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  1. Fulltext Spatio-temporal analysis on enterovirus cases through integrated surveillance in Taiwan
    Chan TC, Hwang JS, Chen RH, King CC, Chiang PH
    BMC Public Health, 2014 Jan 08;14:11.
    PMID: 24400725 DOI: 10.1186/1471-2458-14-11
    BACKGROUND: Severe epidemics of enterovirus have occurred frequently in Malaysia, Singapore, Taiwan, Cambodia, and China, involving cases of pulmonary edema, hemorrhage and encephalitis, and an effective vaccine has not been available. The specific aim of this study was to understand the epidemiological characteristics of mild and severe enterovirus cases through integrated surveillance data.

    METHODS: All enterovirus cases in Taiwan over almost ten years from three main databases, including national notifiable diseases surveillance, sentinel physician surveillance and laboratory surveillance programs from July 1, 1999 to December 31, 2008 were analyzed. The Pearson's correlation coefficient was applied for measuring the consistency of the trends in the cases between different surveillance systems. Cross correlation analysis in a time series model was applied for examining the capability to predict severe enterovirus infections. Poisson temporal, spatial and space-time scan statistics were used for identifying the most likely clusters of severe enterovirus outbreaks. The directional distribution method with two standard deviations of ellipse was applied to measure the size and the movement of the epidemic.

    RESULTS: The secular trend showed that the number of severe EV cases peaked in 2008, and the number of mild EV cases was significantly correlated with that of severe ones occurring in the same week [r = 0.553, p 

    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  2. [Encephalomyelitis caused by enterovirus type 71 in children]
    Koroleva GA, Lukashev AN, Khudiakova LV, Mustafina AN, Lashkevich VA
    Vopr. Virusol., 2010 Nov-Dec;55(6):4-10.
    PMID: 21381332
    Enterovirus type 71 (EV71) is a causative agent of large outbreaks of hand, foot, and mouth disease (HFMD) in Europe (Bulgaria, 1975; Hungary, 1978) and South-East Asia (Malaysia, 1977; Taiwan, 1998; Singapore, 2000-2007; People's Republic of China, 2007-2009). HFMD afflicted children less than 10 years of age and resulted in recovery within 3-7 days. In a small percentage of infants (aged 6 months to 3 years), HFMD was accompanied by acute neurological complications, such as serous meningitis, poliomyelitis-like syndrome (extremity pareses and muscle paralyses); brain stem encephalitis (myoclonic jerks, tremor, lethargy, swallowing and speech disorders, cardiopulmonary failure, pulmonary edema, shock, coma, death). X-ray study revealed pulmonary hemorrhages and edema. Mortality rates were as high as 82-94% in severe cases. Incapacitating motor, respiratory, and psychoemotional disorders persisted in some surviving children. Pathomorphologically, patients with central nervous system disease and cardiopulmonary failure were found to have acute inflammation of the grey matter of the brain stem (medulla oblongata, pons) and spinal cord. Inflammatory changes in the lung and myocardial tissues were negligible or absent. Fatal pulmonary edema was neurogenic in origin and resulted from damage to the respiratory and vasomotor centers of the brain stem.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  3. Development of a sandwich ELISA to detect virus-like-particles in enterovirus A71 vaccines
    Lim PY, Cardosa MJ
    J Virol Methods, 2019 08;270:113-119.
    PMID: 31100287 DOI: 10.1016/j.jviromet.2019.05.005
    The goal of this paper was to develop a sandwich ELISA that can detect intact human enterovirus A71 (EV-A71) virus-like particles (VLPs) in vaccines. This assay specifically detected EV-A71 viruses from different sub-genogroups as well as EV-A71 VLPs, and treatment of VLPs with high heat and low pH reduced or completely abolished detection of the VLPs suggesting that the ELISA detected assembled particles. Using a purified VLP as a reference standard, a quantitative sandwich ELISA (Q-ELISA) was established which was used to monitor the yield and purity of the VLPs during manufacturing. Coupled with immunogenicity studies, the Q-ELISA was used to evaluate the performance of the VLPs and formalin-inactivated EV-A71 vaccine. This assay has the potential to play an important role in the development of an efficient process to produce and purify the VLPs and in examining the quality of EV-A71 vaccines.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  4. Fulltext Characterization of Plaque Variants and the Involvement of Quasi-Species in a Population of EV-A71
    Mandary MB, Masomian M, Ong SK, Poh CL
    Viruses, 2020 Jun 17;12(6).
    PMID: 32560288 DOI: 10.3390/v12060651
    Viral plaque morphologies in human cell lines are markers for growth capability and they have been used to assess the viral fitness and selection of attenuated mutants for live-attenuated vaccine development. In this study, we investigate whether the naturally occurring plaque size variation reflects the virulence of the variants of EV-A71. Variants of two different plaque sizes (big and small) from EV-A71 sub-genotype B4 strain 41 were characterized. The plaque variants displayed different in vitro growth kinetics compared to the parental wild type. The plaque variants showed specific mutations being present in each variant strain. The big plaque variants showed four mutations I97L, N104S, S246P and N282D in the VP1 while the small plaque variants showed I97T, N237T and T292A in the VP1. No other mutations were detected in the whole genome of the two variants. The variants showed stable homogenous small plaques and big plaques, respectively, when re-infected in rhabdomyosarcoma (RD) and Vero cells. The parental strain showed faster growth kinetics and had higher viral RNA copy number than both the big and small plaque variants. Homology modelling shows that both plaque variants have differences in the structure of the VP1 protein due to the presence of unique spontaneous mutations found in each plaque variant This study suggests that the EV-A71 sub-genotype B4 strain 41 has at least two variants with different plaque morphologies. These differences were likely due to the presence of spontaneous mutations that are unique to each of the plaque variants. The ability to maintain the respective plaque morphology upon passaging indicates the presence of quasi-species in the parental population.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
  5. Fulltext Enterovirus 71 can directly infect the brainstem via cranial nerves and infection can be ameliorated by passive immunization
    Tan SH, Ong KC, Wong KT
    J. Neuropathol. Exp. Neurol., 2014 Nov;73(11):999-1008.
    PMID: 25289894 DOI: 10.1097/NEN.0000000000000122
    Enterovirus 71 (EV71)-associated hand, foot, and mouth disease may be complicated by encephalomyelitis. We investigated EV71 brainstem infection and whether this infection could be ameliorated by passive immunization in a mouse model. Enterovirus 71 was injected into unilateral jaw/facial muscles of 2-week-old mice, and hyperimmune sera were given before or after infection. Harvested tissues were studied by light microscopy, immunohistochemistry, in situ hybridization, and viral titration. In unimmunized mice, viral antigen and RNA were detected within 24 hours after infection only in ipsilateral cranial nerves, motor trigeminal nucleus, reticular formation, and facial nucleus; viral titers were significantly higher in the brainstem than in the spinal cord samples. Mice given preinfection hyperimmune serum showed a marked reduction of ipsilateral viral antigen/RNA and viral titers in the brainstem in a dose-dependent manner. With optimum hyperimmune serum given after infection, brainstem infection was significantly reduced in a time-dependent manner. A delay in disease onset and a reduction of disease severity and mortality were also observed. Thus, EV71 can directly infect the brainstem, including the medulla, via cranial nerves, most likely by retrograde axonal transport. This may explain the sudden cardiorespiratory collapse in human patients with fatal encephalomyelitis. Moreover, our results suggest that passive immunization may still benefit EV71-infected patients who have neurologic complications.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  6. Genetic diversity of enterovirus 71 isolated from cases of hand, foot and mouth disease in the 1997, 2000 and 2005 outbreaks, Peninsular Malaysia
    Chua KB, Chua BH, Lee CS, Chem YK, Ismail N, Kiyu A, et al.
    Malays J Pathol, 2007 Dec;29(2):69-78.
    PMID: 19108398
    All known field isolates of enterovirus 71 (EV71) can be divided into three distinct genogroups (A, B, C) and 10 subgenogroups (A, B1-5, C1-4) based on VP1 gene sequences. We examined VP1 gene sequences of 10, 12 and 11 EV71 strains isolated in peninsular Malaysia during the outbreaks of hand, foot and mouth disease in 1997, 2000 and 2005 respectively. Four EV71 strains isolated in the hand, foot and mouth disease outbreak of 2006 in Sarawak (Malaysian Borneo) were included to describe their genetic relationship. Four subgenogroups (C1, C2, B3 and B4) of EV71 co-circulated and caused the outbreak of hand, foot and mouth disease in peninsular Malaysia in 1997. Two subgenogroups (C1 and B4) were noted to cause the outbreak in 2000. In the 2005 outbreak, besides EV71 strains of subgenogroup C1, EV71 strains belonged to subgenogroup B5 were isolated but formed a cluster which was distinct from EV71 strains of the subgenogroup B5 isolated in 2003. The four EV71 strains isolated from clinical specimens of patients with hand, foot and mouth disease in the Sarawak outbreak in early 2006 also belonged to subgenogroup B5. Phylogenetic analysis of the VP1 gene sequences showed that the four Sarawak EV71 isolates belonged to the same cluster as the EV71 strains that were isolated in peninsular Malaysia as early as May 2005. The data suggested that the EV71 strains causing the outbreak in Sarawak could have originated from peninsular Malaysia.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
  7. Molecular phylogeny of modern coxsackievirus A16
    Perera D, Yusof MA, Podin Y, Ooi MH, Thao NT, Wong KK, et al.
    Arch Virol, 2007;152(6):1201-8.
    PMID: 17308978
    A phylogenetic analysis of VP1 and VP4 nucleotide sequences of 52 recent CVA16 strains demonstrated two distinct CVA16 genogroups, A and B, with the prototype strain being the only member of genogroup A. CVA16 G-10, the prototype strain, showed a nucleotide difference of 27.7-30.2% and 19.9-25.2% in VP1 and VP4, respectively, in relation to other CVA16 strains, which formed two separate lineages in genogroup B with nucleotide variation of less than 13.4% and less than 16.3% in VP1 and VP4, respectively. Lineage 1 strains circulating before 2000 were later displaced by lineage 2 strains.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
  8. Fulltext Enterovirus 71 outbreak, Brunei
    AbuBakar S, Sam IC, Yusof J, Lim MK, Misbah S, MatRahim N, et al.
    Emerg Infect Dis, 2009 Jan;15(1):79-82.
    PMID: 19116058 DOI: 10.3201/eid1501.080264
    Enterovirus 71 (EV71) outbreaks occur periodically in the Asia-Pacific region. In 2006, Brunei reported its first major outbreak of EV71 infections, associated with fatalities from neurologic complications. Isolated EV71 strains formed a distinct lineage with low diversity within subgenogroup B5, suggesting recent introduction and rapid spread within Brunei.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  9. Fulltext A generic assay for whole-genome amplification and deep sequencing of enterovirus A71
    Tan le V, Tuyen NT, Thanh TT, Ngan TT, Van HM, Sabanathan S, et al.
    J Virol Methods, 2015 Apr;215-216:30-6.
    PMID: 25704598 DOI: 10.1016/j.jviromet.2015.02.011
    Enterovirus A71 (EV-A71) has emerged as the most important cause of large outbreaks of severe and sometimes fatal hand, foot and mouth disease (HFMD) across the Asia-Pacific region. EV-A71 outbreaks have been associated with (sub)genogroup switches, sometimes accompanied by recombination events. Understanding EV-A71 population dynamics is therefore essential for understanding this emerging infection, and may provide pivotal information for vaccine development. Despite the public health burden of EV-A71, relatively few EV-A71 complete-genome sequences are available for analysis and from limited geographical localities. The availability of an efficient procedure for whole-genome sequencing would stimulate effort to generate more viral sequence data. Herein, we report for the first time the development of a next-generation sequencing based protocol for whole-genome sequencing of EV-A71 directly from clinical specimens. We were able to sequence viruses of subgenogroup C4 and B5, while RNA from culture materials of diverse EV-A71 subgenogroups belonging to both genogroup B and C was successfully amplified. The nature of intra-host genetic diversity was explored in 22 clinical samples, revealing 107 positions carrying minor variants (ranging from 0 to 15 variants per sample). Our analysis of EV-A71 strains sampled in 2013 showed that they all belonged to subgenogroup B5, representing the first report of this subgenogroup in Vietnam. In conclusion, we have successfully developed a high-throughput next-generation sequencing-based assay for whole-genome sequencing of EV-A71 from clinical samples.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
  10. Human enterovirus 71 subgenotype B3 lacks coxsackievirus A16-like neurovirulence in mice infection
    Chan YF, AbuBakar S
    Virol J, 2005;2:74.
    PMID: 16122396
    At least three different EV-71 subgenotypes were identified from an outbreak in Malaysia in 1998. The subgenotypes C2 and B4 were associated with the severe and fatal infections, whereas the B3 virus was associated with mild to subclinical infections. The B3 virus genome sequences had >= 85% similarity at the 3' end to CV-A16. This offers opportunities to examine if there are characteristic similarities and differences in virulence between CV-A16, EV-71 B3 and EV-71 B4 and to determine if the presence of the CV-A16-liked genes in EV-71 B3 would also confer the virus with a CV-A16-liked neurovirulence in mice model infection.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  11. Establishment of Asia-Pacific Network for Enterovirus Surveillance
    Chiu ML, Luo ST, Chen YY, Chung WY, Duong V, Dussart P, et al.
    Vaccine, 2020 01 03;38(1):1-9.
    PMID: 31679864 DOI: 10.1016/j.vaccine.2019.09.111
    Enteroviruses (EV), the major pathogens of hand, foot, and mouth disease (HFMD) and herpangina, affect millions of children each year. Most human enteroviruses cause self-limited infections except polioviruses, enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and several echoviruses (Echo) and coxsackieviruses (CV). Especially, EV-A71 has repeatedly caused large-scale outbreaks in the Asia-Pacific region since 1997. Some Asian countries have experienced cyclical outbreaks of severe EV-A71 infections and initiated development of EV-A71 vaccines. Five EV-A71 vaccine candidates have been clinically evaluated and three of them were approved for marketing in China. However, none of the China-approved products seek marketing approval in other countries. This situation supports a role for collaboration among Asian countries to facilitate clinical trials and licensure of EV-A71 vaccines. Additionally, enterovirus D68 outbreaks have been reported in the US and Taiwan currently and caused severe complications and deaths. Hence, an Asia-Pacific Network for Enterovirus Surveillance (APNES) has been established to estimate disease burden, understand virus evolution, and facilitate vaccine development through harmonizing laboratory diagnosis and data collection. Founded in 2017, the APNES is comprised of internationally recognized experts in the field of enterovirus in Asian countries working to raise awareness of this potentially fatal and debilitating disease. This article demonstrated the summaries of the first expert meeting, 2017 International Workshop on Enterovirus Surveillance and Vaccine Development, held by APNES in Taipei, Taiwan, March 2017.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  12. Fulltext Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005
    Van Tu P, Thao NTT, Perera D, Truong KH, Tien NTK, Thuong TC, et al.
    Emerg Infect Dis, 2007 Nov;13(11):1733-41.
    PMID: 18217559 DOI: 10.3201/eid1311.070632
    During 2005, 764 children were brought to a large children's hospital in Ho Chi Minh City, Vietnam, with a diagnosis of hand, foot, and mouth disease. All enrolled children had specimens (vesicle fluid, stool, throat swab) collected for enterovirus isolation by cell culture. An enterovirus was isolated from 411 (53.8%) of the specimens: 173 (42.1%) isolates were identified as human enterovirus 71 (HEV71) and 214 (52.1%) as coxsackievirus A16. Of the identified HEV71 infections, 51 (29.5%) were complicated by acute neurologic disease and 3 (1.7%) were fatal. HEV71 was isolated throughout the year, with a period of higher prevalence in October-November. Phylogenetic analysis of 23 HEV71 isolates showed that during the first half of 2005, viruses belonging to 3 subgenogroups, C1, C4, and a previously undescribed subgenogroup, C5, cocirculated in southern Vietnam. In the second half of the year, viruses belonging to subgenogroup C5 predominated during a period of higher HEV71 activity.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
  13. Fulltext Molecular epidemiology of enterovirus 71 infection in the central region of Taiwan from 2002 to 2012
    Wu WH, Kuo TC, Lin YT, Huang SW, Liu HF, Wang J, et al.
    PLoS One, 2013;8(12):e83711.
    PMID: 24391812 DOI: 10.1371/journal.pone.0083711
    Enterovirus 71 (EV71), a causative agent of hand, foot, and mouth disease can be classified into three genotypes and many subtypes. The objectives of this study were to conduct a molecular epidemiological study of EV71 in the central region of Taiwan from 2002-2012 and to test the hypothesis that whether the alternative appearance of different EV71 subtypes in Taiwan is due to transmission from neighboring countries or from re-emergence of pre-existing local strains. We selected 174 EV71 isolates and used reverse transcription-polymerase chain reaction to amplify their VP1 region for DNA sequencing. Phylogenetic analyses were conducted using Neighbor-Joining, Maximum Likelihood and Bayesian methods. We found that the major subtypes of EV71 in Taiwan were B4 for 2002 epidemic, C4 for 2004-2005 epidemic, B5 for 2008-2009 epidemic, C4 for 2010 epidemic and B5 for 2011-2012 epidemic. Phylogenetic analysis demonstrated that the 2002 and 2008 epidemics were associated with EV71 from Malaysia and Singapore; while both 2010 and 2011-2012 epidemics originated from different regions of mainland China including Shanghai, Henan, Xiamen and Gong-Dong. Furthermore, minor strains have been identified in each epidemic and some of them were correlated with the subsequent outbreaks. Therefore, the EV71 infection in Taiwan may originate from pre-existing minor strains or from other regions in Asia including mainland China. In addition, 101 EV71 isolates were selected for the detection of new recombinant strains using the nucleotide sequences spanning the VP1-2A-2B region. No new recombinant strain was found. Analysis of clinical manifestations showed that patients infected with C4 had significantly higher rates of pharyngeal vesicles or ulcers than patients infected with B5. This is the first study demonstrating that different EV 71 genotypes may have different clinical manifestations and the association of EV71 infections between Taiwan and mainland China.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification*
  14. Fulltext Comparative genetic analysis of VP4, VP1 and 3D gene regions of enterovirus 71 and coxsackievirus A16 circulating in Malaysia between 1997-2008
    Chan YF, Wee KL, Chiam CW, Khor CS, Chan SY, Amalina W MZ, et al.
    Trop Biomed, 2012 Sep;29(3):451-66.
    PMID: 23018509 MyJurnal
    Three genomic regions, VP4 capsid, VP1 capsid and 3D RNA polymerase of human enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) were sequenced to understand the evolution of these viruses in Malaysia. A total of 42 EV-71 and 36 CV-A16 isolates from 1997- 2008 were sequenced. Despite the presence of many EV-71 subgenotypes worldwide, only subgenotypes B3, B4, B5, C1 and C2 were present in Malaysia. Importation of other subgenotypes such as C3, C4/D and C5 from other countries was infrequent. For CV-A16, the earlier subgenotype B1 was replaced by subgenotypes B2a and the recent B2c. Subgenotype B2a was present throughout the study while B2c only emerged in 2005. No genetic signatures could be attributed to viral virulence suggesting that host factors have a major role in determining the outcome of infection. Only three EV-71 B3 isolates showed non-consistent phylogeny in the 3D RNA polymerase region which indicated occurrence of recombination in EV-71. High genetic diversity was observed in the Malaysian EV-71 but Malaysian CV-A16 showed low genetic diversity in the three genomic regions sequenced. EV-71 showed strong purifying selection, but that occurred to a lesser extent in CV-A16.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
  15. Fulltext Development of live attenuated Enterovirus 71 vaccine strains that confer protection against lethal challenge in mice
    Yee PTI, Tan SH, Ong KC, Tan KO, Wong KT, Hassan SS, et al.
    Sci Rep, 2019 03 18;9(1):4805.
    PMID: 30886246 DOI: 10.1038/s41598-019-41285-z
    Besides causing mild hand, foot and mouth infections, Enterovirus A71 (EV-A71) is associated with neurological complications and fatality. With concerns about rising EV-A71 virulence, there is an urgency for more effective vaccines. The live attenuated vaccine (LAV) is a more valuable vaccine as it can elicit both humoral and cellular immune responses. A miRNA-based vaccine strain (pIY) carrying let-7a and miR-124a target genes in the EV-A71 genome which has a partial deletion in the 5'NTR (∆11 bp) and G64R mutation (3Dp°l) was designed. The viral RNA copy number and viral titers of the pIY strain were significantly lower in SHSY-5Y cells that expressed both let-7a and miR-124a. Inhibition of the cognate miRNAs expressed in RD and SHSY-5Y cells demonstrated de-repression of viral mRNA translation. A previously constructed multiply mutated strain, MMS and the pIY vaccine strain were assessed in their ability to protect 4-week old mice from hind limb paralysis. The MMS showed higher amounts of IFN-γ ex vivo than the pIY vaccine strain. There was absence of EV-A71 antigen in the skeletal muscles and spinal cord micrographs of mice vaccinated with the MMS and pIY strains. The MMS and pIY strains are promising LAV candidates developed against severe EV-A71 infections.
    Matched MeSH terms: Enterovirus A, Human/isolation & purification
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