Recent advances in the molecular epidemiology and control of human enterovirus 71 infection
Highlights
► Human enterovirus 71 has emerged as a major cause of viral encephalitis in the Southeast Asia over the past fifteen years. ► Increased epidemic activity of HEV71 is associated with the regular emergence of new genetic lineages. ► The reason for this increase in HEV71 circulation remains unknown. ► Prevention of HEV71 epidemics is likely to require the development of an effective vaccine. ► Several candidate EV71 vaccines have recently been reported, several of which have been shown to be effective in animal models.
Introduction
Human enterovirus 71 (HEV71) is member of the Genus Enterovirus, Family Picornaviridae, which comprises a group of small, non-enveloped, positive sense single-stranded RNA viruses. HEV71 is a member of the Human Enterovirus A (HEVA) species, which cause hand-food-and-mouth disease (HFMD) in young children. However, infection with HEV71 carries an additional risk of acute neurological disease [1].
HEV71 has emerged as an important cause of viral encephalitis in the Southeast Asia in the past 15 years [2•]. A pattern of increased epidemic activity and endemic circulation of HEV71 has been observed in the region since 1997 and is associated with the regular emergence of new genetic lineages of HEV71. However, the reason for this increase in HEV71 circulation remains unknown.
In this article, I will review recent developments in the molecular epidemiology of HEV71 infection, in the development of animal models of HEV71 infection and in progress towards the development of HEV71 vaccines.
Section snippets
HEV71 genome structure
The 7.5 kb RNA genome of HEV71 has a single open reading frame (ORF) encoding a polyprotein, flanked by 5′ and 3′ untranslated regions (UTRs). The polyprotein is cleaved into 11 proteins: the four capsid proteins (P1 – VP1, VP2, VP3, VP4), and seven non-structural proteins (P2 – 2A, 2B, 2C; P3 – 3A, 3B, 3C, 3D) [1, 2•]. The 5′UTR of HEV71 contains six putative stem-loop structures [3, 4]. Stem-loop I is called the HEV71 cloverleaf and is involved in viral RNA synthesis [5], whilst stem-loops
Molecular epidemiology of HEV71
HEV71 was first isolated in California in 1969 from the stool of an infant with encephalitis [7]. For the next 28 years it caused relatively minor and infrequent epidemics [1]. However, in the past 15 years HEV71 has been associated with increasingly large epidemics in Southeast Asia [1, 2•, 8].
The highly variable sequences of the HEV71 VP1 gene have been used to group HEV71 isolates into four genogroups (A, B, C, D) [9, 10]. Virus isolates from the same genogroup have more than 92% nucleotide
Animal models of HEV71 infection and disease
One of the ongoing challenges in studying the pathogenesis of HEV71 infection is the lack of a suitable animal model. The most authentic animal model of HEV71 infection is the cynomolgus macaque model [38, 39, 40], which mimics human disease closely. However, owing to financial and ethical constraints, this model has not been used extensively. Therefore, several mouse models have been developed to allow investigations of pathogenesis and to perform efficacy studies of vaccines. Most of the
HEV71 vaccine research and development
Several strategies are currently being employed to develop a HEV71 vaccine. The most straightforward of these strategies is to develop inactivated whole virus vaccines, which have been found to confer good protection in animal models. Ong et al. [53] developed a formaldehyde inactivated whole virus vaccine from a mouse-adapted strain of a subgenogroup B3 clinical isolate and showed that active immunisation of infant outbred ICR mice provided complete protection against lethal challenge with the
Conclusion
Human enterovirus 71 (HEV71) has emerged as an important cause of viral encephalitis in the Southeast Asia over the past 15 years. Several distinct lineages from genogroups B and C of HEV71 have evolved and circulated widely in Southeast Asia during this time. Recent studies suggest that recombination events may be the primary driver in the evolution of new genetic lineages. There have been several recent reports of candidate HEV71 vaccines, including formalin-inactivated whole virus, DNA, SVP,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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Advances in anti-EV-A71 drug development research
2024, Journal of Advanced ResearchThe stability and immunogenicity of formalin-inactivated Enterovirus A71 whole virion vaccine after ten years of low temperature storage
2023, Journal of Microbiology, Immunology and InfectionSeparation and purification of highly infectious enterovirus A71 particles using a strong anion-exchange column
2022, Journal of Chromatography AEmergence of a non vaccine-cognate enterovirus A71 genotype C1 in mainland China
2021, Journal of InfectionCitation Excerpt :EV-A71 was first isolated in 1969 from the cerebrospinal fluid of a patient with encephalitis in California, USA. Since then, numerous outbreaks have occurred worldwide and multiple subgenotypes have been detected.6 In mainland China, EV-A71 C4 was the single predominant subgenotype since 20081, and thus the current licensed in-activated EV-A71 vaccines are all C4-based.