher than those in control group (p < 0.05 for HPV16 or HPV18; p < 0.01 for both of them versus all markers). HPV-exposed women with high antibody responses to HPV-16 and 18 L1 capsids as a commercial biomarker had significant seroreactivity to HPV-16 and 18 E7 and Hsp27 (p < 0.05). The recombinant E7 and Hsp27 proteins showed higher efficiency than Hsp20 and Hp91 for detection of individuals exposed to HPV infections (p < 0.05). CONCLUSION: Generally, the levels of serum E7 and Hsp27 were increased in HPV-16 and 18 L1- seropositive women suggesting their potential value as a diagnostic marker for HPV infections.


Assuntos
Anticorpos Antivirais/sangue , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Proteínas de Ligação a DNA/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Proteína HMGB1/imunologia , Proteínas de Choque Térmico HSP27/imunologia , Papillomavirus Humano 16/imunologia , Humanos , Irã (Geográfico) , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Proteínas Recombinantes/imunologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem
12.
Int Immunopharmacol ; 69: 279-288, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30743204

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/metabolismo , Papillomavirus Humano 16/fisiologia , Células Supressoras Mieloides/imunologia , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Peptídeos/metabolismo , Linfócitos T Reguladores/imunologia , Neoplasias do Colo do Útero/imunologia , Adjuvantes Imunológicos , Animais , Células Cultivadas , Citotoxicidade Imunológica , Feminino , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/imunologia , Vacinas contra Papillomavirus/metabolismo , Vacinação , Vacinas de Subunidades
13.
Cancer Immunol Immunother ; 68(5): 753-763, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30806747

RESUMO

The presence of IL-10, produced either by tumor cells or immunosuppressive cells, is frequently associated with a poor prognosis for cancer progression. It may also negatively impact anticancer treatments, such as immunotherapies, that otherwise would promote the activation of cytotoxic T cells capable of detecting and destroying malignant cells. In the present study, we evaluated a new adjuvant approach for anticancer immunotherapy using a plasmid vector encoding a soluble form of the IL-10 receptor (pIL-10R). pIL-10R was coadministered to mice with a DNA vaccine encoding the type 16 human papillomavirus (HPV-16) E7 oncoprotein genetically fused with glycoprotein D of herpes simplex virus (HSV) (pgDE7h). Immunization regimens based on the coadministration of pIL-10R and pgDE7h enhanced the antitumor immunity elicited in mice injected with TC-1 cells, which express HPV-16 oncoproteins. The administration of the DNA vaccines by in vivo electroporation further enhanced the anticancer effects of the vaccines, leading to the activation of tumor-infiltrating polyfunctional E7-specific cytotoxic CD8+ T cells and control of the expansion of immunosuppressive cells. In addition, the combination of immunotherapy and pIL-10R allowed the control of tumors in more advanced growth stages that otherwise would not be treatable by the pgDE7h vaccine. In conclusion, the proposed treatment involving the expression of IL-10R enhanced the antitumor protective immunity induced by pgDE7h administration and may contribute to the development of more efficient clinical interventions against HPV-induced tumors.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Células Epiteliais/fisiologia , Papillomavirus Humano 16/fisiologia , Imunoterapia/métodos , Neoplasias Experimentais/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Receptores de Interleucina-10/imunologia , Animais , Tolerância Imunológica , Interleucina-10/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus/genética , Vacinas contra Papillomavirus/genética , Receptores de Interleucina-10/genética , Vacinas de DNA , Proteínas do Envelope Viral/genética
14.
Appl Microbiol Biotechnol ; 103(7): 3049-3059, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30770966

RESUMO

High-risk papillomavirus (HPV) is one of the major reasons for cervical cancer, causing most lethal gynecologic malignancies worldwide. For cervical cancer progression, oncogene E7 plays vital roles and is used as one of the major targets for cervical tumor diagnosis and treatment. In the clinic, successful treatment of cervical cancer relies on diagnosing the disease at an early stage, where a late-stage diagnosis usually led to treatment failure. In this work, we designed and purified an HPV18 E7 oncogene targeting affibody, named as ZHPV18E7, for in vitro and in vivo imaging and targeted treatment of cervical cancer. In vitro, ZHPV18E7 showed a specific targeting effect against an HPV18 positive cell line; as a contrast, the affibody did not target the HPV18 negative cell line. In vivo, we tested the bio-distribution of the affibody in mice bearing cervical cancer. The whole animal imaging analysis indicated the affibody-targeted tumor tissue specifically with 10 min after injection, and the affibody reached the highest level at tumor tissues 45 min after injection. At the 24th hour after injection, the affibody still maintained a certain level in tumor tissues compared to other organs. To test the therapeutic effect of this affibody, we modified the affibody (i.e., ZHPV18E7) with a clinically used anti-cancer agent (i.e., Pseudomonas exotoxin). In a mice cervical cancer model, ZHPV18E7 was able to deliver Pseudomonas exotoxin to tumor tissues effectively, showing great potential for cancer treatment. This study indicated that ZHPV18E7 could be employed for in vitro imaging and targeted treatment of cervical cancer. Beyond the chemotherapeutic agent used in this work, the affibody could be extended for carrying other therapeutic agents for cervical cancer treatment.


Assuntos
Anticorpos Antivirais/farmacologia , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/terapia , Neoplasias do Colo do Útero/terapia , Imagem Corporal Total , Animais , Anticorpos Antivirais/imunologia , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/virologia
15.
Expert Rev Vaccines ; 18(3): 309-322, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30739514

RESUMO

BACKGROUND: Substantial heterogeneity has been reported in efficacy against high-grade cervical intraepithelial neoplasia (CIN) irrespective of HPV type in phase III results for bivalent and quadrivalent human papillomavirus virus (HPV) vaccines (AS04-HPV and qHPV). Real-world data recently confirmed a very high overall impact of AS04-HPV, supporting the validity of the observed heterogeneity. To explore the reasons for heterogeneous efficacy, we assessed vaccine impact on high-grade lesions not caused by vaccine types. RESEARCH METHODS: We extracted case counts of CIN lesions containing (1) at least one vaccine HPV type, (2) at least one vaccine HPV type and a high-risk non-vaccine type (co-infections) and (3) no vaccine types (non-vaccine or no high-risk HPV types). Based on these, Phase III cross-protective efficacies were estimated with exclusion (3) and with inclusion (2 and 3) of co-infections. RESULTS: Cross-protective efficacy of AS04-HPV against CIN3 lesions ranges from 81.3% (95%CI: 34.7;96.5) (excluding co-infections) to 88.5% (95%CI:62.4;97.8) (including co-infections). For qHPV the efficacy ranges from -58.7% (95%CI: -180.5;8.5) (excluding co-infections) to 13.1% (95%CI: -39.0;45.9) (including co-infections). CONCLUSIONS: Heterogenous overall efficacy against CIN3 between AS04-HPV and qHPV is driven by differential efficacy against lesions that do not contain vaccine types, which may be related to the impact of different adjuvants on the immune response.


Assuntos
Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Neoplasia Intraepitelial Cervical/prevenção & controle , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Humanos , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Adulto Jovem
16.
PLoS Comput Biol ; 15(1): e1006646, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673699

RESUMO

Infections of stratified epithelia contribute to a large group of common diseases, such as dermatological conditions and sexually transmitted diseases. To investigate how epithelial structure affects infection dynamics, we develop a general ecology-inspired model for stratified epithelia. Our model allows us to simulate infections, explore new hypotheses and estimate parameters that are difficult to measure with tissue cell cultures. We focus on two contrasting pathogens: Chlamydia trachomatis and Human papillomaviruses (HPV). Using cervicovaginal parameter estimates, we find that key infection symptoms can be explained by differential interactions with the layers, while clearance and pathogen burden appear to be bottom-up processes. Cell protective responses to infections (e.g. mucus trapping) generally lowered pathogen load but there were specific effects based on infection strategies. Our modeling approach opens new perspectives for 3D tissue culture experimental systems of infections and, more generally, for developing and testing hypotheses related to infections of stratified epithelia.


Assuntos
Epitélio/imunologia , Epitélio/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Modelos Biológicos , Técnicas de Cultura de Células , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/imunologia , Chlamydia trachomatis/patogenicidade , Epitélio/microbiologia , Epitélio/virologia , Feminino , Humanos , Papillomaviridae/imunologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vagina/citologia , Vagina/imunologia
17.
Biochim Biophys Acta Rev Cancer ; 1871(1): 126-137, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605716

RESUMO

Several DNA viruses including Human Papillomavirus (HPV), Epstein-Barr virus (EBV), and Human cytomegalovirus (HCMV) are mechanistically associated with the development of human cancers (HPV, EBV) and/or modulation of the immune system (HCMV). Moreover, a number of distinct mechanisms have been described regarding the modulation of tumor cell response to ionizing radiation and evasion from the host immune system by viral factors. There is further accumulating interest in the treatment with immune-modulatory therapies such as immune checkpoint inhibitors for malignancies with a viral etiology. Also, patients with HPV-positive tumors have a significantly improved prognosis that is attributable to increased intrinsic radiation sensitivity and may also arise from modulation of a cytotoxic T cell response in the tumor microenvironment (TME). In this review, we will highlight recent advances in the understanding of the biological basis of radiation response mediated by viral pathogenic factors and evasion from and modulation of the immune system by viruses.


Assuntos
Neoplasias/imunologia , Neoplasias/virologia , Tolerância a Radiação/fisiologia , Evasão Tumoral/imunologia , Animais , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Humanos , Imunoterapia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Radioterapia , Fatores de Virulência/metabolismo
18.
Nat Commun ; 9(1): 5360, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30560935

RESUMO

Sequence variability in surface-antigenic sites of pathogenic proteins is an important obstacle in vaccine development. Over 200 distinct genomic sequences have been identified for human papillomavirus (HPV), of which more than 18 are associated with cervical cancer. Here, based on the high structural similarity of L1 surface loops within a group of phylogenetically close HPV types, we design a triple-type chimera of HPV33/58/52 using loop swapping. The chimeric VLPs elicit neutralization titers comparable with a mix of the three wild-type VLPs both in mice and non-human primates. This engineered region of the chimeric protein recapitulates the conformational contours of the antigenic surfaces of the parental-type proteins, offering a basis for this high immunity. Our stratagem is equally successful in developing other triplet-type chimeras (HPV16/35/31, HPV56/66/53, HPV39/68/70, HPV18/45/59), paving the way for the development of an improved HPV prophylactic vaccine against all carcinogenic HPV strains. This technique may also be extrapolated to other microbes.


Assuntos
Desenho de Drogas , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Animais , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Avaliação Pré-Clínica de Medicamentos , Epitopos/genética , Epitopos/imunologia , Feminino , Engenharia Genética/métodos , Imunogenicidade da Vacina , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Testes de Neutralização , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Papillomaviridae/genética , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/genética , Filogenia , Organismos Livres de Patógenos Específicos , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia
19.
Iran J Immunol ; 15(4): 246-255, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593739

RESUMO

BACKGROUND: Infection with human papillomavirus type 16 (HPV-16) is known to cause cervical cancer, hence the several HPV therapeutic vaccines are developed in E7 oncoproteins and targeted on cell-mediated immunity. Human dendritic cells (HuDCs) are extensively employed in HPV therapeutic vaccines as the carrier or platform for inducing adaptive immune responses. However, the immunomodulators need to be further investigated for vaccine effects. Gray oyster mushroom (Pleurotus sajor-caju) containing ß-glucans is a potent immunomodulator with potential to be used in vaccines. OBJECTIVE: To study the effect of Pleurotus sajor-caju-ß-glucan Polysaccharides (PBG) on human T-lymphocytes by use of the HuDCs' antigen presentation platform for HPV16 vaccine. METHODS: The HPV16-E7 recombinant proteins were constructed in E. Coli. HuDCs pulsed with E7 peptide were cocultured with the T-lymphocytes treated with and without PBG. The number of T-lymphocytes(CD4; CD8) was detected by flowcytometry, and the viral response of T-lymphocytes was measured via IFN-γ release. RESULTS: The PBG treated group of T-lymphocytes cocultured with the HuDCs pulsed by the HPV16-E7 proteins showed significantly higher numbers of T-lymphocytes and IFN-γ release compared with T-lymphocytes without PBG in vitro. Moreover, a significant improvement in the level of specific IgG neutralizing antibodies to HPV was found in a murine model. Further observed was an increase in the expansion of helper and cytotoxic T-cells and IFN-γ releases in human system. CONCLUSION: PBG treatment of T-lymphocytes could be a useful option for prophylactic and therapeutic vaccines in cervical cancer.


Assuntos
Antígenos de Fungos/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Papillomavirus Humano 16/imunologia , Fatores Imunológicos/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Pleurotus/imunologia , Linfócitos T/imunologia , Neoplasias do Colo do Útero/imunologia , beta-Glucanas/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Apresentação do Antígeno , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Proteínas E7 de Papillomavirus/imunologia , Proteínas E7 de Papillomavirus/metabolismo , Peptídeos/imunologia , Peptídeos/metabolismo
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