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1.
Medicine (Baltimore) ; 100(7): e24855, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607859

RESUMO

BACKGROUND: To analyze the prevalence of latent infection of pathogens of hand, foot, and mouth disease (HFMD) in Chinese healthy population and its influencing factors, so as to provide reference for the prevention and control of HFMD. METHODS: A systematic literature searching about the incidence of latent infection of HFMD was conducted in Chinese and English databases. The inclusion and exclusion criteria of the retrieved literature were established. The qualified literatures were screened and the data were extracted. The pooled rate and its 95% confidence interval was used to assess the latent infection rate of HFMD pathogens in healthy Chinese population, and subgroup analysis was conducted based on gender and age. All statistical analyses were performed using the STATA version 12.0 software. RESULTS: A total of 31 literatures were included in this meta-analysis. The recessive infection rate of HFMD pathogens reported in the literature of Chinese healthy people ranged from 4.59% to 44.12%. The results of meta-analysis showed that the latent infection rate of human enteroviruses (HEVs) in healthy Chinese population was 17.5% (14.9-20.1%), among which, the latent infection rates of EV-A71, CV-A16, and other HEVs were 3.3% (2.2-4.4%), 1.7% (1.0-2.5%), and 15.1% (11.1-17.1%), respectively. The latent infection rates of HEVs in healthy men and women in China were 16.7% (12.9-20.4%) and 14.4% (10.8-18.0%), respectively. The latent infection rates of HEVs in the healthy population aged 0 to 5 years and over 5 years were 24.4% (20.4-28.5%) and 9.4% (6.5-12.2%), respectively. Meta regression showed that the factors affecting the latent infection rate of HEVs in Chinese healthy population included sampling period, sampling area, and study population. CONCLUSION: The latent infection rate of HEVs is high in healthy people in China, but it is mainly caused by other enteroviruses. The latent infection rate of HEVs in male was higher than that of female and was greater in people aged 0 to 5 than that of aged over 5 years. Limited by the quantity and quality of the included studies, more high-quality studies are needed for further verification in the future.


Assuntos
Infecções Assintomáticas/epidemiologia , Doença de Mão, Pé e Boca/epidemiologia , Voluntários Saudáveis/estatística & dados numéricos , /epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Estudos Transversais , Gerenciamento de Dados , Enterovirus/genética , Enterovirus/isolamento & purificação , Enterovirus/patogenicidade , Enterovirus Humano A/genética , Enterovirus Humano A/isolamento & purificação , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Prevalência , Adulto Jovem
2.
J Virol ; 95(6)2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33408178

RESUMO

Coxsackievirus A5 (CV-A5) has recently emerged as a main hand, foot, and mouth disease (HFMD) pathogen. Following a large-scale vaccination campaign against enterovirus 71 (EV-71) in China, the number of HFMD-associated cases with EV-71 was reduced, especially severe and fatal cases. However, the total number of HFMD cases remains high, as HFMD is also caused by other enterovirus serotypes. A multivalent HFMD vaccine containing 4 or 6 antigens of enterovirus serotypes is urgently needed. A formaldehyde-inactivated CV-A5 vaccine derived from Vero cells was used to inoculate newborn Kunming mice on days 3 and 10. The mice were challenged on day 14 with a mouse-adapted CV-A5 strain at a dose that was lethal for 14-day-old suckling mice. Within 14 days postchallenge, groups of mice immunized with three formulations, empty particles (EPs), full particles (FPs), and a mixture of the EP and FP vaccine candidates, all survived, while 100% of the mock-immunized mice died. Neutralizing antibodies (NtAbs) were detected in the sera of immunized mice, and the NtAb levels were correlated with the survival rate of the challenged mice. The virus loads in organs were reduced, and pathological changes and viral protein expression were weak or not observed in the immunized mice compared with those in alum-inoculated control mice. Another interesting finding was the identification of CV-A5 dense particles (DPs), facilitating morphogenesis study. These results demonstrated that the Vero cell-adapted CV-A5 strain is a promising vaccine candidate and could be used as a multivalent HFMD vaccine component in the future.IMPORTANCE The vaccine candidate strain CV-A5 was produced with a high infectivity titer and a high viral particle yield. Three particle forms, empty particles (EPs), full particles (FPs), and dense particles (DPs), were obtained and characterized after purification. The immunogenicities of EP, FP, and the EP and FP mixture were evaluated in mice. Mouse-adapted CV-A5 was generated as a challenge strain to infect 14-day-old mice. An active immunization challenge mouse model was established to evaluate the efficacy of the inactivated vaccine candidate. This animal model mimics vaccination, similar to immune responses of the vaccinated. The animal model also tests protective efficacy in response to the vaccine against the disease. This work is important for the preparation of multivalent vaccines against HFMD caused by different emerging strains.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Vacinação/métodos , Vacinas Virais/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Modelos Animais de Doenças , Doença de Mão, Pé e Boca/virologia , Camundongos , Sorogrupo , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Células Vero , Carga Viral , Vacinas Virais/imunologia , Vírion/imunologia
3.
J Infect ; 82(3): 407-413, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33373653

RESUMO

BACKGROUND: EV-A71 is a common causative agent of hand foot and mouth disease. In mainland China, EV-A71 subgenotype C4 has been the sole circulating genotype since 2008, and was used in the production of multiple licensed vaccines. Here, we report the first detection EV-A71 C1 strains in China. METHODS: Full genomic sequence were obtained. The origin of the EV-A71 C1 strains were tracked down by Bayesian inferences. Recombination was analyzed using Simplot program. And the antigenicity were tested using the microneutralization test. RESULTS: The C1-GD2019 shared high identity with the C1-like lineage recently identified in Europe and was introduced into Guangdong in 2018-2019. Close genetic relatedness between the C1-GD2019 and Europe C1-like strains were observed except for the 3D-3'UTR region. The late showed high similarity with CVA genomes. Antigenic variance was found. The C1-GD2019 could not be effectively neutralized by EV-A71 C4a neutralizing antibody positive samples. CONCLUSION: This is the first report of EV-A71 subgenotype C1 isolated in China. It is a recombinant strain originating from C1-like strains recently identified in Europe and CVA strains. The different antigenicity between the C1 strains and C4a vaccine strains highlighted the importance on closely monitoring the EV-A71 C1 strains in China.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Vacinas , Teorema de Bayes , China/epidemiologia , Enterovirus Humano A/genética , Infecções por Enterovirus/epidemiologia , Europa (Continente) , Genótipo , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Filogenia
4.
Vaccine ; 39(3): 596-604, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33342637

RESUMO

Human hand, foot, and mouth disease (HFMD), an important infectious disease in children, is caused mainly by enterovirus 71 (EV71) and coxsackievirus A16 (CA16). In this study, a bivalent inactivated EV71/CA16 vaccine is developed and evaluated in immunized BALB/c mice injected through the intradermal route. Q-RT-PCR detection of the mRNA of immune signal molecules in local epithelial tissues inoculated with the vaccine indicates activation of innate immunity, which includes upregulation of immune-related chemokines, interferons and CD molecules. Further, the finding that neutralizing antibodies and specific T cellular responses were elicited in adult mice after two immunizations with the vaccine at a 28-day interval, which endowed offspring mice to defend a viral challenge, suggests the successful induction of specific protective antiviral immunity. All these data suggest that immunization with this bivalent EV71/CA16 vaccine via the intradermal route elicits effective immunity against EV71 and CA16 infection.


Assuntos
Enterovirus Humano A , Enterovirus , Doença de Mão, Pé e Boca , Vacinas Virais , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Doença de Mão, Pé e Boca/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Combinadas , Vacinas de Produtos Inativados
5.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(9): 1518-1521, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-33076610

RESUMO

Objective: To analyze the effectiveness and immunogenicity of enterovirus-A71(EV-A71) vaccine in immunization program. Methods: A cohort study was conducted in immunization clinics in Jing'an district in Shanghai from October to December 2017. Children who received EV-A71 vaccine based on a 2-dose schedule (on day 0 and day 30) were enrolled as vaccine group and those who received no EV-A71 vaccine were enrolled as control group. After 1-year follow-up, the effectiveness and neutralizing antibody level and the positive results of antibody immunogenicity in vaccine group were analyzed. Results: A total of 3 018 children aged 8-20 months were enrolled, in whom 1 211 were in vaccine group and 1 807 were in control group. The vaccine effectiveness was 100% against EV-A71-associated hand, foot, and mouth disease (HFMD) indicated by 1 year follow-up (95%CI: -66.99%-100.00%). The geometric mean titer of neutralizing antibody (GMT) was 41.76 (95%CI: 35.60-49.34) at day 60 and 28.44(95%CI: 23.59-34.54) at day 365 in 124 children in vaccine group. Conclusions: In children, EV-A71 vaccine elicited EV-A71-specific immune response. Less EV-A71-associated HFMD cases have been observed, further observation is needed.


Assuntos
Enterovirus , Doença de Mão, Pé e Boca , Vacinas Virais , China , Estudos de Coortes , Enterovirus/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Imunogenicidade da Vacina , Lactente , Vigilância de Produtos Comercializados , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia
6.
Sci Rep ; 10(1): 6117, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273569

RESUMO

Hand, foot, and mouth disease (HFMD) remains a threat to the Asia-Pacific region. The epidemiological characteristics and pathogen spectrum of HFMD vary with space and time. These variations are crucial for HFMD interventions but poorly understood in Sichuan Province, China, particularly after the introduction of the EV-A71 vaccine. Using descriptive methods, regression analyses, spatial autocorrelation analysis, and space-time scan statistics, we analysed the epidemiological and aetiological characteristics of HFMD surveillance data in Sichuan Province between 2011 and 2017 to identify spatio-temporal variations. The dominant serotypes of HFMD have changed from enterovirus 71 and coxsackievirus A16 to other enteroviruses since 2013. The seasonal pattern of HFMD showed two peaks generally occurring from April to July and November to December; however, the seasonal pattern varied by prefecture and enterovirus serotype. From 2011 to 2017, spatio-temporal clusters were increasingly concentrated in Chengdu, with several small clusters in northeast Sichuan. The clusters observed in southern Sichuan from 2011 to 2015 disappeared in 2016-2017. These findings highlight the importance of pathogen surveillance and vaccination strategies for HFMD interventions; future prevention and control of HFMD should focus on Chengdu and its vicinity.


Assuntos
Enterovirus/genética , Doença de Mão, Pé e Boca/epidemiologia , Adolescente , Criança , Pré-Escolar , China , Enterovirus/classificação , Enterovirus/patogenicidade , Feminino , Doença de Mão, Pé e Boca/prevenção & controle , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Masculino , Análise Espaço-Temporal , Vacinação/estatística & dados numéricos
7.
Am J Trop Med Hyg ; 102(6): 1253-1262, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32157992

RESUMO

Hand, foot, and mouth disease (HFMD) is a common infectious disease in the Asia-Pacific region that primarily affects children younger than 5 years. Previous studies have confirmed that the seasonal transmission of this disease is strongly related to meteorological factors, but the results are not consistent. In addition, the associations between weather conditions and HFMD in northwestern China have not been investigated. Therefore, we aimed to examine this issue in Xi'an, the largest city of northwestern China that has been suffering from serious HFMD epidemics. In the current study, data for HFMD and six meteorological factors were collected from 2009 to 2018. Using cross-correlation analysis, the Granger causality test, and the distributed lag nonlinear model, we estimated the quantitative relationships and exposure-lag-response effects between weekly meteorological factors and HFMD incidence among children. We found that the seasonal distribution of HFMD in Xi'an has two peaks each year and is significantly impacted by the weekly temperature, precipitation, and evaporation over an 8-week period. Higher values of temperature and evaporation had positive associations with disease transmission, whereas the association between precipitation and HFMD showed an inverted-U shape. The maximum relative risks (RRs) of HFMD for the weekly mean temperature (approximately 31.1°C), weekly cumulative evaporation (57.9 mm), and weekly cumulative precipitation (30.0 mm) were 1.56 (95% CI: 1.35-1.81), 1.40 (95% CI: 1.05-1.88), and 1.16 (95% CI: 1.11-1.70), respectively. The identified risk determinants and lag effects could provide important information for early interventions to reduce the local disease burden.


Assuntos
Doença de Mão, Pé e Boca/epidemiologia , Estações do Ano , Tempo (Meteorologia) , Criança , Pré-Escolar , China/epidemiologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Umidade , Incidência , Lactente , Fotoperíodo , Fatores de Risco , Temperatura , Vacinas Virais/imunologia
8.
Cell Host Microbe ; 27(2): 249-261.e5, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32027857

RESUMO

Hand, foot, and mouth disease is a common childhood illness primarily caused by coxsackievirus A16 (CVA16), for which there are no current vaccines or treatments. We identify three CVA16-specific neutralizing monoclonal antibodies (nAbs) with therapeutic potential: 18A7, 14B10, and NA9D7. We present atomic structures of these nAbs bound to all three viral particle forms-the mature virion, A-particle, and empty particle-and show that each Fab can simultaneously occupy the mature virion. Additionally, 14B10 or NA9D7 provide 100% protection against lethal CVA16 infection in a neonatal mouse model. 18A7 binds to a non-conserved epitope present in all three particles, whereas 14B10 and NA9D7 recognize broad protective epitopes but only bind the mature virion. NA9D7 targets an immunodominant site, which may overlap the receptor-binding site. These findings indicate that CVA16 vaccines should be based on mature virions and that these antibodies could be used to discriminate optimal virion-based immunogens.


Assuntos
Anticorpos Neutralizantes , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/virologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/ultraestrutura , Proteínas do Capsídeo/imunologia , Linhagem Celular , Microscopia Crioeletrônica , Enterovirus/imunologia , Enterovirus/ultraestrutura , Enterovirus Humano A/ultraestrutura , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Camundongos , Vacinas Virais/imunologia , Vírion/imunologia
9.
J Virol ; 94(6)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31896594

RESUMO

Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed lifelong susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful for in vivo EV71 vaccine efficacy testing.IMPORTANCE The development of new vaccines for EV71 relies on the availability of small animal models suitable for in vivo efficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Glicoproteínas de Membrana Associadas ao Lisossomo/imunologia , Receptores Depuradores/imunologia , Vacinas Virais/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Avaliação de Medicamentos , Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidade , Doença de Mão, Pé e Boca/genética , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/patologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Camundongos , Camundongos Transgênicos , Receptores Depuradores/genética , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/farmacologia , Vacinas Virais/genética , Vacinas Virais/imunologia
10.
Clin Microbiol Infect ; 26(3): 373-380, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31279839

RESUMO

OBJECTIVES: Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) were responsible for 43.3% (235 123/543 243) and 24.8% (134 607/543 243) of all laboratory-confirmed hand, foot and mouth disease (HFMD) cases during 2010-2015 in China. Three monovalent EV71 vaccines have been licensed in China while bivalent EV71/CA16 vaccines are under development. A comparative cost-effectiveness analysis of bivalent EV71/CA16 versus monovalent EV71 vaccination would be useful for informing the additional value of bivalent HFMD vaccines in China. METHODS: We used a static model parameterized with the national HFMD surveillance data during 2010-2013, virological HFMD surveillance records from all 31 provinces in mainland China during 2010-2013 and caregiver survey data of costs and health quality of life during 2012-2013. We estimated the threshold vaccine cost (TVC), defined as the maximum additional cost that could be paid for a cost-effective bivalent EV71/CA16 vaccine over a monovalent EV71 vaccine, as the outcome. The base case analysis was performed from a societal perspective. Several sensitivity analyses were conducted by varying assumptions governing HFMD risk, costs, discounting and vaccine efficacy. RESULTS: In the base case, choosing the bivalent EV71/CA16 over monovalent EV71 vaccination would be cost-effective only if the additional cost of the bivalent EV71/CA16 compared with the monovalent EV71 vaccine is less than €4.7 (95% CI 4.2-5.2). Compared with the TVC in the base case, TVC increased by up to €8.9 if all the test-negative cases were CA16-HFMD; decreased by €1.1 with an annual discount rate of 6% and exclusion of the productivity loss; and increased by €0.14 and €0.3 with every 1% increase in bivalent vaccine efficacy against CA16-HFMD and differential vaccine efficacy against EV71-HFMD, respectively. CONCLUSIONS: Bivalent EV71/CA16 vaccines can be cost-effective compared with monovalent EV71 vaccines, if suitably priced. Our study provides further evidence for determining the optimal use of HFMD vaccines in routine paediatric vaccination programme in China.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Vacinas Virais/imunologia , Algoritmos , Pré-Escolar , China/epidemiologia , Análise Custo-Benefício , Enterovirus Humano A/classificação , Enterovirus Humano A/genética , Humanos , Lactente , Modelos Teóricos , Avaliação de Resultados em Cuidados de Saúde , Vacinação
11.
PLoS One ; 14(11): e0225569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31774839

RESUMO

BACKGROUND: Enterovirus 71 (EV71) vaccine, which was put into market in China in 2016, has been viewed as a promising prevention measure against severe and fatal hand, foot and mouth disease (HFMD). This study aimed to investigate the knowledge of HFMD and acceptability of EV71 vaccine among parents of under-five in Chongqing, China. METHODOLOGY /PRINCIPAL FINDINGS: A cross-sectional survey was conducted in 2017. A validated questionnaire consisting of three sections including demographic information, knowledge of HFMD, acceptability and reasons for declining vaccination was developed based on literature review. Factors associated with unwillingness to receive EV71 vaccine were explored using multivariate logistic regression. A total of 992 parents finished the questionnaire with a response rate of 91.9%. Awareness of HFMD and EV71 vaccine were reported by 823 (83.0%) parents and 386 (38.9%) parents respectively. Knowledge about HFMD was with a mean score of 5.0 (standard deviation = 3.5) out of a total score of 12. Only 369 (37.2%) participants were classified as with good knowledge level about HFMD. 279 (28.1%) participants had their children received EV71 vaccine and 271 (27.3%) expressed willingness to vaccinate their children after a short-time education about EV71 vaccine. Acceptability of EV71 vaccine increased along with parents' education level (p = 0.008) and HFMD knowledge level (p<0.001). Parents of scattered children had higher acceptability than those of preschool children (p = 0.002). 442 (44.6%) of participants were unwilling to have their children vaccinated with EV71 vaccine. The most common reasons for declining EV71 vaccine were doubts about its safety (56.6%) and efficacy (48.3%), and the necessity of vaccination (38.3%). Physicians and vaccination certificate were the parents' most trusted sources of vaccine information. CONCLUSIONS: Parents' knowledge about HFMD was not sufficient, and nearly half of the parents expressed unwillingness to vaccinate their children with EV71 vaccine. Our findings stress that more efforts by health authorities in Chongqing are needed to increase the acceptability of EV71 vaccine, especially among parents of preschool children with lower education level.


Assuntos
Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Doença de Mão, Pé e Boca/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Vacinação/psicologia , Vacinas Virais/uso terapêutico , Adulto , Pré-Escolar , China/epidemiologia , Estudos Transversais , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/complicações , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Masculino , Pais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adulto Jovem
12.
Am Fam Physician ; 100(7): 408-414, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573162

RESUMO

Hand-foot-and-mouth disease is caused by human enteroviruses and coxsackieviruses. Outbreaks can occur in the spring to fall and are common in North America, and most cases occur in patients younger than 10 years. Hand-foot-and-mouth disease is transmitted by fecal-oral, oral-oral, and respiratory droplet contact. Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations. Lesions usually resolve in seven to 10 days; however, in rare cases, patients may have neurologic or cardiopulmonary complications. The differential diagnosis for childhood rashes and oral enanthems is broad and includes erythema multiforme, herpes, measles, and varicella. Treatment is supportive and directed toward hydration and pain relief as needed with acetaminophen or ibuprofen. Oral lidocaine is not recommended, and antiviral treatment is not available. The best methods to prevent the spread of hand-foot-and-mouth disease are handwashing and disinfecting potentially contaminated surfaces and fomites.


Assuntos
Doença de Mão, Pé e Boca , Animais , Criança , Pré-Escolar , Diagnóstico Diferencial , Exantema/etiologia , Feminino , Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/fisiopatologia , Doença de Mão, Pé e Boca/prevenção & controle , Doença de Mão, Pé e Boca/terapia , Humanos , Lactente , Masculino
13.
Emerg Microbes Infect ; 8(1): 1445-1455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595827

RESUMO

Coxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection model. The 3-day-old neonatal mice exhibited clinical symptoms such as hind limb paralysis and death. The severe inflammatory reactions were closely related to the abnormal expression of the acute phase response proinflammatory cytokine IL-6 and an imbalance in the IFN-γ/IL-4 ratio. Importantly, the inactivated CVA4 whole-virus vaccine induced humoral immune responses in adult females and the maternal antibodies afforded mice complete protection against lethal dose challenges of homologous or heterologous CVA4 strains. Both IFN-α2a and antiserum inhibited the replication of CVA4 and increased the survival rates of neonatal mice during the early stages of infection. This neonatal murine model of CVA4 infection will be useful for the development of prophylactic and therapeutic vaccines and for screening of antiviral drugs targeting CVA4 to decrease morbidity and mortality.


Assuntos
Anticorpos Antivirais/uso terapêutico , Antivirais/uso terapêutico , Modelos Animais de Doenças , Doença de Mão, Pé e Boca/prevenção & controle , Imunização Passiva , Vacinas Virais/administração & dosagem , Animais , Animais Recém-Nascidos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Avaliação Pré-Clínica de Medicamentos , Enterovirus/efeitos dos fármacos , Feminino , Doença de Mão, Pé e Boca/imunologia , Imunidade Humoral , Camundongos , Camundongos Endogâmicos ICR , Vacinas de Produtos Inativados/imunologia , Carga Viral , Vacinas Virais/imunologia
14.
Lancet Child Adolesc Health ; 3(10): 697-704, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31375313

RESUMO

BACKGROUND: Inactivated monovalent enterovirus A71 (EV-A71) vaccines are now available in China to reduce the substantial public health burden of hand, foot, and mouth disease. However, post-licensure monitoring of vaccine effectiveness is important. We did an observational test-negative study of EV-A71 vaccine effectiveness. METHODS: Children with hand, foot, and mouth disease who were admitted to Henan Children's Hospital (Zhengzhou, China) within 7 days of illness onset were invited to participate in this test-negative case-control study. Participant vaccination history with EV-A71, including the number of doses received and the date of each dose of vaccination, was elicited from parents or legal guardians of participants with a standardised questionnaire. Children must have received two doses before hospitalisation to be counted as fully vaccinated. Patients who had received a single dose before hospitalisation were classified as partly vaccinated. Children who had received no EV-A71 vaccine before hospitalisation were classified as unvaccinated. Throat swabs and stool samples collected from patients were tested by RT-PCR to identify EV-A71 and other enteroviruses. The primary outcome of the study was paediatric hand, foot, and mouth disease associated with EV-A71 requiring hospitalisation. We estimated vaccine effectiveness with conditional logistic regression models adjusted for potential confounders. FINDINGS: Between Feb 15, 2017, and Feb 15, 2018, we enrolled 1803 children aged 6-71 months with hand, foot, and mouth disease. 234 (13%) children tested positive for EV-A71, 1529 (85%) tested positive for other enteroviruses-528 (29%) were positive for Coxsackievirus (CV)-A6 and 342 (19%) were positive for CV-A16-and 29 (2%) tested negative for all enteroviruses. 11 (1%) children with neither throat swab nor stool testing results were excluded from further analyses. Overall vaccine effectiveness was estimated to be 85·4% (95% CI 53·2 to 95·4) for fully vaccinated children and 63·1% (13·1 to 84·3) for partly vaccinated children. The vaccine effectiveness for full vaccination was estimated to be 91·1% (35·1 to 98·8) among non-severe cases compared with 73·3% (-32·6 to 94·6) in severe cases. The vaccine effectiveness for partial vaccination was 77·9% (4·3 to 94·9) in children aged 24-71 months and 40·8% (-71·1 to 79·5) in children aged 6-23 months. We found no significant association between full or partial vaccination and CV-A6 or CV-A16-related hand, foot, and mouth disease. INTERPRETATION: EV-A71 vaccination was effective in preventing non-severe hand, foot, and mouth disease associated with EV-A71 virus infection in children aged 6-71 months, and we found evidence that one dose of vaccination provided partial protection for children aged 24-71 months. Introduction of multivalent vaccines could further reduce the burden of hand, foot, and mouth disease. FUNDING: The National Science Fund for Distinguished Young Scholars.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Vacinação/estatística & dados numéricos , Vacinas Virais/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Enterovirus Humano A/isolamento & purificação , Feminino , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/virologia , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença
15.
Sci Rep ; 9(1): 8046, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142826

RESUMO

The high incidence, seasonal pattern and frequent outbreaks of hand, foot, and mouth disease (HFMD) represent a threat for millions of children in mainland China. And advanced response is being used to address this. Here, we aimed to model time series with a long short-term memory (LSTM) based on the HFMD notified data from June 2008 to June 2018 and the ultimate performance was compared with the autoregressive integrated moving average (ARIMA) and nonlinear auto-regressive neural network (NAR). The results indicated that the identified best-fitting LSTM with the better superiority, be it in modeling dataset or two robustness tests dataset, than the best-conducting NAR and seasonal ARIMA (SARIMA) methods in forecasting performances, including the minimum indices of root mean square error, mean absolute error and mean absolute percentage error. The epidemic trends of HFMD remained stable during the study period, but the reported cases were even at significantly high levels with a notable high-risk seasonality in summer, and the incident cases projected by the LSTM would still be fairly high with a slightly upward trend in the future. In this regard, the LSTM approach should be highlighted in forecasting the epidemics of HFMD, and therefore assisting decision makers in making efficient decisions derived from the early detection of the disease incidents.


Assuntos
Aprendizado Profundo , Epidemias/prevenção & controle , Monitoramento Epidemiológico , Doença de Mão, Pé e Boca/epidemiologia , Modelos Estatísticos , Pré-Escolar , China/epidemiologia , Simulação por Computador , Conjuntos de Dados como Assunto , Previsões/métodos , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Incidência , Estações do Ano
16.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde, LIS-bvsms | ID: lis-46421

RESUMO

A doença mão-pé-boca é uma enfermidade contagiosa causada pelo vírus Coxsackie da família dos enterovírus que habitam normalmente o sistema digestivo e também podem provocar estomatites (espécie de afta que afeta a mucosa da boca). Embora possa acometer também os adultos, ela é mais comum na infância, antes dos cinco anos de idade. O nome da doença se deve ao fato de que as lesões aparecem mais comumente em mãos, pés e boca.


Assuntos
Infecções por Coxsackievirus/prevenção & controle , Enterovirus , Doenças Transmissíveis , Atenção Integrada às Doenças Prevalentes na Infância , Doença de Mão, Pé e Boca/prevenção & controle , Viroses , Doença de Mão, Pé e Boca
17.
Medicine (Baltimore) ; 98(14): e15077, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946358

RESUMO

BACKGROUND: Enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16) are the most common causative agents causing hand, foot, and mouth disease (HFMD). However, coxsackievirus A6 (CV-A6), previously largely ignored, became the predominant pathogen in China in 2012. The objective of this study is to investigate the genetic characteristics and molecular epidemiology of HFMD caused by CV-A6 to guide the diagnosis and treatment of the disease, as well as disease prevention. MATERIAL AND METHODS: A total of 138 suspected HFMD cases were enrolled in this study and analyses based on complete VP1 nucleotide sequences were performed to determine the evolutionary trajectory of emerging CV-A6. RESULTS: Among 138 samples in Jiujiang, 125 (90.58%) were positive for enterovirus, the most frequently presented serotypes were CV-A6 (77, 61.60%), CV-A16 (28, 22.40%), EV-A71 (6, 4.80%) and untyped enteroviruses (14, 11.20%). Seventy-seven CV-A6 positive specimens were analyzed for the complete VP1 sequences by sequencing and 36 representative isolates were selected to perform nucleotide sequence similarity analysis. The results showed that 36 strains isolated from HFMD patients were clustered closely to the mainland China and were far from prototype strain CV-A6/Gdula (AY421764) and other international subtypes. Moreover, phylogenetic analysis of the VP1 gene revealed that 36 circulating strains were not significantly concentrated in one branch, but were widely distributed in each branch. CONCLUSIONS: Continuous surveillance of HFMD etiological agents other than EV-A71 and CV-A16 is necessary. CV-A6 is emerging as the most common pathogen causing HFMD. Closely monitoring the magnitude and trend of CV-A6 epidemic and the trend of pathogenic spectrum changes can provide scientific basis for this disease prevention and control to the department of disease control.


Assuntos
Enterovirus/isolamento & purificação , Doença de Mão, Pé e Boca/virologia , Sequência de Bases , Proteínas do Capsídeo/genética , Criança , Pré-Escolar , China/epidemiologia , Surtos de Doenças , Enterovirus/classificação , Enterovirus/genética , Feminino , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Lactente , Masculino , Epidemiologia Molecular , Análise de Sequência de DNA
18.
J Virol ; 93(13)2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30996087

RESUMO

Enterovirus A71 (EV-A71) is a major pathogen that causes hand-foot-and-mouth disease (HFMD), which occasionally results in severe neurological complications. In this study, we developed four EV-A71 (rgEV-A71) strains by reverse genetics procedures as possible vaccine candidates. The four rgEV-A71 viruses contained various codon-deoptimized VP1 capsid proteins (VP1-CD) and showed replication rates and antigenicity similar to that of the wild-type virus, while a fifth virus, rg4643C4VP-CD, was unable to form plaques but was still able to be examined by median tissue culture infectious dose (TCID50) titers, which were similar to those of the others, indicating the effect of CD on plaque formation. However, the genome stability showed that there were some mutations which appeared during just one passage of the VP1-CD viruses. Thus, we further constructed VP1-CD rgEV-A71 containing high-fidelity determinants in 3D polymerase (CD-HF), and the number of mutations in CD-HF rgEV-A71 was shown to have decreased. The CD-HF viruses showed less virulence than the parental strain in a mouse infection model. After 14 days postimmunization, antibody titers had increased in mice infected with CD-HF viruses. The mouse antisera showed similar neutralizing antibody titers against various CD-HF viruses and different genotypes of EV-A71. The study demonstrates the proof of concept that VP1 codon deoptimization combined with high-fidelity 3D polymerase decreased EV-A71 mutations and virulence in mice but retained their antigenicity, indicating it is a good candidate for next-generation EV-A71 vaccine development.IMPORTANCE EV-A71 can cause severe neurological diseases with fatality in infants and young children, but there are still no effective drugs to date. Here, we developed a novel vaccine strategy with the combination of CD and HF substitutions to generate the genetically stable reverse genetics virus. We found that CD combined with HF polymerase decreased the virulence but maintained the antigenicity of the virus. This work demonstrated the simultaneous introduction of CD genome sequences and HF substitutions as a potential new strategy to develop attenuated vaccine seed virus. Our work provides insight into the development of a low-virulence candidate vaccine virus through a series of genetic editing of virus sequences while maintaining its antigenicity and genome stability, which will provide an additional strategy for next-generation vaccine development of EV-A71.


Assuntos
Proteínas do Capsídeo/imunologia , Códon , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/prevenção & controle , Enterovirus/imunologia , Imunogenicidade da Vacina/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes , Antígenos Virais/genética , Antígenos Virais/imunologia , Sequência de Bases , Proteínas do Capsídeo/genética , Enterovirus/genética , Enterovirus/crescimento & desenvolvimento , Enterovirus Humano A/genética , Enterovirus Humano A/imunologia , Infecções por Enterovirus/virologia , Instabilidade Genômica , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Virulência , Replicação Viral
19.
Sci Rep ; 9(1): 4805, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30886246

RESUMO

Besides causing mild hand, foot and mouth infections, Enterovirus A71 (EV-A71) is associated with neurological complications and fatality. With concerns about rising EV-A71 virulence, there is an urgency for more effective vaccines. The live attenuated vaccine (LAV) is a more valuable vaccine as it can elicit both humoral and cellular immune responses. A miRNA-based vaccine strain (pIY) carrying let-7a and miR-124a target genes in the EV-A71 genome which has a partial deletion in the 5'NTR (∆11 bp) and G64R mutation (3Dp°l) was designed. The viral RNA copy number and viral titers of the pIY strain were significantly lower in SHSY-5Y cells that expressed both let-7a and miR-124a. Inhibition of the cognate miRNAs expressed in RD and SHSY-5Y cells demonstrated de-repression of viral mRNA translation. A previously constructed multiply mutated strain, MMS and the pIY vaccine strain were assessed in their ability to protect 4-week old mice from hind limb paralysis. The MMS showed higher amounts of IFN-γ ex vivo than the pIY vaccine strain. There was absence of EV-A71 antigen in the skeletal muscles and spinal cord micrographs of mice vaccinated with the MMS and pIY strains. The MMS and pIY strains are promising LAV candidates developed against severe EV-A71 infections.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Vacinas Virais/administração & dosagem , Virulência/genética , Animais , Antígenos Virais/análise , Antígenos Virais/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Enterovirus Humano A/genética , Enterovirus Humano A/isolamento & purificação , Genoma Viral/genética , Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/virologia , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Camundongos , MicroRNAs/genética , Mutação , RNA Viral/isolamento & purificação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Carga Viral , Vacinas Virais/genética , Vacinas Virais/imunologia , Replicação Viral/imunologia
20.
Antiviral Res ; 164: 139-146, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30817941

RESUMO

Coxsackievirus A10 (CVA10) has emerged as one of the major pathogens of hand, foot, and mouth disease in recent years. However, there are no approved vaccines or effective drugs against CVA10. Several experimental CVA10 vaccines have been shown to elicit neutralizing antibodies that could confer protection against viral infection. However, neutralizing antigenic sites on CVA10 capsid have not been well characterized. Here, we report the characterization of linear neutralization epitopes of CVA10 and the development of a CVA10 vaccine based on the identified epitopes. We showed that peptide VP2-P28, corresponding to residues 136 to 150 of VP2, were recognized by anti-inactivated CVA10 sera and effectively inhibited anti-CVA10 sera-mediated neutralization, suggesting that this peptide contains neutralizing epitopes. Insertion of VP2-P28 into hepatitis B core antigen (HBc) resulted in a chimeric virus-like particle (VLP; designated HBc-P28) with the CVA10 epitope exposed on the particle surface. HBc-P28 VLP elicited strong antibody responses against VP2-P28 in mice. Anti-HBc-P28 sera could neutralize both CVA10 clinical isolates and prototype strain, consistent with the fact that the VP2-P28 sequence is highly conserved among CVA10 strains. In addition, anti-HBc-P28 sera failed to cross-neutralize other HFMD-causing enteroviruses, indicating that neutralizing antibodies elicited by HBc-P28 VLP were CVA10-specific. Importantly, anti-HBc-P28 sera were able to provide efficient protection against lethal CVA10 infection in recipient mice. Collectively, these data show that peptide VP2-P28 represents a CVA10-specific linear neutralizing antigenic site and chimeric VLP displaying this peptide is a promising epitope-based CVA10 vaccine candidate.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Enterovirus/prevenção & controle , Epitopos/imunologia , Vacinas de Partículas Semelhantes a Vírus/genética , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Enterovirus , Enterovirus Humano A , Infecções por Enterovirus/imunologia , Feminino , Doença de Mão, Pé e Boca/prevenção & controle , Vírus da Hepatite B/genética , Imunogenicidade da Vacina , Camundongos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem
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