The largest outbreak of hand; foot and mouth disease in Singapore in 2008: The role of enterovirus 71 and coxsackievirus A strains

Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge 117597, Singapore.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases (Impact Factor: 2.33). 10/2010; 14(12):e1076-81. DOI: 10.1016/j.ijid.2010.07.006
Source: PubMed

ABSTRACT During 2008, Singapore experienced its largest ever outbreak of hand, foot and mouth disease (HFMD), resulting in 29686 cases, including four cases of encephalitis and one fatality.
A total of 51 clinical specimens from 43 patients with suspected HFMD at the National University Hospital, Singapore were collected for virus isolation and identification by reverse transcription polymerase chain reaction (RT-PCR) and sequencing.
Enteroviruses were identified in 34 samples (66.7%), with 11 samples (21.6%) being positive for enterovirus 71 (EV71). Other non-EV71 enteroviruses (including coxsackievirus A4, A6, A10, and A16) were identified in 23 samples (45.1%). The most prevalent virus serotypes were CA6, CA10, and EV71. CA6 and CA10 accounted for 35.3% of all HFMD cases, which may explain the high transmissibility and low fatality that characterized this unprecedented epidemic associated with relatively mild disease. Phylogenetic analyses of 10 circulating EV71 strains indicated that they belonged to two subgenogroups, i.e., B5 (80%) and C2 (20%). The VP1 sequences of the 2008 EV71 strains also exhibited continuous mutations during the outbreak, reflecting the relatively high mutation rate of the EV71 capsid protein, which may have implications for future vaccine development.
A safe and effective vaccine against EV71 is certainly warranted in view of its potential neurovirulence and its role in HFMD epidemics of recurring frequency with resultant fatalities in Asia, as well as other parts of the world.

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    • "Interestingly, there were only four cases of encephalitis and one fatality. The high transmissibility and low fatality of the Singapore HFMD epidemic might due to the dominance of CA6 and CA10 infection [Wu et al., 2010]. "
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    • "In most cases, this illness is mild and self-limiting, but more severe clinical symptoms may occur when there are complications, such as encephalitis, aseptic meningitis, and acute flaccid paralysis (Chen et al. 2007). HFMD is most frequently caused by Coxsackie virus A16 (CA16) and enterovirus 71 (EV71) (Zhang et al. 2009; Wu et al. 2010), among which EV71 is more commonly associated with severe symptoms, including central nervous system disorders and even deaths resulting from pulmonary edema in a small proportion of children, particularly those aged 5 years and younger (Zhang et al. Chun Chen, Hualiang Lin, and Xiaoquan Li contributed to this work equally. "
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    • "Over the last decade, HFMD has become endemic in the Asia Pacific region with outbreaks occurring in Singapore, Malaysia, Japan and China every few years (WHO, 2011). After the eradication of poliovirus, EV71 has been regarded as the most important neurotropic enterovirus and a threat to global public health (Bible et al., 2007; Qiu, 2008; Wu et al., 2010). There are no specific antivirals or vaccines for EV71 infection and prevention is mainly achieved by disrupting virus transmission by surveillance, improved hygiene and temporary closure of childcare centers and schools during outbreaks . "
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    ABSTRACT: Human enterovirus 71 (EV71) has become a major public health threat across Asia Pacific. The virus causes hand, foot, and mouth disease which can lead to neurological complications in young children. There are no specific antivirals or vaccines against EV71 infection. The major neutralizing epitope of EV71 is located in the carboxy-terminal half of the VP1 protein at amino acid positions 215-219 (Lim et al., 2012). To study the immunogenicity of VP1 we have developed a baculovirus vector which displays VP1 as a type II transmembrane protein, providing an accessible C-terminus. Immunization of mice with this recombinant baculovirus elicited neutralizing antibodies against heterologous EV71 in an in vitro microneutralization assay. Passive protection of neonatal mice confirmed the prophylactic efficacy of the antisera. Additionally, EV71 specific T cell responses were stimulated. Taken together, our results demonstrate that the display of VP1 as a type II transmembrane protein efficiently stimulated both humoral and cellular immunities.
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