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1.
Medicine (Baltimore) ; 100(41): e27457, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731120

RESUMO

ABSTRACT: Human papillomavirus (HPV) vaccination in young women is low. Women aged 21 to 65 years in the United States (U.S.) have not reached the Healthy People 2020 objective of 93% for cervical cancer screening. The main aim of this study was to investigate the association between HPV vaccination status and cervical cancer screening among privately insured women aged 21 to 26 years in the U.S.This was a retrospective cohort study using the IBM MarketScan database (2006-2016). The study population included 190,982 HPV-vaccinated women and 763,928 matched unvaccinated women. Adjusted incidence rate ratio (IRR) and the 95% confidence intervals (CIs) were obtained using the generalized estimating equations models with a Poisson distribution.Among a total of 954,910 women included in the analysis, age (mean [SD]) was 23.3 [1.6] years. During 967,317 person-years of follow-up, a total of 475,702 incidents of cervical cancer screening were identified. The incidence density rates of cervical cancer screening were 461 per 1000 person-years (PY) for unvaccinated women and 787 per 1000 PY for those who received 3 doses of the HPV vaccine. After adjusting for other covariates, the IRR of cervical cancer screening was 34% higher among HPV-vaccinated women with at least one vaccine dose than unvaccinated women (adjusted IRR = 1.34, 95% CI: 1.33-1.35; P < .0001). The IRR of cervical cancer screening varied by the dose of HPV vaccination. There was evidence of a linear dose-response relationship between the number of HPV vaccine doses and cervical cancer screening (P-trend < .0001). Compared with unvaccinated women, the IRR of cervical cancer screening were 14%, 39%, and 60% higher among those who received 1, 2, and 3 doses of the HPV vaccine, respectively.In this large retrospective cohort study of privately insured women, HPV-vaccinated women were more likely to be screened for cervical cancer compared with unvaccinated women.


Assuntos
Programas de Rastreamento/estatística & dados numéricos , Neoplasias do Colo do Útero/prevenção & controle , Cobertura Vacinal/estatística & dados numéricos , Adulto , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Seguro Saúde/estatística & dados numéricos , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
2.
Nature ; 597(7875): 279-284, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34471285

RESUMO

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.


Assuntos
Alphapapillomavirus/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Células-Tronco/citologia , Alphapapillomavirus/isolamento & purificação , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/imunologia , Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA/imunologia , Humanos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , RNA-Seq , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Células-Tronco/imunologia , Fator 1 de Transcrição de Linfócitos T/metabolismo , Linfócitos T/imunologia , Transcrição Genética
3.
Life Sci ; 285: 119945, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34516991

RESUMO

AIMS: Human papillomavirus (HPV) L1, L2 and E7 proteins were used as target antigens for development of preventive and therapeutic vaccines. Moreover, linkage of antigens to heat shock proteins (HSPs) could enhance the potency of vaccines. Curcumin and nanocurcumin compounds were suggested as the chemopreventive and chemotherapeutic agents against cancer. In this study, two multiepitope DNA and peptide-based vaccine constructs (L1-L2-E7 and HSP70-L1-L2-E7) were used along with curcumin and nanocurcumin to evaluate immune responses, and protective/therapeutic effects in tumor mouse model. MAIN METHODS: At first, the multiepitope L1-L2-E7 and HSP70-L1-L2-E7 fusion genes were subcloned in eukaryotic and prokaryotic expression vectors. The recombinant multiepitope peptides were generated in E. coli strain. Then, the cytotoxic effects of curcumin and nanocurcumin were evaluated on HEK-293 T non-cancerous and C3 cancerous cells. Finally, mice vaccination was performed using different regimens. Curcumin and nanocurcumin compounds were administered alone or along with different vaccine constructs. KEY FINDINGS: Our data indicated that the use of nanocurcumin along with the multiepitope HSP70-L1-L2-E7 vaccine construct could completely protect mice against HPV-related C3 tumor cells, and eradicate tumors in a therapeutic test. Furthermore, nanocurcumin showed higher protection than curcumin alone. Generally, curcumin and nanocurcumin compounds could reduce tumor growth synergistically with the multiepitope vaccine constructs, but they did not influence the immune responses in different regimens. SIGNIFICANCE: These data demonstrated that the designed multiepitope vaccine constructs along with curcumin and nanocurcumin can be used as a promising method for HPV vaccine development.


Assuntos
Antineoplásicos/farmacologia , Vacinas Anticâncer/imunologia , Proteínas do Capsídeo/imunologia , Curcumina/farmacologia , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/imunologia , Animais , Antineoplásicos/administração & dosagem , Vacinas Anticâncer/genética , Proteínas do Capsídeo/administração & dosagem , Proteínas do Capsídeo/genética , Clonagem Molecular , Curcumina/administração & dosagem , Citocinas/metabolismo , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Escherichia coli , Feminino , Vetores Genéticos , Células HEK293 , Proteínas de Choque Térmico HSP70/administração & dosagem , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/imunologia , Humanos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Proteínas Oncogênicas Virais/administração & dosagem , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/administração & dosagem , Proteínas E7 de Papillomavirus/genética , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Neoplasias do Colo do Útero/terapia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia
4.
J Immunol Methods ; 498: 113136, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34464605

RESUMO

Well-characterized HPV serology assays are required to evaluate performance of biosimilar candidate vaccines, reduced dosing schedules and novel administration methods. We report characterization of an expanded assay, M9ELISA, that detects antibodies to HPV virus-like particles (VLP) of nine types using direct IgG ELISA on the Meso Scale Discovery (MSD) electrochemiluminescence platform. The method is based on the previously published M4ELISA which detects antibodies to HPV6,11,16, and 18. It has been modified to add detection of antibodies to HPV31,33,45,52 and 58, and to streamline assay and reduce background. The M9ELISA plates were prepared with purified type specific L1 + L2 VLPs coated on 10-spot/well standard MSD microplates. Results of ELISA on three serial dilutions of serum were read on MSD imager, and titers calculated using the parallel line method. Evaluations included dynamic range, assay reproducibility, and stability over time. We compared M9ELISA results to those from a pseudovirion-based neutralization assay in sera from a mixed cohort of unvaccinated and vaccinated individuals (n = ~116) and to competitive Luminex immunoassay (cLIA) results in sera from a predominantly unvaccinated cohort (n = 4426). The linear range of the assay extended over 5 logs, with inter-assay reproducibility coefficient of variation ≤25% for all types. The pre-coated plates were stable for at least 2 years. Spearman correlation of antibody titers showed excellent correlation with PBNA (r = 0.86-0.97) and moderate correlation (r = 0.52-0.68) with cLIA. Thus, the M9ELISA can serve as a useful platform for high-throughput, sensitive and simultaneous quantitation of the antibody responses to nine HPV vaccine types.


Assuntos
Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática , Imunogenicidade da Vacina , Imunoglobulina G/sangue , Vacinas contra Papillomavirus/imunologia , Testes Sorológicos , Biomarcadores/sangue , Técnicas Eletroquímicas , Ensaios de Triagem em Larga Escala , Humanos , Medições Luminescentes , Vacinas contra Papillomavirus/administração & dosagem , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
5.
Sci Rep ; 11(1): 14064, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234252

RESUMO

We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were < 55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections (≥ 2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p = 0.003), MMR expression (p = 0.01), clinical stage (p = 0.048), histologic grade (p = 0.015) and mixed HPV infection (p = 0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.


Assuntos
Afro-Americanos , Papillomaviridae , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/mortalidade , Adulto , Idoso , Biomarcadores Tumorais , Coinfecção/complicações , Coinfecção/virologia , Suscetibilidade a Doenças , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , Vigilância em Saúde Pública , Recidiva , Neoplasias do Colo do Útero/epidemiologia
6.
Front Immunol ; 12: 678318, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248960

RESUMO

Cervical cancer caused by human papillomavirus (HPV) infections is the fourth most common cancer in women worldwide. Current prophylactic HPV vaccines have achieved promising success in preventing HPV infection. However, still 570,000 new cases were reported in 2018. The current primary treatment for the patient with cervical cancer is either surgery or chemoradiotherapy. Cervical cancer still lacks standard medical therapy. HPV18 induced cervical cancer has the worst prognosis and high mortality compared to other HPV infections. The development of HPV18 related with cervical malignancy requires the persistent infection of cervical-vaginal epithelium by HPV18 subtype, which can take years to transform the epithelium. This period of repeated infection provides a window for therapeutic intervention. Neutralizing antibodies formulated as topical agents that inhibit HPV18 infection should reduce the chance of cervical malignancy. We previously demonstrated that potent neutralizing anti-sera against HPV18 infection were induced by HPV18 viral like particle (VLP) generated in mammalian cells. We, therefore, isolated two potent neutralizing antibodies, 2A12 and 8H4, from over 3,810 hybridomas prepared from mice immunized with HPV18 VLP. 2A12 and 8H4 exhibited excellent potency, with 50% virus-inhibitory concentrations (IC50) of 0.4 and 0.9 ng/ml, respectively. Furthermore, 2A12 and 8H4 recognized distinct and non-overlapping quaternary epitopes and bound specifically with HPV18. Humanized 2A12 (Hu2A12) retained comparable neutralizing activity against HPV18 infection in various acidic pH settings and in hydrogel formulation with IC50 values of 0.04 to 0.77 ng/ml, indicating that Hu2A12 will be a promising candidate for clinical development as a topical vaginal biopharmaceutical agent against HPV18 infection.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Papillomavirus Humano 18 , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/etiologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Feminino , Papillomavirus Humano 18/fisiologia , Humanos , Imunização , Camundongos , Terapia de Alvo Molecular , Testes de Neutralização , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Taiwan J Obstet Gynecol ; 60(4): 700-705, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247810

RESUMO

OBJECTIVE: To generate immunity against human papillomavirus (HPV), the use of a recombinant DNA vaccine to carry an appropriate target gene is a promising and cost-effective approach. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent immunomodulatory cytokine that enhances the efficacy of vaccines by promoting the development and prolongation of humoral and cellular immunity. In this study, we linked codon-optimized GM-CSF (cGM-CSF) to the HPV16 E7 sequence as fused protein and evaluated the immunogenic potential of this DNA vaccine. MATERIALS AND METHODS: We have demonstrated that cGM-CSF enhanced immunity against tumor challenges by generating and promoting the proliferation of HPV16 E7-specific CD8+ T cells, which secrete IFN-γ in the murine model. In this study, we aimed to evaluate the immunogenic potential of DNA vaccine that constructed by linking codon-optimized GM-CSF to HPV16 E7 sequence in the animal model. We study the half-life of RNA decay and cellular location of HPV16 E7 by Q-PCR and Western blot. We also assess immune response in the animal model by flow cytometry and ELISA. RESULTS: The cGM-CSF-E7 sequence increased and extended the expression of E7 mRNA, in comparison with the E7 sequence alone. Mice vaccinated with the cGM-CSF-E7 DNA vaccine exhibited a slower rate of tumor growth than those vaccinated with the unconjugated E7 DNA vaccine. We also found that the CD4 and CD8+ T cells from these mice showed strong secretion of IFN-γ. CONCLUSION: Through in vivo antibody depletion experiments, we demonstrated that both CD4+ and CD8+ T cells play an important role in the suppression of tumor growth.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Papillomavirus Humano 16/imunologia , Imunidade Celular/genética , Vacinas contra Papillomavirus/imunologia , Vacinas de DNA/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/imunologia , Códon , Modelos Animais de Doenças , Feminino , Papillomavirus Humano 16/genética , Humanos , Camundongos , Vacinas contra Papillomavirus/genética , Vacinas de DNA/virologia
8.
BMC Infect Dis ; 21(1): 582, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134644

RESUMO

BACKGROUND: Refugees are frequently not immune to vaccine-preventable infections. Adherence to consensus guidelines on vaccination and infectious diseases screening among refugees resettling in the U.S. is unknown. We sought to determine rates of vaccine completion and infectious diseases screening in refugees following resettlement. METHODS: We conducted a retrospective cohort study of refugees resettling in a region in the U.S. using medical data from June 2013-April 2015. We determined the proportion of vaccine-eligible refugees vaccinated with measles-mumps-rubella (MMR), hepatitis A/B, tetanus, diphtheria, and acellular pertussis (Tdap), and human papillomavirus (HPV) following resettlement. We also determined the proportion of refugees who completed HIV and hepatitis C (HCV) screening. RESULTS: One hundred and eleven subjects were included, primarily from Iraq (53%), Afghanistan (19%), and Eritrea (11%). Of the 84 subjects who were vaccine-eligible, 78 (93%) initiated and 42 (50%) completed vaccinations within one year of resettlement. Odds of completing vaccination were higher for men (OR: 2.38; 95%CI:1.02-5.71) and for subjects with English proficiency (OR: 3.70; 95%CI:1.04-17.49). Of the 78 subjects (70%) completing HIV screening, two (3%) were diagnosed with HIV. Nearly all subjects completed screening for HCV, and one had active infection. CONCLUSION: While most refugees initiate vaccinations, only 50% completed vaccinations and 70% completed HIV screening within 1 year of resettlement. There is a need to emphasize vaccine completion and HIV screening in refugee patients following resettlement.


Assuntos
Doenças Transmissíveis/diagnóstico , Refugiados/estatística & dados numéricos , Vacinação/estatística & dados numéricos , Adulto , Idoso , Estudos de Coortes , Doenças Transmissíveis/imunologia , Feminino , Infecções por HIV/diagnóstico , Vacinas contra Hepatite B/imunologia , Humanos , Masculino , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Pessoa de Meia-Idade , Razão de Chances , Vacinas contra Papillomavirus/imunologia , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
9.
Dokl Biochem Biophys ; 498(1): 193-198, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34189649

RESUMO

The anogenital type HPV6 L1 major capsid protein was synthesized in a plant expression system on the basis of tomato fruits. The content of HPV6 L1 reached 380 µg per 1 mg of total soluble protein of raw fruit mass, which was represented as a single band with a molecular mass of 56 kDa on the SDS electrophoregram. When orally administrated to mice, the vaccine material from the tomato fruit transgenic for HPV6 L1 induced highly effective antibody immune response with a high titer. The cross-reactivity during the interaction of the antibody to the HPV6 L1 protein from peripheral blood serum of mice vaccinated with HPV6 L1 with the antigenic proteins HPV16 L1, HPV18 L1, HPV31 L1, and HPV45 L1 was found. This is promising for creating a vaccine with a broad reactivity against dangerous anogenital papillomatoses and cervical cancer.


Assuntos
Anticorpos Antivirais/imunologia , Proteínas do Capsídeo/imunologia , Lycopersicon esculentum/metabolismo , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Animais , Reações Cruzadas , Feminino , Frutas/genética , Frutas/metabolismo , Lycopersicon esculentum/genética , Camundongos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia
11.
Lancet Infect Dis ; 21(10): 1458-1468, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34081923

RESUMO

BACKGROUND: Quadrivalent and bivalent vaccines against oncogenic human papillomavirus (HPV) are used worldwide with different reported overall efficacies against HPV infections. Although protective concentrations of vaccine-induced antibodies are still not formally defined, we evaluated the sustainability of neutralising antibodies in vaccine trial participants 2-12 years after vaccination and the correlation with reported vaccine efficacy. METHODS: We did a follow-up analysis of data from the Finnish cohorts of two international, randomised, double-blind, phase 3 trials of HPV vaccines, PATRICIA (bivalent, HPV16 and 18) and FUTURE II (quadrivalent, HPV6, 11, 16, and 18). In 2002 and 2004-05, respectively, Finnish girls aged 16-17 years participated in one of these two trials and consented to health registry follow-up with the Finnish Cancer Registry. The cohorts were also linked with the Finnish Maternity Cohort (FMC) that collects first-trimester serum samples from nearly all pregnant Finnish women, resulting in 2046 post-vaccination serum samples obtained during up to 12 years of follow-up. We obtained serum samples from the FMC-based follow-up of the FUTURE II trial (from the quadrivalent vaccine recipients) and the PATRICIA trial (from corresponding bivalent vaccine recipients who were aligned by follow-up time, and matched by the number of pregnancies). We assessed neutralising antibody concentrations (type-specific seroprevalence) to HPV6, 16, and 18, and cross-neutralising antibody responses to non-vaccine HPV types 31, 33, 45, 52, and 58 from 2 to 12 years after vaccination. FINDINGS: Up to Dec 31, 2016, we obtained and analysed 577 serum samples from the quadrivalent vaccine recipients and 568 from the bivalent vaccine recipients. In 681 first-pregnancy serum samples, neutralising antibodies to HPV6, 16, and 18 were generally found up to 12 years after vaccination. However, 51 (15%) of 339 quadrivalent vaccine recipients had no detectable HPV18 neutralising antibodies 2-12 years after vaccination, whereas all 342 corresponding bivalent vaccine recipients had HPV18 neutralising antibodies.. In seropositive quadrivalent vaccine recipients, HPV16 geometric mean titres (GMT) halved by years 5-7 (GMT 3679, 95% CI 2377 to 4708) compared with years 2-4 (6642, 2371 to 13 717). Between 5 and 12 years after vaccination, GMT of neutralising antibodies to HPV16 and 18 were 5·7 times and 12·4 times higher, respectively, in seropositive bivalent vaccine recipients than in the quadrivalent vaccine recipients. Cross-neutralising antibodies to HPV31, 33, 45, 52, and 58 were more prevalent in the bivalent vaccine recipients but, when measurable, sustainable up to 12 years after vaccination with similar GMTs in both vaccine cohorts. Seroprevalence for HPV16, 31, 33, 52, and 58 significantly correlated with vaccine efficacy against persistent HPV infections in the bivalent vaccine recipients only (rs=0·90, 95% CI 0·09 to 0·99, p=0·037, compared with rs=0·62, 95% CI -0·58 to 0·97, p=0·27 for the quadrivalent vaccine recipients). Correlation of protection with prevalence of neutralising or cross-neutralising HPV antibodies was not significant in the quadrivalent vaccine recipients. INTERPRETATION: The observed significant differences in the immunogenicity of the two vaccines are in line with the differences in their cross-protective efficacy. Protective HPV vaccine-induced antibody titres can be detected up to 12 years after vaccination. FUNDING: Academy of Finland and Finnish Cancer Foundation.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções por Papillomavirus/sangue , Vacinas contra Papillomavirus/imunologia , Adolescente , Alphapapillomavirus/genética , Alphapapillomavirus/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Estudos de Coortes , Reações Cruzadas , Método Duplo-Cego , Feminino , Finlândia , Seguimentos , Humanos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologia
12.
Viruses ; 13(5)2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068358

RESUMO

Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for the global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission-dynamic model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV infections are persistent in the MSM population, with sustained circulation of the virus among unvaccinated individuals. Coverage around 75% of both sexes would be necessary to eliminate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between a vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70-75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV elimination may be achieved if men's coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.


Assuntos
Vírus Oncogênicos/imunologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Infecções Tumorais por Vírus/prevenção & controle , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Programas de Imunização , Masculino , Redes Neurais de Computação , Papillomaviridae/classificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/transmissão , Vacinas contra Papillomavirus/imunologia , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/transmissão , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinação , Cobertura Vacinal
13.
Sci Rep ; 11(1): 13404, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183739

RESUMO

Cervical cancer continues to impose a heavy burden worldwide, and human papilloma virus (HPV) infection, especially persistent infection with type 16 (HPV-16), is known to be the primary etiological factor. Therapeutic vaccines are urgently needed because prophylactic vaccines are ineffective at clearing pre-existing HPV infection. Here, two recombinant Listeria strains (LMΔ-E6E7 & LIΔ-E6E7) with deletions of the actA and plcB genes, expressing the shuffled HPV-16 E6E7 protein were constructed. The strains were delivered into the spleen and liver by intravenous inoculation, induced antigen-specific cellular immunity and were eliminated completely from the internal organs several days later. Intravenously treating with single strain for three times, or with both strains alternately for three times significantly reduced the tumor size and prolonged the survival time of model mice. Combination immunotherapy with two strains seemed more effective than immunotherapy with single strain in that it enhanced the survival of the mice, and the LMΔ-E6E7-prime-LIΔ-E6E7-boost strategy showed significant stronger efficacy than single treatment with the LIΔ-E6E7 strain. The antitumor effect of this treatment might due to its ability to increase the proportion of CD8+ T cells and reduce the proportion of T regulatory cells (Tregs) in the intratumoral milieu. This is the first report regarding Listeria ivanovii-based therapeutic vaccine candidate against cervical cancer. Most importantly we are the first to confirm that combination therapy with two different recombinant Listeria strains has a more satisfactory antitumor effect than administration of a single strain. Thus, we propose a novel prime-boost treatment strategy.


Assuntos
Papillomavirus Humano 16/imunologia , Listeria/imunologia , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Proteínas Repressoras/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Vacinas Anticâncer/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Celular/imunologia , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/virologia , Vacinação/métodos
14.
Sci Rep ; 11(1): 12397, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117331

RESUMO

Cervical cancer, caused by human papillomavirus (HPV), is the fourth most common type of cancer among women worldwide. While HPV prophylactic vaccines are available, they have no therapeutic effects and do not clear up existing infections. This study aims to design a therapeutic vaccine against cervical cancer using reverse vaccinology. In this study, the E6 and E7 oncoproteins from HPV16 were chosen as the target antigens for epitope prediction. Cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) epitopes were predicted, and the best epitopes were selected based on antigenicity, allergenicity, and toxicity. The final vaccine construct was composed of the selected epitopes, along with the appropriate adjuvant and linkers. The multi-epitope vaccine was evaluated in terms of physicochemical properties, antigenicity, and allergenicity. The tertiary structure of the vaccine construct was predicted. Furthermore, several analyses were also carried out, including molecular docking, molecular dynamics (MD) simulation, and in silico cloning of the vaccine construct. The results showed that the final proposed vaccine could be considered an effective therapeutic vaccine for HPV; however, in vitro and in vivo experiments are required to validate the efficacy of this vaccine candidate.


Assuntos
Vacinas Anticâncer/imunologia , Epitopos/imunologia , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinas Anticâncer/química , Biologia Computacional , Epitopos/química , Feminino , Humanos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/química , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/química , Proteínas Repressoras/química , Proteínas Repressoras/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia
16.
J Med Virol ; 93(8): 5188-5192, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33851736

RESUMO

The prevalence of human papillomavirus (HPV) types varies geographically between various countries and different parts of the same country. The efficacy of the HPV vaccines is dependent on the prevalent HPV types. Here, we have studied the prevalence of high-risk HPV (hrHPV) and its genotypes in women in our population. Cervical samples of 2443 women were screened for the presence of hrHPV using the careHPV system. To determine the HPV genotypes, viral DNA was isolated from the hrHPV-positive samples, nested PCR was used to amplify the L1 hypervariable region, and was subjected to Sanger sequencing. The prevalence of hrHPV was found to be 2%. HPV16 (52%), HPV33 (40%), HPV18 (4%), HPV31 (2%), and HPV66 (2%) genotypes were found in this study. In Kerala, HPV16 and HPV33 genotypes were found to be significantly higher compared with the other HPV types detected. As the bivalent (Cervarix) and quadrivalent (Gardasil-4) vaccines offer limited cross-protection against HPV33, nonavalent (Gardasil 9) vaccine would be more effective in preventing cervical carcinoma in Kerala.


Assuntos
Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , Adulto , Idoso , DNA Viral/genética , Feminino , Genótipo , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Papillomaviridae/classificação , Papillomaviridae/imunologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/genética , Filogenia , Prevalência , População Rural
19.
J Pediatr ; 234: 149-157.e3, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33689710

RESUMO

OBJECTIVES: To evaluate among pediatricians and family physicians human papillomavirus (HPV) vaccination recommendation practices for 11- to 12-year-old youth; report parental refusal/deferral of HPV vaccination; and report barriers to HPV vaccination changed over time. STUDY DESIGN: We surveyed nationally representative networks of pediatricians and family physicians in 2008, 2010, 2013-2014, and 2018. Male vaccination questions were not asked in 2008; barriers and parental vaccine refusal questions were not asked in 2010. RESULTS: Response rates were 80% in 2008 (680/848), 72% in 2010 (609/842), 70% in 2013-2014 (582/829), and 65% in 2018 (588/908). The proportion of physicians strongly recommending HPV vaccination for 11- to 12-year-old patients increased from 53% in 2008 to 79% in 2018 for female patients and from 48% in 2014 to 76% in 2018 for male patients (both P < .0001). The proportion of physicians indicating ≥50% of parents refused/deferred HPV vaccination remained steady for female patients (24% in 2008 vs 22% in 2018, P = .40) and decreased for male patients (42% in 2014 vs 28% in 2018, P < .001). Physician barriers to providing HPV vaccination were rare and decreased over time. Increasing numbers of physicians reported perceived parental barriers of vaccine safety concerns (5% "major barrier" in 2008 vs 35% in 2018, P < .0001) and moral/religious concerns (5% in 2008 vs 25% in 2018, P < .0001). CONCLUSIONS: Between 2008 and 2018, more primary care physicians reported recommending HPV vaccination for adolescents, fewer reported barriers, and more physicians reported parents who had vaccine safety or moral/religious concerns.


Assuntos
Atitude do Pessoal de Saúde , Pediatria/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Recusa de Vacinação/psicologia , Vacinação/psicologia , Adolescente , Criança , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estudos Longitudinais , Masculino , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Pais/psicologia , Inquéritos e Questionários , Vacinação/estatística & dados numéricos , Recusa de Vacinação/estatística & dados numéricos
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