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Coxsackievirus B3 (CVB3) is the pathogen causing hand, foot and mouth disease (HFMD), which manifests across a spectrum of clinical severity from mild to severe. However, CVB3-infected mouse models mainly demonstrate viral myocarditis and pancreatitis, failing to replicate human HFMD symptoms. Although several enteroviruses have been evaluated in Syrian hamsters and rhesus monkeys, there is no comprehensive data on CVB3. In this study, we have first tested the susceptibility of Syrian hamsters to CVB3 infection via different routes. The results showed that Syrian hamsters were successfully infected with CVB3 by intraperitoneal injection or nasal drip, leading to nasopharyngeal colonization, acute severe pathological injury, and typical HFMD symptoms. Notably, the nasal drip group exhibited a longer viral excretion cycle and more severe pathological damage. In the subsequent study, rhesus monkeys infected with CVB3 through nasal drips also presented signs of HFMD symptoms, viral excretion, serum antibody conversion, viral nucleic acids and antigens, and the specific organ damages, particularly in the heart. Surprisingly, there were no significant differences in myocardial enzyme levels, and the clinical symptoms resembled those often associated with common, mild infections. In summary, the study successfully developed severe Syrian hamsters and mild rhesus monkey models for CVB3-induced HFMD. These models could serve as a basis for understanding the disease pathogenesis, conducting pre-trial prevention and evaluation, and implementing post-exposure intervention. [ABSTRACT FROM AUTHOR]

Abstract A candidate hand, foot, and mouth disease vaccine comprising of human enterovirus A71 (EV-A71) virus-like particles (VLPs) was tested in rabbits to evaluate the potential local and systemic effects of this vaccine. The rabbits received more than double the full human dose and one additional dose according to the n + 1 recommended scheme. The three doses were given mixed with Alhydrogel adjuvant as intramuscular (IM) injections. Vaccinations were well-tolerated, with no indication of overt toxicity in any parameter observed. An EV-A71 specific immune response in the form of antibodies that specifically reacted with the virus capsid proteins VP1 and VP0, the complete VLP, and EV-A71 viruses of different subgenotypes to that of the vaccine could be demonstrated. A boosting effect in the form of higher EV-A71 specific antibody titers was observed after the subsequent doses, and these enhanced titers were shown to be statistically significant in one-way ANOVA analyses. Fortnightly intramuscular administration of EV-A71 VLP vaccine did not result in any test article-related changes in immunotoxicity as defined by increased serum IL-6, and in general IL-6 concentrations remained below the lower limit of quantitation for the majority of animals throughout the study. Although increased indicators of inflammation at the injection site were observed in animals sacrificed immediately after the last vaccination, these largely reversed at the end of the recovery phase. No findings suggestive of systemic or delayed toxicity were recorded in this independently conducted study. In conclusion, repeated IM administration of the EV-A71 VLP vaccine were locally and systemically well-tolerated in rabbits and immunogenic, supporting the clinical development of the vaccine. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) remain the predominant etiological agents of hand, foot, and mouth disease (HFMD). The clinical manifestations caused by the two viruses are obviously different. CV-A16 usually triggers a repeated infection, and airway epithelial integrity is often the potential causative factor of respiratory repeated infections. Our previous studies have demonstrated that there were some differentially expressed miRNAs involved in the regulation of adhesion function of epithelial barrier in EV-A71 and CV-A16 infections. In this study, we compared the differences between EV-A71 and CV-A16 infections on the airway epithelial barrier function in human bronchial epithelial (16HBE) cells and further screened the key miRNA which leaded to the formation of these differences. Our results showed that more rapid proliferation, more serious destruction of 16HBE cells permeability, more apoptosis and disruption of intercellular adhesion-associated molecules were found in CV-A16 infection as compared to EV-A71 infection. Furthermore, we also identified that microRNA-4516 (miR-4516), which presented down-regulation in EV-A71 infection and up-regulation in CV-A16 infection was an important regulator of intercellular junctions by targeting Poliovirus receptor related protein 1(PVRL1). The expressions of PVRL1, claudin4, ZO-1 and E-cadherin in CV-A16-infected cells were significantly less than those in EV-A71-infected cells, while the expressions of these proteins were subverted when pre-treated with miR-4516-overexpression plasmid in EV-A71 infected and miR-4516-knockdown plasmid in CV-A16 infected 16HBE cells. Thus, these data suggested that the opposite expression of miR-4516 in EV-A71 and CV-A16 infections might be the initial steps leading to different epithelial impairments of 16HBE cells by destroying intercellular adhesion, which finally resulted in different outcomes of EV-A71 and CV-A16 infections. [ABSTRACT FROM AUTHOR]

Highlights: [•] A description of the VP1 gene diversity and polymorphism in the Asia-Pacific area. [•] Analyses of the characteristics of the VP1 gene and protein and their function. [•] Analyses of the VP1 evolutional dynamics from 1994 to 2013. [ABSTRACT FROM AUTHOR]

Abstract: Background: In 2010, China experienced the largest outbreak on record of Enterovirus 71 (EV71)-associated Hand Foot and Mouth Disease (HFMD) with more than 1.7 million cases, 27,000 patients with severe neurological complications and 905 deaths. Understanding of the seroprevalence of neutralizing antibodies (NAb) against EV71 and their protective role against HFMD in children is crucial for the implementation of future therapeutic and prophylactic intervention. Objectives: To correlate the prevalence of NAb against EV71 genotype C4a in children prior to the 2011 epidemic season with severe EV71-associated HFMD disease during the subsequent 2011 epidemic season. Study design: 614 sera samples were collected from children without HFMD. EV71 NAb were tested by a quantitative PCR assay. Samples with NAb ≥1:8 were scored as positive. Results: 122 (19.9%) of 614 sera were EV71-seropositive. The NAb seroprevalence was highest in infants 0–5 months of age (28.6%) and lowest in children 1–1.9 years of age (13.4%). 64.1% of severe EV71-associated HFMD occurred in children 1–2.9 years. Conclusions: Despite the large 2010 outbreak, the overall seroprevalence of EV71 in children is relatively low. The seropositive rate of EV71 NAb prior to the 2011 season was inversely correlated with the number of EV71-infected severe cases in 2011. Loss of maternal antibodies in infants and lack of acquired anti-EV71 immunity are responsible for increased proportion of severe HFMD in the 1–2 years age group. Our data suggest that future vaccination campaigns should be initiated as early as 6 months. [Copyright &y& Elsevier]