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novel marker for recombination in the 3'-untranslated region of members of the species human enterovirus a.human enterovirus a (hev-a) is a species in the genus enterovirus. viruses belonging to this species are often responsible for hand, foot and mouth disease and associated acute neurological disease. studies of the 3' untranslated region (utr) of human enterovirus 71 (hev71) revealed a possible role in virus replication. we compared the 3'-utrs of all members of hev-a and confirmed the presence of a secondary structure comprising three stem-loop domains (slds). sld-z is situated closest to the st ...201323178966
development of a coxsackievirus a16 neutralization assay based on pseudoviruses for measurement of neutralizing antibody titer in human serum.serum neutralizing antibody titers are indicative of protective immunity against coxsackievirus a16 (cv-a16) and enterovirus 71 (ev71), the two main etiological agents of hand, foot and mouth disease (hfmd), and provide the basis for evaluating vaccine efficacy. the current cv-a16 neutralization assay based on inhibition of cytopathic effects requires manual microscopic examination, which is time-consuming and labor-intensive. in this study, a high-throughput neutralization assay was developed b ...201323178532
detection of human enterovirus 71 and coxsackievirus a16 in an outbreak of hand, foot, and mouth disease in henan province, china in 2009.during 2009, an outbreak of hand, foot, and mouth disease (hfmd) enrolled 490 people in henan province, causing the death of two children. in order to investigate the pathogens responsible for this outbreak and characterize their genetic characteristics, a total of 508 clinical specimens (stool, throat swab, and vesicle fluid) were collected from the center for disease control and prevention of henan province. virological investigations (virus isolation, conventional reverse transcription pcr, a ...201323080402
a new factor influencing pathogen detection by molecular assay in children with both mild and severe hand, foot, and mouth disease.this study aimed to find novel information concerning pathogen detection and some probable coinfection factors in hand, foot, and mouth disease (hfmd). in this study, 1104 clinically diagnosed hfmd patients were included. enterovirus 71 (ev71), coxsackievirus a16 (ca16), and 14 different respiratory pathogens were examined from nasopharyngeal swabs using polymerase chain reaction (pcr) or reverse transcriptase pcr (rt-pcr). to evaluate the immune activation in hfmd patients, 8 cytokines and igm ...201323535205
molecular epidemiology of human enterovirus 71 strains in the nanchang region of china in 2011.hand, foot, and mouth disease (hfmd) is caused by enteroviruses, most commonly enterovirus 71 (ev71) and coxsackievirus a16 (ca16). in general, ev71 infection is more likely to induce severe complications and mortality than other enterovirus infections. the present study focuses on the molecular epidemiology of human ev71 strains in the nanchang region of china in 2011. overall, 651 specimens (throat or rectal swabs) were collected, and one-step reverse transcriptase-polymerase chain reaction wa ...201323514913
glycyrrhizic acid as the antiviral component of glycyrrhiza uralensis fisch. against coxsackievirus a16 and enterovirus 71 of hand foot and mouth disease.the radices of glycyrrhiza uralensis fisch. and herbal preparations containing glycyrrhiza spp. have been used for thousands of years as an herbal medicine for the treatment of viral induced cough, viral hepatitis, and viral skin diseases like ulcers in china. glycyrrhizic acid (ga) is considered the principal component in glycyrrhiza spp. with a wide spectrum of antiviral activity.201323454684
hand, foot, and mouth disease: current scenario and indian perspective.hand, foot, and mouth disease (hfmd), first reported in new zealand in 1957 is caused by coxsackievirus a16 (cva16) and human enterovirus 71 (hev71) and occasionally by coxsackievirus a4-a7, a9, a10, b1-b3, and b5. this is characterized by erythematous papulo vesicular eruptions over hand, feet, perioral area, knees, buttocks and also intraorally mostly in the children. hfmd has been known for its self limiting course. only small scale outbreaks have been reported from united states, europe, aus ...201323442455
phylogenetic analysis of enterovirus 71 circulating in beijing, china from 2007 to 2009.the major pathogens of hand, foot and mouth disease (hfmd) in beijing, china from 2007 to 2009 were identified in this study. a total of 186 hfmd cases were included, and 136 cases (73%) were positive for enterovirus (ev). in 2007, 75% (27/36) were coxsackievirus a16 (ca16) positive and 19% (7/36) were enterovirus 71 (ev71) positive cases. however, ev71 was the predominant virus in 2008, when 56% (31/55) of the cases were positive for ev71 and 22% (12/55) were positive for ca16. in 2009, ev71 an ...201323418551
epidemiology and etiological characteristics of hand, foot and mouth disease in huizhou city between 2008 and 2011.to study epidemiological features and etiological characteristics of hand, foot and mouth disease (hfmd), 42,012 cases were investigated from april 2008 to december 2011 in huizhou, china. the average incidence rate was 21.16 per 10,000. the highest peak of hfmd incidence was detected between april and july each year, accounting for 55.93 % of all reported cases; another peak occurred in october through december, accounting for 24.17 % of the cases. of the reported cases, 89.75 % were in childre ...201323229012
ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture.it has been shown in animal models that ribavirin-resistant poliovirus with a g64s mutation in its 3d polymerase has high replication fidelity coupled with attenuated virulence. here, we describe the effects of mutagenesis in the human enterovirus 71 (hev71) 3d polymerase on ribavirin resistance and replication fidelity. seven substitutions were introduced at amino acid position 3d-g64 of a hev71 full-length infectious cdna clone (26m). viable clone-derived virus populations were rescued from th ...201323175376
cleavage of interferon regulatory factor 7 by enterovirus 71 3c suppresses cellular responses.enterovirus 71 (ev71) is a positive-stranded rna virus which is capable of inhibiting innate immunity. among virus-encoded proteins, the 3c protein compromises the type i interferon (ifn-i) response mediated by retinoid acid-inducible gene-i (rig-i) or toll-like receptor 3 that activates interferon regulatory 3 (irf3) and irf7. in the present study, we report that enterovirus 71 downregulates irf7 through the 3c protein, which inhibits the function of irf7. when expressed in mammalian cells, the ...201323175366
lncrna expression signatures in response to enterovirus 71 infection.outbreaks of hand, foot, and mouth disease caused by enterovirus 71 (ev71) have become considerable threats to the health of infants and young children. to identify the cellular long noncoding rnas (lncrnas) involved in the host response to ev71 infection, we performed comprehensive lncrna and mrna profiling in ev71-infected rhabdomyosarcoma cells through microarray. we observed the differential expression of more than 4800 lncrnas during infection. further analysis showed 160 regulated enhancer ...201323220233
microrna-23b inhibits enterovirus 71 replication through downregulation of ev71 vpl protein.enterovirus 71 (ev71) is one of the causative pathogens of hand-foot-and-mouth disease and effective antiviral agents and vaccines against this virus have, to date, not been available. micrornas (mirnas) are a recently discovered class of rnas with the function of post-transcriptional gene expression regulation. it has been demonstrated that mirnas play important roles in the complicated interaction network between virus and host, while few studies have explored the role of mirnas in ev71 infect ...201323594713
complete genome sequencing and analysis of six enterovirus 71 strains with different clinical phenotypes.hand, foot and mouth diseases (hfmd) caused by enterovirus 71(ev71) presents a broad spectrum of clinical manifestations ranging from mild febrile disease to fatal neurolocal disease. however, the mechanism of virulence is unknown.201323577963
a safety study of inactivated enterovirus 71 vaccine.enterovirus 71 (ev71) is one of the major causative agents for hand, foot and mouth disease (hfmd) in childhood. nowadays, hfmd or ev71 infections have already become an important public health issue throughout the world. vaccination may be the most effective measure to control the transmission of the virus. therefore, to pave ev71 vaccine into human clinical trial, in the present study a comprehensive preclinical safety assessment of inactivated ev71 vaccine including single- and repeat-dose to ...201323571172
iridoid and bis-iridoid glucosides from the fruit of gardenia jasminoides.three new iridoid glucosides, 6″-o-trans-feruloylgenipin gentiobioside (1), 2'-o-trans-caffeoylgardoside (2), jasmigeniposide a (3), and one new bis-iridoid glucoside, jasmigeniposide b (4), along with six known analogues (5-10), were isolated from the fruit of gardenia jasminoides. their structures were established on the basis of spectroscopic analyses and chemical methods. anti-virus activity of isolated compounds were evaluated in vitro and only compound 9 showed moderate inhibitory activity ...201323567862
mri characteristics of brainstem encephalitis in hand-foot-mouth disease induced by enterovirus type 71--will different mri manifestations be helpful for prognosis?the mri characteristics of 21 hfmd patients with brainstem encephalitis resulting from ev71 infection were examined to identify lesion patterns helpful in disease classification and prognosis. the author reviewed the clinical and mri data of 21 children with brainstem encephalitis infected during the ev71 outbreak in hainan, china from may 2008 to september 2010. thirteen cases of brainstem encephalitis were classified as type i based on unilateral or bilateral symmetrical patch-like hyperintens ...201323561930
immune responses to baculovirus-displayed enterovirus 71 vp1 antigen.the increased distribution and neurovirulence of enterovirus 71 is an important health threat for young children in asia pacific. vaccine design has concentrated on inactivated virus with the most advanced undergoing phase iii clinical trials. by using a subunit vaccine approach, production costs could be reduced by lowering the need for biocontainment. in addition, novel mutations could be rapidly incorporated to reflect the emergence of new enterovirus 71 subgenogroups. to circumvent the probl ...201323560917
chlorine dioxide inactivation of enterovirus 71 in water and its impact on genomic targets.to control the waterborne transmission of enterovirus 71(ev71), which is associated with hand foot and mouth disease (hfmd), it is essential to know the inactivation effectiveness of disinfectants on ev71 in water. in this article, we present a comparative analysis of the effects on ev71 following exposure to chlorine dioxide (clo2) under different doses, ph, and temperature conditions. we show that the ev71 exhibited strong resistance to clo2 (more than the ms2 standard) and that ct value range ...201323560857
the enterovirus 71 a-particle forms a gateway to allow genome release: a cryoem study of picornavirus uncoating.since its discovery in 1969, enterovirus 71 (ev71) has emerged as a serious worldwide health threat. this human pathogen of the picornavirus family causes hand, foot, and mouth disease, and also has the capacity to invade the central nervous system to cause severe disease and death. upon binding to a host receptor on the cell surface, the virus begins a two-step uncoating process, first forming an expanded, altered "a-particle", which is primed for genome release. in a second step after endocyto ...201323555253
enterovirus 71 protease 2apro targets mavs to inhibit anti-viral type i interferon responses.enterovirus 71 (ev71) is the major causative pathogen of hand, foot, and mouth disease (hfmd). its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether ev71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. here, we show that ev71 inhibits anti-viral type i interferon (ifn ...201323555247
a phase i, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine.large-scale outbreaks of enterovirus 71 (ev71) infections have occurred in asia-pacific regions. severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against ev71.201323541623
beta-actin variant is necessary for enterovirus 71 replication.enterovirus 71 (ev71) is one of the main etiological agents of the hand, foot and mouth disease (hfmd) and has been known to cause fatal neurological complications such as herpangina, aseptic meningitis, poliomyelitis-like paralysis and encephalitis. ev71 is endemic in the asia-pacific region and causes occasional epidemics. in order to better understand ev71 infection, we compared the proteome between ev71-susceptible and ev71-resistant human rhabdomyosarcoma (rd) cell line. we found significan ...201323535377
association of interleukin-17f gene polymorphism with enterovirus 71 encephalitis in patients with hand, foot, and mouth disease.enterovirus 71 (ev71) is one of the common pathogenic agents of hand, foot, and mouth disease (hfmd) and is associated with severe complications including encephalitis. interleukin (il)-17f plays an important role in tissue inflammation by inducing release of proinflammatory cytokines and chemokines. we investigated the association between ev71 encephalitis and of il-17f 7488t/c (rs763780) gene polymorphism, which is known to cause a his-to-arg substitution at amino acid 161. the study was perfo ...201323519962
synthesis and antiviral activity of n-phenylbenzamide derivatives, a novel class of enterovirus 71 inhibitors.a series of novel n-phenylbenzamide derivatives were synthesized and their anti-ev 71 activities were assayed in vitro. among the compounds tested, 3-amino-n-(4-bromophenyl)-4-methoxybenzamide (1e) was active against the ev 71 strains tested at low micromolar concentrations, with ic50 values ranging from 5.7 ± 0.8-12 ± 1.2 μm, and its cytotoxicity to vero cells (tc50 = 620 ± 0.0 μm) was far lower than that of pirodavir (tc50 = 31 ± 2.2 μm). based on these results, compound 1e is a promising lead ...201323519203
fluorescent primer-based in vitro transcription system of viral rna-dependent rna polymerases.viral infection is a leading cause of disease and death. although vaccines are the most effective method of controlling viral infections, antiviral drugs are also important. here, we established an in vitro transcription system by using fluorescein isothiocyanate-conjugated primers for rna polymerases of viruses that are important disease-causing human pathogens (influenza, hepatitis c, japanese encephalitis viruses, and enterovirus 71). this technology will allow us to analyze rna polymerase ac ...201323103398
quantification of the dynamics of enterovirus 71 infection by experimental-mathematical investigation.enterovirus 71 (ev71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. ev71 outbreaks are a major public health concern in asia-pacific countries. by performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among ev71 strains and can be associated with their epidemiological backgrounds. this is the first report demonstrating the dynamics of ...201323097444
antigenic analysis of divergent genotypes human enterovirus 71 viruses by a panel of neutralizing monoclonal antibodies: current genotyping of ev71 does not reflect their antigenicity.in recent year, enterovirus 71 (ev71)-associated hand, foot and mouth disease (hfmd) has become an important public health issue in china. ev71 has been classified into genotypes a, b1-b5 and c1-c5. with such genetic diversity, whether the convalescent or recovery antibody responses can cross-protect infections from other genotypes remains a question. understanding of the antigenicity of such diverse genetic ev71 isolates is crucial for the ev71 vaccine development. here, a total of 186 clones a ...201323088887
recombinant vp1 protein expressed in pichia pastoris induces protective immune responses against ev71 in mice.human enterovirus 71 (ev71) is one of the major causative agents of hand, foot and mouth disease and is also associated with serious neurological diseases in children. currently, there are no effective antiviral drugs or vaccines against ev71 infection. vp1, one of the major immunogenic capsid proteins of ev71, is widely considered to be the candidate antigen for an ev71 vaccine. in this study, vp1 of ev71 was expressed as a secretory protein with an n-terminal histidine tag in the methylotrophi ...201323159634
microrna-548 down-regulates host antiviral response via direct targeting of ifn-λ1.interferon (ifn)-mediated pathways are a crucial part of the cellular response against viral infection. type iii ifns, which include ifn-λ1, 2 and 3, mediate antiviral responses similar to type i ifns via a distinct receptor complex. ifn-λ1 is more effective than the other two members. transcription of ifn-λ1 requires activation of irf3/7 and nuclear factor-kappa b (nf-κb), similar to the transcriptional mechanism of type i ifns. using reporter assays, we discovered that viral infection induced ...201323150165
impact of endothelial nitric oxide synthase gene polymorphism on severity of enterovirus 71-infection in chinese children.genetic polymorphism g894t on the endothelial nitric oxide synthase (enos) gene has been reported as a susceptibility factor in a number of diseases, but evidence of its effect on enterovirus 71 (ev71) infection is lacking. this study investigated the possible association between this polymorphism (rs1799983) and disease severity in chinese children with ev71 infection.201324140479
characterization of enterovirus 71 capsids using subunit protein-specific polyclonal antibodies.enterovirus 71 (ev71), a member of the enterovirus genus of the picornaviridae family, is one of the major causative agents of hand-foot-and-mouth disease (hfmd), which is prevalent in the asia-pacific region. in this article, a set of capsid subunit protein-specific antibodies was used to characterize the ev71 structural protein processing and to determine the composition and assembly of ev71 capsids. sds-page and western blot analyses showed that the capsids of a purified ev71 preparation, whi ...201323046991
adoptive transfer of macrophages from adult mice reduces mortality in mice infected with human enterovirus 71.human enterovirus 71 (ev71) causes hand, foot and mouth disease in children under 6 years of age, and the neurological complications of this virus can lead to death. until now, no vaccines or drugs have been available for the clinical control of this epidemic. macrophages can engulf pathogens and mediate a series of host immune responses that play a role in the defence against infectious diseases. using immunohistochemistry, we observed the localizations of virus in muscle tissues of ev71-infect ...201323065110
bedside immunochromatographic test for enterovirus 71 infection in children.enterovirus 71 (ev71) causes frequent outbreaks worldwide, particularly in the asia-pacific area. its quick spread is a critical challenge for public health and timely preventive measures and clinical management therefore rely on early detection. there is a need for a rapid, easy-to-use, and reliable method for detecting ev71 infections.201324084600
is a monovalent vaccine against enterovirus 71 sufficient? a review of enterovirus 71 vaccine development based on enterovirus surveillance in taiwan. 201324079713
enterovirus 71 vp1 activates calmodulin-dependent protein kinase ii and results in the rearrangement of vimentin in human astrocyte cells.enterovirus 71 (ev71) is one of the main causative agents of foot, hand and mouth disease. its infection usually causes severe central nervous system diseases and complications in infected infants and young children. in the present study, we demonstrated that ev71 infection caused the rearrangement of vimentin in human astrocytoma cells. the rearranged vimentin, together with various ev71 components, formed aggresomes-like structures in the perinuclear region. electron microscopy and viral rna l ...201324073199
environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells.alkylphenols, such as nonylphenol (np) and 4-octylphenol (4-op), have the potential to disturb immune system due to their weak estrogen-like activity, an effect with potential serious public health impact due to the worldwide distribution of these substances. plasmacytoid dendritic cells (pdcs) can secrete large amounts of type i ifns and are critical in immune regulation. however, there has been limited study about the influence of alkylphenols on the function of pdcs.201324039973
[relationship between g6pd deficiency and hand-foot-mouth disease induced by enterovirus 71].to study the influence of glucose-6-phosphate dehydrogenase (g6pd) deficiency on hand-foot-mouth disease (hfmd) induced by enterovirus 71 (ev71) , and possible mechanisms.201324034918
[cloning, expression and activity determination of capsid protein vp1 of enterovirus type 71]. 201324027809
crystal structure of 2a proteinase from hand, foot and mouth disease virus.ev71 is responsible for several epidemics worldwide; however, the effective antiviral drug is unavailable to date. the 2a proteinase (2a(pro)) of ev71 presents a promising drug target due to its multiple roles in virus replication, inhibition of host protein synthesis and evasion of innate immunity. we determined the crystal structure of ev71 2a(pro) at 1.85å resolution, revealing that the proteinase maintains a chymotrypsin-like fold. the active site is composed of the catalytic triads c110a, h ...201323973886
proteomic analysis of extremely severe hand, foot and mouth disease infected by enterovirus 71.to clarify the molecular mechanisms that participate in the severe hand, foot and mouth disease (hfmd) infected by enterovirus 71 and to detect any related protein biomarkers, we performed proteomic analysis of protein extracts from 5 extremely severe hfmd children and 5 healthy children.201323961958
transgenic mouse model for the study of enterovirus 71 neuropathogenesis.enterovirus 71 (ev71) typically causes mild hand-foot-and-mouth disease in children, but it can also cause severe neurological disease. recently, epidemic outbreaks of ev71 with significant mortality have been reported in the asia-pacific region, and ev71 infection has become a serious public health concern worldwide. however, there is little information available concerning ev71 neuropathogenesis, and no vaccines or anti-ev71 drugs have been developed. previous studies of this disease have used ...201323959904
soluble interleukin-6 receptor-mediated innate immune response to dna and rna viruses.the interleukin-6 (il-6) receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. the soluble il-6 receptor (sil6r) has been identified as a potential therapeutic target for preventing coronary heart disease. however, little is known about the role of this receptor during viral infection. in this study, we show that sil6r, but not il-6, is induced by viral infection via the cyclooxygenase-2 pathway. interestingly, sil6r, but not il-6, exhibited ext ...201323946454
[epidemiological and etiological characteristics of hand-foot-mouth disease in ningbo, zhejiang province, 2008-2011].to analyze the epidemiological characteristics of hand foot and mouth disease (hfmd) in ningbo.201323937841
enterovirus 71 binding to psgl-1 on leukocytes: vp1-145 acts as a molecular switch to control receptor interaction.some strains of enterovirus 71 (ev71), but not others, infect leukocytes by binding to a specific receptor molecule: the p-selectin glycoprotein ligand-1 (psgl-1). we find that a single amino acid residue within the capsid protein vp1 determines whether ev71 binds to psgl-1. examination of capsid sequences of representative ev71 strains revealed that the psgl-1-binding viruses had either a g or a q at residue 145 within the capsid protein vp1 (vp1-145g or q), whereas psgl-1-nonbinding viruses ha ...201323935488
patterns of polymorphism and divergence in the vp1 gene of enterovirus 71 circulating in the asia-pacific region between 1994 and 2013.enterovirus 71 has been implicated in several outbreaks of hand, foot and mouth disease in the asia-pacific region. the present study aimed to achieve comprehensive evolutionary dynamic aspects of ev71 during 1994-2013, based on phylogenetic analyses of the vp1 sequences. the results indicated that 4 genotypes, namely c4, c1, c2 and b4 are the predominant strains, especially in southeast asian countries. no common ancestor was shared in different countries. fourteen sites of substitutions were d ...201323933074
plasma b-type natriuretic peptide study in children with severe enterovirus 71 infection: a pilot study.severe enterovirus 71 (ev71) infections in children can result in acute heart failure. b-type natriuretic peptide (bnp) is a good biomarker of myocardial stress. the purpose of this study was to use plasma bnp for the detection of ev71 infection with cardiac involvement.201323932576
[retrospective analysis of clinical and epidemiological characteristics of hand-foot-and-mouth disease deceased cases in zhejiang province].to understand the clinical and epidemiological characteristics of hand-foot-and-mouth disease (hfmd) deceased cases.201323927799
genetic and antigenic characterization of enterovirus 71 in ho chi minh city, vietnam, 2011.enterovirus 71 (ev71) frequently causes fatal infections in young children in asia. in 2011, ev71 epidemics occurred in southern vietnam. we conducted genetic and antigenic analysis of the ev71 isolates and found that 94% of them were genotype c4a related to two lineages circulating in china and 6% were genotype c5 which have circulated in vietnam since 2003. antigenic variants were not detected. ev71 vaccines are being developed. longitudinal enterovirus surveillance data are critical to formul ...201323922846
neutralization of five subgenotypes of enterovirus 71 by taiwanese human plasma and taiwanese plasma derived intravenous immunoglobulin.enterovirus 71 (ev71) commonly occurs in children, causing hand, foot and mouth disease (hfmd) in about 29% of patients. studies have suggested that patients develop meningitis and encephalopathy with a mortality rate of 4-26%. ev71 subgenotypes including b4, b5, c2, c4 and c5 have caused hfmd epidemics in taiwan. in terms of therapeutical strategy, intravenous immunoglobulin (ivig) has been shown to improve patient conditions. in this study, the ev71 neutralizing titer was evaluated in 75 human ...201323515089
calcium flux and calpain-mediated activation of the apoptosis-inducing factor contribute to enterovirus 71-induced apoptosis.enterovirus 71 (ev71) is a causative agent of an array of childhood diseases with severe neurological manifestations implicated. ev71 infection is known to induce caspase-dependent apoptosis in cell cultures and animal models. however, whether an alternative apoptotic pathway independent of caspase activation can be triggered by ev71 infection has not been explored. in this study, we showed that calcium (ca²⁺)-activated calpains are capable of mediating caspase-independent pathway activation dur ...201323515028
structure of human enterovirus 71 in complex with a capsid-binding inhibitor.human enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. as of now, no cure is available for enterovirus 71 infections. small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. here we report a 3.2-å-resolution x-ray structure of the enterovirus 71 virion complexed with the capsid-binding inhibit ...201323509286
crystal structure of enterovirus 71 rna-dependent rna polymerase complexed with its protein primer vpg: implication for a trans mechanism of vpg uridylylation.picornavirus rna replication is initiated by vpg uridylylation, during which the hydroxyl group of the third tyrosine residue of the virally encoded protein vpg is covalently linked to two ump molecules by rna-dependent rna polymerase (rdrp; also known as 3d(pol)). we previously identified site 311, located at the base of the palm domain of the enterovirus 71 (ev71) rdrp, to be the site for ev71 vpg binding and uridylylation. here we report the crystal structure of ev71 3d(pol) complexed with vp ...201323487447
display of the viral epitopes on lactococcus lactis: a model for food grade vaccine against ev71.in this study, we have developed a system for display of antigens of enterovirus type 71 (ev71) on the cell surface of l. lactis. the viral capsid protein (vp1) gene from a local viral isolate was utilized as the candidate vaccine for the development of oral live vaccines against ev71 using l. lactis as a carrier. we expressed fusion proteins in e. coli and purified fusion proteins were incubated with l. lactis. we confirmed that mice orally fed with l. lactis displaying these fusion proteins on ...201323476790
cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children: implications for vaccine development.recently, enterovirus 71 (ev71) has caused life-threatening outbreaks involving neurological and cardiopulmonary complications in asian children with unknown mechanism. ev71 has one single serotype but can be phylogenetically classified into 3 main genogroups (a, b and c) and 11 genotypes (a, b1∼b5 and c1∼c5). in taiwan, nationwide ev71 epidemics with different predominant genotypes occurred in 1998 (c2), 2000-2001 (b4), 2004-2005 (c4), and 2008 (b5). in this study, sera were collected to measur ...201323459633
neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71 genotype c4 inhibit infection at pre- and post-attachment steps.enterovirus 71 (ev71) is a major causative agent of hand, foot and mouth disease, which has been prevalent in asia-pacific regions, causing significant morbidity and mortality in young children. antibodies elicited by experimental ev71 vaccines could neutralize infection in vitro and passively protect animal models from lethal challenge, indicating that neutralizing antibodies play an essential role in protection. however, how neutralizing antibodies inhibit infection in vitro remains unclear.201323451250
human scarb2 transgenic mice as an infectious animal model for enterovirus 71.enterovirus 71 (ev71) and coxsackievirus (cva) are the most common causative factors for hand, foot, and mouth disease (hfmd) and neurological disorders in children. lack of a reliable animal model is an issue in investigating ev71-induced disease manifestation in humans, and the current clinical therapies are symptomatic. we generated a novel ev71-infectious model with hscarb2-transgenic mice expressing the discovered receptor human scarb2 (hscarb2). the challenge of hscarb2-transgenic mice wit ...201323451246
complete genome analysis of the c4 subgenotype strains of enterovirus 71: predominant recombination c4 viruses persistently circulating in china for 14 years.genetic recombination is a well-known phenomenon for enteroviruses. to investigate the genetic characterization and the potential recombination of enterovirus 71 (ev71) circulating in china, we determined the 16 complete genome sequences of ev71 isolated from hand foot mouth disease (hfmd) patients during the large scale outbreak and non-outbreak years since 1998 in china. the full length genome sequences of 16 chinese ev71 in present study were aligned with 186 genome sequences of ev71 availabl ...201323441179
the interplays between autophagy and apoptosis induced by enterovirus 71.enterovirus 71 (ev71) is the causative agent of human diseases with distinct severity, from mild hand, foot and mouth disease to severe neurological syndromes, such as encephalitis and meningitis. the lack of understanding of viral pathogenesis as well as lack of efficient vaccine and drugs against this virus impedes the control of ev71 infection. ev71 virus induces autophagy and apoptosis; however, the relationship between ev71-induced autophagy and apoptosis as well as the influence of autopha ...201323437282
subneutralizing antibodies to enterovirus 71 induce antibody-dependent enhancement of infection in newborn mice.antibody-dependent enhancement (ade) of virus infections can be induced by subneutralizing concentrations of specific antibodies. we recently demonstrated ade in human monocytes infected with enterovirus 71 (ev71). the current study was designed to extend these observations by determining the effect of ade on the pathogenesis of ev71 infection in newborn mice. we compared the clinical manifestations, mortality, virus titer, histopathology, and serum levels of cytokines and chemokines in newborn ...201323408291
antiviral activity of isatis indigotica root-derived clemastanin b against human and avian influenza a and b viruses in vitro.clemastanin b, 7s,8r,8'r-(-)-lariciresinol-4,4'-bis-o-β-d-glucopyranoside, is one of the major lignans extracted from isatis indigotica root (iir). in this study, the anti-influenza activities of clemastanin b were evaluated in vitro. clemastanin b was found to inhibit different subtypes of human (h1n1, including swine-origin h1n1; h3n2 and influenza b) and avian influenza viruses (h6n2, h7n3, h9n2) at different magnitudes of activity (ic50 0.087-0.72 mg/ml) while this compound was inactive agai ...201323403777
efficacy of alcohols and alcohol-based hand disinfectants against human enterovirus 71.human enterovirus 71 (hev71) infections are a significant public health threat in the asia-pacific region and occasionally cause severe neurological complications and even death in children. although good hand hygiene is important for controlling infection, relevant data regarding the efficacy of widely used hand disinfectants against hev71 are still lacking.201323399482
recombinant baculovirus associated with bilosomes as an oral vaccine candidate against hev71 infection in mice.human enterovirus 71 (hev71) is one of the major pathogen responsible for hand, foot and mouth disease (hfmd). currently no effective vaccine or antiviral drugs are available. like poliovirus, ev71 is transmitted mainly by the feco-oral route. to date the majority of the studied ev71 vaccine candidates are administered parenterally. injectable vaccines induce good systemic immunity but mucosal responses are often unsatisfactory, whereas mucosal vaccines provide both systemic and mucosal immunity ...201323390538
hexamethonium reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis.among enterovirus 71 infections, brainstem encephalitis progressing abruptly to cardiac dysfunction and pulmonary edema causes rapid death within several hours. however, no currently known early indicators and treatments can monitor or prevent the unexpectedly fulminant course. we investigate the possible mechanisms and treatment of fatal enterovirus 71 infections to prevent the abrupt progression to cardiac dysfunction and pulmonary edema by using an animal model.201323388515
development of a sensitive and specific epitope-blocking elisa for universal detection of antibodies to human enterovirus 71 strains.human enterovirus 71 (ev71) is a common cause of hand, foot and mouth disease (hfmd) in young children. it is often associated with severe neurological diseases and mortalities in recent outbreaks across the asia pacific region. currently, there is no efficient universal antibody test available to detect ev71 infections.201323383215
study of the integrated immune response induced by an inactivated ev71 vaccine.enterovirus 71 (ev71), a major causative agent of hand-foot-and-mouth disease (hfmd), causes outbreaks among children in the asia-pacific region. a vaccine is urgently needed. based on successful pre-clinical work, phase i and ii clinical trials of an inactivated ev71 vaccine, which included the participants of 288 and 660 respectively, have been conducted. in the present study, the immune response and the correlated modulation of gene expression in the peripheral blood mononuclear cells (pbmcs) ...201323372725
inhibition of enterovirus 71 infections and viral ires activity by fructus gardeniae and geniposide.fructus gardeniae has long been used by traditional chinese medical practitioners for its anti-inflammatory, anti-oxidant, anti-tumor and anti-hyperlipidemic characteristics. here we describe our finding that f. gardeniae greatly reduces anti-enterovirus 71 (ev71) activity, resulting in significant decreases in ev71 virus yields, ev71 infections, and internal ribosome entry site activity. we also found that geniposide, a primary f. gardeniae component, inhibited both ev71 replication and viral i ...201323353754
immunogenicity and safety of an enterovirus 71 vaccine in healthy chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial.enterovirus 71 (ev71) outbreaks are a socioeconomic burden, especially in the western pacific region. results of phase 1 clinical trials suggest an ev71 vaccine has a clinically acceptable safety profile and immunogenicity. we aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this ev71 vaccine in healthy chinese children.201323352749
enterovirus 71 infection cleaves a negative regulator for viral internal ribosomal entry site-driven translation.far-upstream element-binding protein 2 (fbp2) is an internal ribosomal entry site (ires) trans-acting factor (itaf) that negatively regulates enterovirus 71 (ev71) translation. this study shows that ev71 infection cleaved fbp2. live ev71 and the ev71 replicon (but not uv-inactivated virus particles) induced fbp2 cleavage, suggesting that viral replication results in fbp2 cleavage. the results also showed that virus-induced proteasome, autophagy, and caspase activity co-contribute to ev71-induced ...201323345520
breastfeeding, previous epstein-barr virus infection, enterovirus 71 infection, and rural residence are associated with the severity of hand, foot, and mouth disease.severe hand, foot, and mouth disease (hfmd) is likely to develop critical complications such as brainstem encephalitis, acute pulmonary edema, and circulatory failure, which cause child mortality during outbreaks. this study aims to investigate factors that predict the severity of hfmd. one hundred sixteen in-patient children with severe hfmd and 202 with mild hfmd were retrospectively enrolled. potential factors were collected for each child including sex, age, residence, modes of delivery, bir ...201323344210
excretion of enterovirus 71 in persons infected with hand, foot and mouth disease.hand, foot and mouth disease (hfmd) is a common illness in young children. it also can be seen in adults occasionally. enterovirus 71 (ev71), a pathogen that causes not only hfmd but also neurological complications and even death, has caused many hfmd outbreaks in china. however, till now the data about the duration of ev71 shedding is very limited.201323343115
strategies to develop antivirals against enterovirus 71.enterovirus 71 (ev71) is an important human pathogen which may cause severe neurological complications and death in children. the virus caused several outbreaks in the asia-pacific region during the past two decades and has been considered a significant public health problem in the post-poliovirus eradication era. unlike poliovirus, there is no effective vaccine or approved antivirals against ev71. to explore anti-ev71 agents therefore is of vital importance. several strategies have been employe ...201323339605
functional comparison of scarb2 and psgl1 as receptors for enterovirus 71.human scavenger receptor class b, member 2 (scarb2), and p-selectin glycoprotein ligand-1 (psgl1) have been identified to be the cellular receptors for enterovirus 71 (ev71). we compared the ev71 infection efficiencies of mouse l cells that expressed scarb2 (l-scarb2) and psgl1 (l-psgl1) and the abilities of scarb2 and psgl1 to bind to the virus. l-scarb2 cells bound a reduced amount of ev71 compared to l-psgl1 cells. however, ev71 could infect l-scarb2 cells more efficiently than l-psgl1 cells. ...201323302872
rupintrivir is a promising candidate for treating severe cases of enterovirus-71 infection: evaluation of antiviral efficacy in a murine infection model.enterovirus-71 (ev71) infections can cause life-threatening diseases with neurological symptoms. currently, no direct targeting antivirals are available to combat severe ev71 infection. rupintrivir (ag7088) is a compound originally designed for rhinovirus 3c protease. previous computational analyses by us and crystallography studies by others suggested that rupintrivir is also a high affinity inhibitor to ev71 3c. thus, we aimed to further evaluate its anti-ev71 activity in vivo at clinically ac ...201323295352
enterovirus 71 infection increases expression of interferon-gamma-inducible protein 10 which protects mice by reducing viral burden in multiple tissues.enterovirus 71 (ev71) infection has induced fatal encephalitis in thousands of young children in the asia-pacific region over the last decade. ev71 infection continues to cause serious problems in areas with outbreaks, because vaccines and antiviral therapies are not available. lymphocytes are present in the brains of infected patients and mice, and they protect mice from infection by decreasing the viral burden. the chemokines responsible for recruiting lymphocytes to infected organs are yet to ...201323288420
antiviral drug discovery for the treatment of enterovirus 71 infections.enterovirus 71 (ev71) is a small, positive-sense, single-stranded rna virus in the genus enterovirus, family picornavirus. it causes hand, foot and mouth disease in infants and children, which in a small percentage of cases progresses to central nervous system infection, ranging from aseptic meningitis to fatal encephalitis. sporadic cases of ev71 infection occur throughout the world, but large epidemics have occurred recently in southeast asia and china. there are currently no approved vaccines ...201323261847
human enterovirus 71 strains in the background population and in hospital patients in finland.human enterovirus 71 (hev71) is a common cause of severe outbreaks of hand-foot- and mouth disease, aseptic meningitis and encephalitis in asian populations but has not caused such epidemics in all populations.201323261080
progress on the research and development of human enterovirus 71 (ev71) vaccines.enterovirus 71 (ev71) infections, which can cause severe complications, have become one of the serious public health issues in the western pacific region and china. to date, a number of pharmaceutical companies and institutes have initiated the research and development of ev71 vaccines as a countermeasure. as is the case with innovative vaccine development, there are several critical bottlenecks in ev71 vaccine development that must be overcome before the clinical trials, including the selection ...201323247645
quinacrine impairs enterovirus 71 rna replication by preventing binding of polypyrimidine-tract binding protein with internal ribosome entry sites.since the 1980s, epidemics of enterovirus 71 (ev71) and other enteroviruses have occurred in asian countries and regions, causing a wide range of human diseases. no effective therapy is available for the treatment of these infections. internal ribosome entry sites (iress) are indispensable for the initiation of translation in enteroviruses. several cellular factors, as well as the ribosome, are recruited to the conserved ires during this process. quinacrine intercalates into the rna architecture ...201323301007
changing aetiology of hand, foot and mouth disease in linyi, china, 2009-2011.millions of hand, foot and mouth disease cases occur annually and the disease is considered a significant public health threat in china. we have focused on linyi for 3 years to analyse the aetiological spectrum and epidemic changes. the reported number of cases of hfmd in linyi declined in 2011,with the percentage of hev71 dropping to 11%. although cva16 rose to 51% in 2011, the number of cva16 cases did not change significantly compared with the previous 2 years. other types of enteroviruses we ...201423910234
differential interferon pathway gene expression patterns in rhabdomyosarcoma cells during enterovirus 71 or coxsackievirus a16 infection.exposure of cells to type i interferon (ifn) induces an antiviral state that prevents viral infection, but viruses can utilize multiple tactics to antagonize the host immune system. enterovirus 71 (ev71) and coxsackievirus a16 (cva16) are two major pathogens that cause hand, foot, and mouth disease (hfmd), which is prevalent among children. we found that both ev71 and ca16 have different reactions to type i ifn pretreatment and induction patterns of type i ifn on rhabdomyosarcoma (rd) cells. fur ...201424735544
coxsackievirus a6 and enterovirus 71 causing hand, foot and mouth disease in cuba, 2011-2013.hand, foot and mouth disease (hfmd) is usually caused by coxsackievirus a16 or enterovirus 71 (ev71). between 2011 and 2013, hfmd cases were reported from different cuban provinces. a total of 42 clinical specimens were obtained from 23 patients. detection, identification and phylogenetic analysis of enterovirus-associated hfmd were carried out by virus isolation, specific enterovirus pcr and partial vp1 sequences. hev was detected in 11 hfmd cases. emerging genetic variants of coxsackievirus a6 ...201424719197
development of a sandwich elisa for the quantification of enterovirus 71.since 2008, enterovirus 71 (ev71) has been responsible for high-mortality seasonal epidemics of hand, foot and mouth disease in china. currently many groups in the world are in the process of developing ev71 vaccines to combat this deadly disease. we have developed three ev71-specific monoclonal antibodies, and in this study we report the establishment of a fast and cost-effective sandwich elisa kit for measurement of virus concentration in ev71 vaccines using a pair of mouse anti-ev71 monoclona ...201423728855
molecular epidemiology of enterovirus 71, coxsackievirus a16 and a6 associated with hand, foot and mouth disease in spain.hand, foot and mouth disease (hfmd) is a childhood illness frequently caused by genotypes belonging to the enterovirus a species, including coxsackievirus (cv)-a16 and enterovirus (ev)-71. between 2010 and 2012, several outbreaks and sporadic cases of hfmd occurred in different regions of spain. the objective of the present study was to describe the enterovirus epidemiology associated with hfmd in the country. a total of 80 patients with hfmd or atypical rash were included. detection and typing ...201424033818
coxsackievirus a16: epidemiology, diagnosis, and vaccine.coxsackievirus 16 (ca16) is one of the major pathogens associated with hand, foot, and mouth disease (hfmd) in infants and young children. in recent years, ca16 and human enterovirus 71 (ev71) have often circulated alternatively or together in the western pacific region, which has become an important public health problem in this region. hfmd caused by ca16 infection is generally thought to be mild and self-limiting. however, recently several severe and fatal cases involving ca16 have been repor ...201424231751
cryo-electron microscopy study of insect cell-expressed enterovirus 71 and coxsackievirus a16 virus-like particles provides a structural basis for vaccine development.enterovirus 71 (ev71) and coxsackievirus a16 (ca16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (hfmd), a childhood illness with occasional severe neurological complications. a number of vaccine candidates against ev71 or ca16 have been reported; however, no vaccine is currently available for clinical use. here, we generated a secreted version of ev71 and ca16 virus-like particles (vlps) using a baculovirus-insect cell expression syst ...201424672036
a combination vaccine comprising of inactivated enterovirus 71 and coxsackievirus a16 elicits balanced protective immunity against both viruses.enterovirus 71 (ev71) and coxsackievirus a16 (ca16) are the two major causative agents of hand, foot and mouth disease (hfmd), which is an infectious disease frequently occurring in children. a bivalent vaccine against both ev71 and ca16 is highly desirable. in the present study, we compare monovalent inactivated ev71, monovalent inactivated ca16, and a combination vaccine candidate comprising of both inactivated ev71 and ca16, for their immunogenicity and in vivo protective efficacy. the two mo ...201424657161
improved detection limit in rapid detection of human enterovirus 71 and coxsackievirus a16 by a novel reverse transcription-isothermal multiple-self-matching-initiated amplification assay.rapid detection of human enterovirus 71 (ev71) and coxsackievirus a16 (cva16) is important in the early phase of hand-foot-and-mouth disease (hfmd). in this study, we developed and evaluated a novel reverse transcription-isothermal multiple-self-matching-initiated amplification (rt-imsa) assay for the rapid detection of ev71 and cva16 by use of reverse transcriptase, together with a strand displacement dna polymerase. real-time rt-imsa assays using a turbidimeter and visual rt-imsa assays to det ...201424648558
new coxsackievirus b4 genotype circulating in inner mongolia autonomous region, china.hand, foot, and mouth disease (hfmd) surveillance was initiated in the inner mongolia autonomous region of china in 2007, a crucial scrutiny for monitoring the prevalence of enterovirus serotypes associated with hfmd patients. however, this surveillance mostly focused on enterovirus 71 (ev-a71) and coxsackievirus a16; therefore, information on other enterovirus serotypes is limited. to identify the other circulating enterovirus serotypes in the hfmd outbreaks in inner mongolia in 2010, clinical ...201424595311
enterovirus infection in children attending two outpatient clinics in zhejiang province, china.enteroviruses are responsible for hand, foot, and mouth disease, and have caused many deaths in china during recent years. but the natural history of enterovirus infection in children, especially asymptomatic children, is not yet clear. from april 2011 to may 2012, 505 stool and throat swab samples of children attending outpatients clinics in two hospitals were collected weekly to test for enterovirus 71, coxsackievirus a16, and other enterovirus nucleic acids by real-time rt-pcr. two hundred si ...201424519430
dermatological spectrum of hand, foot and mouth disease from classical to generalized exanthema.hand, foot and mouth disease (hfmd) is classically defined as a childhood fever accompanied by a rash with vesicles or erosions of the oral mucosa, hands, feet and sometimes the buttocks. severe neurological complications are associated with enterovirus 71 outbreaks in asia. recently, it has been suggested that hfmd is related to coxsackie virus a6 (cv-a6) when there is an atypical rash. the objective of the study is to determine the dermatological pattern of hfmd and to identify the virus serot ...201424463804
hand, foot and mouth disease in guangdong, china, in 2013: new trends in the continuing epidemic.millions of incidents of hand, foot and mouth disease occur annually in china, with eva71 and cva16 as two major causative pathogens. a provincial surveillance system has been implemented in guangdong for almost 5 years to analyze the aetiological spectrum and epidemic changes. an unusual enterovirus type, cva6, was identified as the predominant serotype associated with an hfmd epidemic from late 2012 to 2013. in contrast to virus strains isolated before, all cva6/chn/2012-2013 strains segregate ...201424428125
prevalence of multiple enteroviruses associated with hand, foot, and mouth disease in shijiazhuang city, hebei province, china: outbreaks of coxsackieviruses a10 and b3.hand, foot, and mouth disease (hfmd) has been one of the most common infectious diseases in shijiazhuang city, as is the situation in china overall. in the national hfmd surveillance system, the pathogen detection was focused on ev-a71 and cva16, and therefore, information on the other evs is very limited. in order to identify the circulating ev serotypes in the hfmd outbreaks in shijiazhuang city during 2010-2012, 4045 patients presented with hfmd were recruited in the study, and clinical sampl ...201424392117
human enterovirus 71 uncoating captured at atomic resolution.human enterovirus 71 (ev71) is the major causative agent of severe hand-foot-and-mouth diseases (hfmd) in young children, and structural characterization of ev71 during its life cycle can aid in the development of therapeutics against hfmd. here, we present the atomic structures of the full virion and an uncoating intermediate of a clinical ev71 c4 strain to illustrate the structural changes in the full virion that lead to the formation of the uncoating intermediate prepared for rna release. alt ...201424352461
detection and characterization of viruses causing hand, foot and mouth disease from children in seri kembangan, malaysia.hand, foot and mouth disease (hfmd) is a common viral infection among infants and children. the major causative agents of hfmd are enterovirus 71 (ev71) and coxsackievirus a16 (cva16). recently, coxsackievirus a6 (cva6) infections were reported in neighboring countries. infected infants and children may present with fever, mouth/throat ulcers, rashes and vesicles on hands and feet. moreover, ev71 infections might cause fatal neurological complications. since 1997, ev71 caused fatalities in saraw ...201425776590
first isolation and genomic characterization of enterovirus a71 and coxsackievirus a16 from hand foot and mouth disease patients in the lao pdr.enterovirus a71 (ev-a71) and coxsackievirus a16 (cv-a16) are major aetiological agents of hand, foot and mouth disease in asia. we established the first genomic characterization of strains isolated in 2011 from lao patients. isolates were related to ev-a71 genotype c4 and cv-a16 genotype b1a that circulated in neighbouring countries during the same period. this confirms the regional character of hand, foot and mouth disease epidemiology and makes plausible the occurrence of severe disease in the ...201425566395
evaluation of monovalent and bivalent vaccines against lethal enterovirus 71 and coxsackievirus a16 infection in newborn mice.enterovirus 71 (ev71) and coxsackievirus a16 (cva16) have caused severe epidemics of hand, foot and mouth disease (hfmd) in the asia pacific in recent years, particularly in infants and young children. this disease has become a serious public health problem, as no vaccines or antiviral drugs have been approved for ev71 and ca16 infections. in this study, we compared four monovalent vaccines, including formalin-inactivated ev71 virus (iev71), ev71 virus-like particles (vlps) (vev71), formalin-ina ...201425483672
[research advances in molecular epidemiology and vaccines of coxsackievirus a16].epidemics of hand, foot and mouth disease (hfmd) have mainly been caused by coxsackievirus a16 (cva16) and enterovirus a 71 (ev-a71), which circulated alternatively or together in the affected area. cva16 has caused numerous outbreaks and epidemics in multiple countries and geographical regions, and has become an important public health problem. based on an analysis of the complete vp1 coding region, all cva16 strains can be divided into genotypes a, b1, and b2. furthermore, genotype b1 can be d ...201425272607
the role of enterovirus 71 and coxsackievirus a strains in a large outbreak of hand, foot, and mouth disease in 2012 in changsha, china.during 2012, changsha experienced a large outbreak of hand, foot, and mouth disease (hfmd), resulting in 25,438 cases, including 42 severe cases and eight deaths.201425236389
long-term immunogenicity studies of formalin-inactivated enterovirus 71 whole-virion vaccine in macaques.enterovirus 71 (ev71) has caused epidemics of hand, foot and mouth diseases in asia during the past decades and no vaccine is available. a formalin-inactivated ev71 candidate vaccine (ev71vac) based on b4 subgenotype has previously been developed and found to elicit strong neutralizing antibody responses in mice and humans. in this study, we evaluated the long-term immunogenicity and safety of this ev71vac in a non-human primate model. juvenile macaques were immunized at 0, 3 and 6 weeks either ...201425197967
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