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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 Infections/prevention & control
Development of enterovirus 71 vaccines

Lee MS, Chang LY

Expert Rev Vaccines, 2010 Feb;9(2):149-56.
PMID: 20109026 DOI: 10.1586/erv.09.152

Enterovirus 71 (EV71) was first isolated in 1969 in California, USA. Several epidemic outbreaks with high mortality rates have occurred in European and Asian Countries (Bulgaria in 1975, Hungary in 1978, Malaysia in 1997, Taiwan in 1998 and China in 2008). EV71 CNS involvement may be associated with neurological sequelae, delayed neurodevelopment and reduced cognitive functioning. Since poliovirus was nearly eradicated by vaccination, EV71 is now considered as one of the top candidates for new vaccine development against human enteroviruses. Recently, several EV71 vaccine candidates, including live-attenuated virus, inactivated whole virus, recombinant viral protein, virus-like particle and DNA vaccines, have been evaluated in animals but no clinical trial has yet been conducted. Based on historical experiences with poliovirus vaccines and animal studies, the inactivated whole-virus vaccines are feasible and could be licensed readily, so these are targeted for preparing clinical trials in several organizations in Asia.

Matched MeSH terms: Enterovirus Infections/prevention & control*
Impact of genetic changes, pathogenicity and antigenicity on Enterovirus- A71 vaccine development

Yee PTI, Laa Poh C

Virology, 2017 06;506:121-129.
PMID: 28384566 DOI: 10.1016/j.virol.2017.03.017

Enterovirus-A71 (EV-A71) is an etiological agent of the hand, foot and mouth disease (HFMD). EV-A71 infection produces high fever and ulcers in children. Some EV-A71 strains produce severe infections leading to pulmonary edema and death. Although the protective efficacy of the inactivated vaccine (IV) was ≥90% against mild HFMD, there was approximately 80% protection against severe HFMD. The monovalent EV-A71 IV elicits humoral immunity but lacks long-term immunogenicity. Spontaneous mutations of the EV-A71 genome could lead to antigenicity changes and the virus may not be neutralized by antibodies elicited by the IV. A better alternative would be the live attenuated vaccine (LAV) that elicits cellular and humoral immunity. The LAV induces excellent antigenicity and chances of reversion is reduced by presence of multiple mutations which could reduce pathogenicity. Besides CV-A16, outbreaks have been caused by CV-A6 and CV-A10, hence the development of bivalent and trivalent vaccines is required.

Matched MeSH terms: Enterovirus Infections/prevention & control*
Fulltext Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease

Ong KC, Devi S, Cardosa MJ, Wong KT

J Virol, 2010 Jan;84(1):661-5.
PMID: 19864378 DOI: 10.1128/JVI.00999-09

Enterovirus 71 (EV71) causes childhood hand, foot, and mouth disease and neurological complications, and no vaccines or therapeutic drugs are currently available. Formaldehyde-inactivated whole-virus vaccines derived from EV71 clinical isolates and a mouse-adapted virus (MAV) were tested in a mouse model of EV71 encephalomyelitis. After only two immunizations, given to mice at 1 and 7 days of age, the MAV vaccine protected mice at 14 days of age from disease. Tissues from immunized mice were negative for virus by viral culture, reverse transcriptase PCR, immunohistochemistry analysis, and in situ hybridization. Cross-neutralizing EV71 antibodies to strains with genotypes B3, B4, and C1 to C5 generated in immunized adult mice were able to passively protect 14-day-old mice from disease.

Matched MeSH terms: Enterovirus Infections/prevention & control*
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 Infections/prevention & control*
Fulltext Immunization with recombinant enterovirus 71 viral capsid protein 1 fragment stimulated antibody responses in hamsters

Ch'ng WC, Stanbridge EJ, Wong KT, Ong KC, Yusoff K, Shafee N

Virol J, 2012;9:155.
PMID: 22877087 DOI: 10.1186/1743-422X-9-155

Enterovirus 71 (EV71) causes severe neurological diseases resulting in high mortality in young children worldwide. Development of an effective vaccine against EV71 infection is hampered by the lack of appropriate animal models for efficacy testing of candidate vaccines. Previously, we have successfully tested the immunogenicity and protectiveness of a candidate EV71 vaccine, containing recombinant Newcastle disease virus capsids that display an EV71 VP1 fragment (NPt-VP11-100) protein, in a mouse model of EV71 infection. A drawback of this system is its limited window of EV71 susceptibility period, 2 weeks after birth, leading to restricted options in the evaluation of optimal dosing regimens. To address this issue, we have assessed the NPt-VP11-100 candidate vaccine in a hamster system, which offers a 4-week susceptibility period to EV71 infection. Results obtained showed that the NPt-VP11-100 candidate vaccine stimulated excellent humoral immune response in the hamsters. Despite the high level of antibody production, they failed to neutralize EV71 viruses or protect vaccinated hamsters in viral challenge studies. Nevertheless, these findings have contributed towards a better understanding of the NPt-VP11-100 recombinant protein as a candidate vaccine in an alternative animal model system.

Matched MeSH terms: Enterovirus Infections/prevention & control
Fulltext Immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy Chinese children: a report of further observations

Liu L, Mo Z, Liang Z, Zhang Y, Li R, Ong KC, et al.

BMC Med, 2015;13:226.
PMID: 26381232 DOI: 10.1186/s12916-015-0448-7

To investigate the long-term effects on immunity of an inactivated enterovirus 71 (EV71) vaccine and its protective efficacy.

Matched MeSH terms: Enterovirus Infections/prevention & control*
Non-clinical safety assessment of repeated intramuscular administration of an EV-A71 VLP vaccine in rabbits

Salmons B, Lim PY, Djurup R, Cardosa J

Vaccine, 2018 10 29;36(45):6623-6630.
PMID: 30293762 DOI: 10.1016/j.vaccine.2018.09.062

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.

Matched MeSH terms: Enterovirus Infections/prevention & control*
Partial protection against enterovirus 71 (EV71) infection in a mouse model immunized with recombinant Newcastle disease virus capsids displaying the EV71 VP1 fragment

Ch'ng WC, Stanbridge EJ, Ong KC, Wong KT, Yusoff K, Shafee N

J Med Virol, 2011 Oct;83(10):1783-91.
PMID: 21837796 DOI: 10.1002/jmv.22198

Enterovirus 71 (EV71) infection may cause severe neurological complications, particularly in young children. Despite the risks, there are still no commercially available EV71 vaccines. Hence, a candidate vaccine construct, containing recombinant Newcastle disease virus capsids that display an EV71 VP1 fragment (NPt-VP1(1-100) ) protein, was evaluated in a mouse model of EV71 infection. Previously, it was shown that this protein construct provoked a strong immune response in vaccinated adult rabbits. That study, however, did not address the issue of its effectiveness against EV71 infection in young animals. In the present study, EV71 viral challenge in vaccinated newborn mice resulted in more than 40% increase in survival rate. Significantly, half of the surviving mice fully recovered from their paralysis. Histological analysis of all of the surviving mice revealed a complete clearance of EV71 viral antigens from their brains and spinal cords. In hind limb muscles, the amounts of the antigens detected correlated with the degrees of tissue damage and paralysis. Findings from this study provide evidence that immunization with the NPt-VP1(1-100) immunogen in a newborn mouse model confers partial protection against EV71 infection, and also highlights the importance of NPt-VP1(1-100) as a possible candidate vaccine for protection against EV71 infections.

Matched MeSH terms: Enterovirus Infections/prevention & control*
Immunogenicity of a truncated enterovirus 71 VP1 protein fused to a Newcastle disease virus nucleocapsid protein fragment in mice

Ch'ng WC, Saw WT, Yusoff K, Shafee N

Acta Virol., 2011;55(3):227-33.
PMID: 21978156

Enterovirus 71 (EV71) is one of the viruses that cause hand, foot and mouth disease. Its viral capsid protein 1 (VP1), which contains many neutralization epitopes, is an ideal target for vaccine development. Recently, we reported the induction of a strong immune response in rabbits to a truncated VP1 fragment (Nt-VP1t) displayed on a recombinant Newcastle disease virus (NDV) capsid protein. Protective efficacy of this vaccine, however, can only be tested in mice, since all EV71 animal models thus far were developed in mouse systems. In this study, we evaluated the type of immune responses against the protein developed by adult BALB/c mice. Nt-VP1t protein induced high levels of VP1 IgG antibody production in mice. Purified VP1 antigen stimulated activation, proliferation and differentiation of splenocytes harvested from these mice. They also produced significant levels of IFN-γ, a Th1-related cytokine. Taken together, Nt-VP1t protein is a potent immunogen in adult mice and our findings provide the data needed for testing of its protective efficacy in mouse models of EV71 infections.

Matched MeSH terms: Enterovirus Infections/prevention & control*
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 Infections/prevention & control
Fulltext Inhibition of enterovirus 71 (EV-71) infections by a novel antiviral peptide derived from EV-71 capsid protein VP1

Tan CW, Chan YF, Sim KM, Tan EL, Poh CL

PLoS One, 2012;7(5):e34589.
PMID: 22563456 DOI: 10.1371/journal.pone.0034589

Enterovirus 71 (EV-71) is the main causative agent of hand, foot and mouth disease (HFMD). In recent years, EV-71 infections were reported to cause high fatalities and severe neurological complications in Asia. Currently, no effective antiviral or vaccine is available to treat or prevent EV-71 infection. In this study, we have discovered a synthetic peptide which could be developed as a potential antiviral for inhibition of EV-71. Ninety five synthetic peptides (15-mers) overlapping the entire EV-71 capsid protein, VP1, were chemically synthesized and tested for antiviral properties against EV-71 in human Rhabdomyosarcoma (RD) cells. One peptide, SP40, was found to significantly reduce cytopathic effects of all representative EV-71 strains from genotypes A, B and C tested, with IC(50) values ranging from 6-9.3 µM in RD cells. The in vitro inhibitory effect of SP40 exhibited a dose dependent concentration corresponding to a decrease in infectious viral particles, total viral RNA and the levels of VP1 protein. The antiviral activity of SP40 peptide was not restricted to a specific cell line as inhibition of EV-71 was observed in RD, HeLa, HT-29 and Vero cells. Besides inhibition of EV-71, it also had antiviral activities against CV-A16 and poliovirus type 1 in cell culture. Mechanism of action studies suggested that the SP40 peptide was not virucidal but was able to block viral attachment to the RD cells. Substitutions of arginine and lysine residues with alanine in the SP40 peptide at positions R3A, R4A, K5A and R13A were found to significantly decrease antiviral activities, implying the importance of positively charged amino acids for the antiviral activities. The data demonstrated the potential and feasibility of SP40 as a broad spectrum antiviral agent against EV-71.

Matched MeSH terms: Enterovirus Infections/prevention & control

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