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1.
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
2.
Nat Commun ; 11(1): 5253, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067459

RESUMO

Enterovirus 71 (EV71)-neutralizing antibodies correlate with protection and have potential as therapeutic agents. We isolate and characterize a panel of plasmablast-derived monoclonal antibodies from an infected child whose antibody response focuses on the plateau epitope near the icosahedral 3-fold axes. Eight of a total of 19 antibodies target this epitope and three of these potently neutralize the virus. Representative neutralizing antibodies 38-1-10A and 38-3-11A both confer effective protection against lethal EV71 challenge in hSCARB2-transgenic mice. The cryo-electron microscopy structures of the EV71 virion in complex with Fab fragments of these potent and protective antibodies reveal the details of a conserved epitope formed by residues in the BC and HI loops of VP2 and the BC and HI loops of VP3 spanning the region around the 3-fold axis. Remarkably, the two antibodies interact with the epitope in quite distinct ways. These plateau-binding antibodies provide templates for promising candidate therapeutics.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Enterovirus Humano A/imunologia , Infecções por Enterovirus/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Enterovirus Humano A/química , Enterovirus Humano A/genética , Infecções por Enterovirus/virologia , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização
3.
Zhonghua Yu Fang Yi Xue Za Zhi ; 54(9): 1010-1016, 2020 Sep 06.
Artigo em Chinês | MEDLINE | ID: mdl-32907294

RESUMO

Enterovirus 71 (EV71) is one of the main pathogens of hand, foot and mouth disease (HFMD) and the main pathogen of severe HFMD. In 2015, three EV71 vaccines were successively marketed in China as powerful prevention and control tools for HFMD caused by EV71. To understand the efficacy, immunogenicity, safety and quality stability of the domestic EV71 vaccine after entering into the market and analyze potential problems in its application, this article incorporates research regarding the immune effect, population effect, safety, quality testing and evaluation results, vaccination willingness and vaccination behavior survey to explore the vaccination strategies for the donll stic EV71 vaccine. EV71 vaccine has good immunogenicity, safety, protective efficacy, and good quality stability after entering into the market, however, only a few study focused on its safety when inoculating with other immunization planning vaccines simultaneously. Strengthen safety monitoring and discuss the safety of the EV71 vaccine especially when simultaneously inoculate with other immunization program vaccines are still necessary. Enterovirus evolution and recombination, whilst the probable impact of the EV71 vaccine can be the reason for future changes of HFMD epidemic strains, hence continuous monitoring of antigenic mutations and genetic evolution of enterovirus should be responded to. Encouraging the R&D of polyvalent vaccines against HFMD is also necessary. Parents' lack of HFMD and EV71 vaccine knowledge was common, therefore HFMD knowledge should be strengthened at the same time when introducing the EV71 vaccine to the public. Also, it should be emphasized that the EV71 vaccine can only prevent HFMD caused by EV71.


Assuntos
Enterovirus Humano A/imunologia , Enterovirus/imunologia , Doença de Mão, Pé e Boca , Vacinas Virais , China , Humanos , Imunização , Intenção , Marketing , Vacinação
4.
PLoS Pathog ; 16(9): e1008857, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32936838

RESUMO

An outbreak of the hand-foot-mouth disease with severe neurological cases, mainly caused by the genotype C1 enterovirus A71 (EV-A71), occurred in Taiwan between 2018 and early 2019. In the recent decade, the most dominant EV-A71 genotypes in Taiwan were B5 and C4 but changed to C1 in 2018. Antibody-mediated immunity plays a key role in limiting the EV-A71 illness in humans. However, the level of neutralizing activities against genotype C1 virus by human polyclonal and monoclonal antibodies (MAbs) remains largely unclear. In the study, we demonstrated that that 39% (9 in 23) of post-infection sera from the genotype B5- or C4-infected patients in 2014-2017 exhibit reduced titers with the 2018-2019 genotype C1 viruses than with the earlier B5 and C4 viruses tested. This finding with polyclonal sera is confirmed with human MAbs derived from genotype B5 virus-infected individuals. The 2018-2019 genotype C1 virus is resistant to the majority of canyon-targeting human MAbs, which may be associated with the residue change near or at the bottom of the canyon region on the viral capsid. The remaining three antibodies (16-2-11B, 16-3-4D, and 17-1-12A), which target VP1 S241 on the 5-fold vertex, VP3 E81 on the 3-fold plateau and VP2 D84 on the 2-fold plateau of genotype C1 viral capsid, respectively, retained neutralizing activities with variable potencies. These neutralizing antibodies were also found to be protective against a lethal challenge of the 2018-2019 genotype C1 virus in an hSCARB2-transgenic mice model. These results indicate that the EV-A71-specific antibody response may consist of a fraction of poorly neutralizing antibodies against 2018-2019 genotype C1 viruses among a subset of previously infected individuals. Epitope mapping of protective antibodies that recognize the emerging genotype C1 virus has implications for anti-EV-A71 MAbs and the vaccine field.


Assuntos
Antígenos Virais/genética , Enterovirus Humano A/genética , Variação Genética , Genoma Viral , Genótipo , Doença de Mão, Pé e Boca/genética , Animais , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Criança , Pré-Escolar , Enterovirus Humano A/imunologia , Enterovirus Humano A/isolamento & purificação , Feminino , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/imunologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Taiwan
5.
Int J Infect Dis ; 97: 47-53, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32531432

RESUMO

PURPOSE: To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. METHODS: We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. RESULTS: A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01, HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. CONCLUSIONS: Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified.


Assuntos
Enterovirus Humano A/imunologia , Vacinas Virais/imunologia , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Pré-Escolar , China , Feminino , Variação Genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas com Motivo Tripartido/genética , Sequenciamento Completo do Exoma
6.
PLoS Negl Trop Dis ; 14(3): e0008124, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126083

RESUMO

Enterovirus-A71 (EV-A71) cyclically causes hand-foot-mouth disease (HFMD) epidemics in Asian children. An EV-A71 epidemic occurred in Southern Vietnam in 2011, but its scale is not clear. We collected residual sera from non-HFMD Vietnamese inpatients in 2012-2013 to determine seroprevalence of EV-A71 neutralizing antibodies, and measured cross-reactive neutralizing antibody titers against three EV-A71 genogroups. About 23.5% of 1-year-old children in Southern Vietnam has been infected by EV-A71, and the median age of infection was estimated to be 3 years. No significant antigenic variation could be detected among the three EV-A71 genogroups. The high seroprevalence of EV-A71 neutralizing antibody in children living in southern Vietnam indicates the necessity of introducing EV-A71 vaccines in southern Vietnam, particularly for children under 6 months of age. Moreover, it is critical to understand EV-A71 disease burden for formulating national vaccination policy.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Soroepidemiológicos , Vietnã/epidemiologia
7.
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
8.
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
9.
Virol Sin ; 35(1): 64-72, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31512106

RESUMO

Enterovirus A71 (EV-A71) is the major pathogen responsible for the severe hand, foot and mouth disease worldwide, for which few effective antiviral drugs are presently available. Interferon-α (IFN-α) has been used in antiviral therapy for decades; it has been reported that EV-A71 antagonizes the antiviral activity of IFN-α based on viral 2Apro-mediated reduction of the interferon-alpha receptor 1 (IFNAR1); however, the mechanism remains unknown. Here, we showed a significant increase in IFNAR1 protein induced by IFN-α in RD cells, whereas EV-A71 infection caused obvious down-regulation of the IFNAR1 protein and blockage of IFN-α signaling. Subsequently, we observed that EV-A71 2Apro inhibited IFNAR1 translation by cleavage of the eukaryotic initiation factor 4GI (eIF4GI), without affecting IFNAR1 mRNA levels induced by IFN-α. The inhibition of IFNAR1 translation also occurred in puromycin-induced apoptotic cells when caspase-3 cleaved eIF4GI. Importantly, we verified that 2Apro could activate cellular caspase-3, which was subsequently involved in eIF4GI cleavage mediated by 2Apro. Furthermore, inhibition of caspase-3 activation resulted in the partial restoration of IFNAR1 in cells transfected with 2A or infected with EV-A71, suggesting the pivotal role of both viral 2Apro and caspase-3 activation in the disturbance of IFN-α signaling. Collectively, we elucidate a novel mechanism by which cellular caspase-3 contributes to viral 2Apro-mediated down-regulation of IFNAR1 at the translation level during EV-A71 infection, indicating that caspase-3 inhibition could be a potential complementary strategy to improve clinical anti-EV-A71 therapy with IFN-α.


Assuntos
Caspase 3/genética , Regulação para Baixo , Enterovirus Humano A/imunologia , Interações Hospedeiro-Patógeno , Biossíntese de Proteínas , Receptor de Interferon alfa e beta/genética , Caspase 3/imunologia , Linhagem Celular Tumoral , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Receptor de Interferon alfa e beta/imunologia , Rabdomiossarcoma , Transdução de Sinais
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.
Front Immunol ; 10: 2564, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787970

RESUMO

Enterovirus and Coxsackievirus are the major viruses that cause hand, foot, and mouth disease (HFMD) outbreaks worldwide. Several studies have shown the potential of viral envelope protein 1 (VP1) on providing protective effects from viral strains of different genotypes. However, whether VP1 has the cross-protection in Enteroviruses or Coxsackievirus has not been studied in-depth. In this study, the vp1 gene of Enterovirus 71 (EV71) and Coxsackievirus B3 (CB3) was inserted into the vector pET22b (+) to form the respective expression plasmids pEVP1 or pCVP1, and then transformed into Escherichia coli strain BL21 (DE3). The recombinant EVP1 or CVP1 protein was overexpressed successfully and effectively purified to homogeneity. Then, we identified that EVP1 and CVP1 protein could generate effectively specific humoral immunity and cellular immunity in mice, what's more, we determined the cross-protection of VP1 between EV71 and CB3 in a murine model. The results showed that immunization with EVP1 could effectively induce specific IgG and secretory IgA against CVP1 and the sera from EVP1-immunized mice could neutralize CB3 with mean titers 1:440. In contrast, no measurable neutralizing antibodies to EV71 were detected in CVP1-immunized mice. Then, newborn BALB/C mice, whose mother was immunized with EVP1 or CVP1, were administered with different lethal doses of EV71 or CB3. The EVP1 immunized group showed a 90% protective efficacy for a CB3 dosage of 120 LD50, but the CVP1 immunized group showed no significantly different protective efficacy against 15 LD50 of EV71 compared with the BSA immunized group. Hence, EVP1 is a promising subunit vaccine candidate against Enterovirus 71 and Coxsackievirus B3 caused HFMD.


Assuntos
Infecções por Coxsackievirus/prevenção & controle , Enterovirus Humano A/imunologia , Enterovirus Humano B/imunologia , Infecções por Enterovirus/prevenção & controle , Proteínas Estruturais Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Proteção Cruzada/imunologia , Modelos Animais de Doenças , Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Imunidade Heteróloga , Interferon gama/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Proteínas Estruturais Virais/genética , Vacinas Virais/genética , Vacinas Virais/imunologia
12.
Viruses ; 12(1)2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878072

RESUMO

Enterovirus 71 (EV71) infection causes hand-foot-mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children, thereby presenting a serious risk to public health. It is important to determine the mechanisms underlying the regulation of EV71 infection. In this study, we initially show that the interleukin enhancer-binding factor 2 (ILF2) reduces EV71 50% tissue culture infective dose (TCID50) and attenuates EV71 plaque-formation unit (PFU), thereby repressing EV71 infection. Microarray data analyses show that ILF2 mRNA is reduced upon EV71 infection. Cellular studies indicate that EV71 infection represses ILF2 mRNA expression and protein production in human leukemic monocytes (THP-1) -differentiated macrophages and human rhabdomyosarcoma (RD) cells. In addition, EV71 nonstructural protein 2B interacts with ILF2 in human embryonic kidney (HEK293T) cells. Interestingly, in the presence of EV71 2B, ILF2 is translocated from the nucleus to the cytoplasm, and it colocalizes with 2B in the cytoplasm. Therefore, we present a distinct mechanism by which EV71 antagonizes ILF2-mediated antiviral effects by inhibiting ILF2 expression and promoting ILF2 translocation from the nucleus to the cytoplasm through its 2B protein.


Assuntos
Núcleo Celular/metabolismo , Enterovirus Humano A/imunologia , Proteína do Fator Nuclear 45/antagonistas & inibidores , Proteína do Fator Nuclear 45/genética , Translocação Genética , Proteínas não Estruturais Virais/metabolismo , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Células HEK293 , Humanos , Proteína do Fator Nuclear 45/imunologia , Rabdomiossarcoma/virologia , Células THP-1 , Proteínas não Estruturais Virais/genética , Replicação Viral
13.
BMC Infect Dis ; 19(1): 995, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771520

RESUMO

BACKGROUND: In 2017, an outbreak of onychomadesis occurred in kindergarten H, Hubei province, China. We investigated the field to learn about the magnitude and reason of the outbreak. METHODS: The case definition was that a child with onychomadesis or transverse ridging (Beau's line) in fingernails and toenails without previous traumatic or systemic disease in kindergarten H from Sep. 1st to Nov. 30th, 2017. A retrospective cohort study was carried out to analyze the epidemiological relationship between onychomadesis and the hand-foot-mouth disease (HFMD) in Primary Class #2, kindergarten H. We also performed a serological survey for neutralizing antibodies against coxsackie virus A6 (CVA6), coxsackie virus A10 (CVA10) among 15 cases and six healthy children in the kindergarten. Meanwhile, some children were carried out with routine blood, fungal microscopic and microelement tests. Indoor environment examinations had been done for all classes. RESULTS: A total of 20 cases were identified in Kindergarten H. Seventy-five percent (15/20) cases occurred in Primary Class #2. Fifty-five percent of the cases (11/20) had suffered from HFMD within two months. The median time between onychomadesis and HFMD was 45 days (ranging from 31 to 58 days). A retrospective cohort study in Primary Class #2 showed the attack rate was 90.0% among 10 children who suffered from HFMD in the past two months compared to 30.0% among 20 children who didn't (Rate Ratio [RR] =3.0, 95% Confidence Interval [CI] =1.5-6.0). The positive rates of neutralizing antibodies were 66.7% for CVA6 and 26.7% for CVA10 in tested cases. The result of routine blood, fungal microscopic, microelements tests were normal in cases. The indicators of environment were within the normal range. CONCLUSION: The results of this study suggested that the outbreak of onychomadesis in Hubei province was probably associated with HFMD epidemic within two months.


Assuntos
Doença de Mão, Pé e Boca/epidemiologia , Doenças da Unha/epidemiologia , Doenças da Unha/etiologia , Anticorpos Neutralizantes , Anticorpos Antivirais , Pré-Escolar , China/epidemiologia , Surtos de Doenças , Enterovirus Humano A/imunologia , Feminino , Doença de Mão, Pé e Boca/etiologia , Humanos , Incidência , Masculino , Estudos Retrospectivos , Instituições Acadêmicas
14.
Arch Virol ; 164(12): 2975-2984, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31570994

RESUMO

Coxsackievirus A16 (CV-A16) is one of the main causative agents of hand, foot and mouth disease (HFMD) in young children and has become prevalent in the Asia-Pacific region in recent years. However, no approved vaccines or drugs are available for CV-A16 infection. CV-A16 virus-like particles (VLPs) are a potential vaccine candidate; however, whether the intranasal route of immunization is suitable for inducing immune responses against CV-A16 infection has not been clarified. In this study, the comprehensive immunogenicity and protective efficacy of the CV-A16 VLP vaccine were evaluated by multiple methods in a mouse model. In mice, a high neutralizing antibody (NTAb) titre could be elicited by intranasal immunization with CV-A16 VLPs, which produced NTAb levels similar to those induced by intranasal immunization with inactivated CV-A16. Passive immunity with NTAbs provided very good protection, as the survival rate of the immunized neonatal mice was 100% after challenges with CV-A16 at a dose of 1000 LD50. Passive protective effects were transferred to the neonates via the mother, thus protecting all the pups against challenges with the homologous or heterologous strains of CV-A16 at a dose of 1000 LD50. In addition, intranasal immunization with CV-A16 VLPs also induced the production of mucosal secretory IgA (s-IgA) antibodies, which may inhibit CV-A16 virus invasion. This study provides valuable supplemental information to facilitate our understanding of the specific protective efficacy of CV-A16 VLPs and has significance for development of the candidate vaccine into a safe and effective vaccine.


Assuntos
Enterovirus Humano A/imunologia , Infecções por Enterovirus/prevenção & controle , Nariz/virologia , Vacinas Virais/administração & dosagem , Animais , Animais Recém-Nascidos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Enterovirus Humano A/genética , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Imunização , Camundongos , Camundongos Endogâmicos ICR , Vacinas Virais/genética , Vacinas Virais/imunologia
15.
J Biomed Sci ; 26(1): 81, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31630680

RESUMO

As a neurotropic virus, enterovirus A71 (EV-A71) emerge and remerge in the Asia-Pacific region since the 1990s, and has continuously been a threat to global public health, especially in children. Annually, EV-A71 results in hand-foot-and-mouth disease (HFMD) and occasionally causes severe neurological disease. Here we reviewed the global epidemiology and genotypic evolution of EV-A71 since 1997. The natural selection, mutation and recombination events observed in the genetic evolution were described. In addition, we have updated the antigenicity and virulence determinants that are known to date. Understanding EV-A71 epidemiology, genetic evolution, antigenicity, and virulence determinants can expand our insights of EV-A71 pathogenesis, which may benefit us in the future.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus/epidemiologia , Evolução Molecular , Doença de Mão, Pé e Boca/epidemiologia , Antígenos Virais/imunologia , Enterovirus Humano A/genética , Enterovirus Humano A/imunologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/virologia , Genótipo , Doença de Mão, Pé e Boca/virologia , Humanos , Virulência
16.
PLoS One ; 14(10): e0224110, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622436

RESUMO

BACKGROUND: During recent 20 years, enterovirus 71 (EV71) has emerged as a major concern among children, particularly in the Asia-Pacific region. To understand current EV71 serostatus, to find risk factors associated with EV71 infection and to establish future EV71 vaccine policy, we performed a seroepidemiology study in Taiwan in 2017. METHODS: After informed consent was obtained, we enrolled preschool children, 6-15-year-old students, 16-50-year-old people. They received a questionnaire and a blood sample was collected to measure the EV71 neutralization antibody. RESULTS: Altogether, 920 subjects were enrolled with a male-to-female ratio of 1.03. The EV71 seropositive rate was 10% (8/82) in infants, 4% (6/153) in 1-year-old children, 8% (7/83) in 2-year-old children, 8% (13/156) in 3-5-year-old children, 31% (38/122) in 6-11-year-old primary school students, 45% (54/121) in 12-15-year-old high school students and 75% (152/203) in 16-50-year-old people. Risk factors associated with EV71 seropositivity in preschool children were female gender, having siblings, more siblings, and contact with herpangina or hand-foot-and-mouth disease. The risk factor with EV71 seropositivity in 16-50-year-old people was having children in their families in addition to older age (p<0.001). Compared with the rates in 1997, 1999 and 2007, the rates in children were significantly lower in 2017. CONCLUSION: EV71 seropositive rates were very low, at 4% to 10%, in preschool children and not high, at 31%, in primary school students. Preschool children are highly susceptible and need EV71 vaccine most.


Assuntos
Infecções por Enterovirus/diagnóstico , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Criança , Pré-Escolar , Enterovirus Humano A/imunologia , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/complicações , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/complicações , Doença de Mão, Pé e Boca/diagnóstico , Herpangina/complicações , Herpangina/diagnóstico , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Taiwan/epidemiologia , Adulto Jovem
17.
Monoclon Antib Immunodiagn Immunother ; 38(5): 220-223, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31603742

RESUMO

Several members of enteroviruses (EVs) that belong to the EVs A and B species cause hand, foot, and mouth disease (HFMD) in infants and young children. The virus-specific protease 2Apro is conserved in all the EV species, thus developing a monoclonal antibody (mAb) against 2Apro may facilitate the identification from the HFMD-associated pathogens. In this study, we achieved a murine mAb, named 5A3, specifically toward EVA71 2Apro by using the traditional hybridoma technique. The mAb 5A3 recognizes 2Apro of both EVs A and B species, which was demonstrated by indirect fluorescent assay and Western blotting. Furthermore, a conserved N-terminal epitope on 2Apro recognized by mAb 5A3 was defined by using an overlapping peptide-based enzyme-linked immunosorbent assay (ELISA). Therefore, the unique mAb targeting conserved EVs 2Apro can be used as an important tool during both identifying the causative agent of HFMD and elucidating the pathological mechanism of HFMD.


Assuntos
Anticorpos Monoclonais/imunologia , Enterovirus Humano A/imunologia , Epitopos/imunologia , Peptídeo Hidrolases/imunologia , Animais , Antígenos Virais/imunologia , Western Blotting , Chlorocebus aethiops , Reações Cruzadas , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Hibridomas , Camundongos Endogâmicos BALB C , Células Vero
18.
J Biomed Sci ; 26(1): 65, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481071

RESUMO

Enterovirus A71 (EV-A71) is an important emerging virus posing a threat to children under five years old. EV-A71 infection in infants or young children can cause hand-foot-and-mouth disease, herpangina, or severe neurological complications. However, there are still no effective antivirals for treatment of these infections. In this review, we summarize the antiviral compounds developed to date based on various targets of the EV-A71 life cycle. Moreover, development of a vaccine would be the most effective approach to prevent EV-A71 infection. Therefore, we also summarize the development and clinical progress of various candidate EV-A71 vaccines, including inactivated whole virus, recombinant VP1 protein, synthetic peptides, viral-like particles, and live attenuated vaccines.


Assuntos
Antivirais/uso terapêutico , Enterovirus Humano A/imunologia , Infecções por Enterovirus/terapia , Vacinas Virais/uso terapêutico , Animais , Humanos , Camundongos
19.
J Infect Chemother ; 25(12): 1074-1077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401030

RESUMO

Enterovirus 71 (EV71), a newly emerging life-threatening pathogen induces hand-foot-mouth disease (HFMD), no effective vaccines or specific anti-viral treatments are currently available. In this study, the activity of hederacolchiside C (HSC) against EV71 was investigated, and the antiviral mechanism was explored. HSC displayed apparent antiviral activity in EV71-infected cells probably through activating the host innate immunity. Comparing with EV71-infected group at 24 hpi, the group pretreated with HSC dramatically increased the expression of MAVS, p-IRF3, IRF3 and IFN-ß, the innate immune effectors related to innate immunity. In addition, HSC displayed stronger antiviral activity in EV71-infected suckling mice in comparison with Ribavirin, a broad-spectrum antiviral drug. The results suggest that HSC could have potential as a pharmaceutical drug for HFMD.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/tratamento farmacológico , Pulsatilla/química , Saponinas/farmacologia , Animais , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Enterovirus Humano A/efeitos dos fármacos , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Camundongos , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Saponinas/uso terapêutico , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
20.
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
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