Review Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Virology. May 12, 2015; 4(2): 78-95
Published online May 12, 2015. doi: 10.5501/wjv.v4.i2.78
Therapeutic and prevention strategies against human enterovirus 71 infection
Chee Choy Kok, SEALS Microbiology, Level 4, Campus Centre, Prince of Wales Hospital, Randwick 2031 NSW, Australia
Author contributions: Kok CC solely contributed to this paper.
Conflict-of-interest: Kok CC is an employee of SEALS Microbiology. The author declares that there is no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Chee Choy Kok, PhD, SEALS Microbiology, Level 4, Campus Centre, Prince of Wales Hospital, Barker Street, Randwick 2031 NSW, Australia.
Telephone: +61-2-93829197 Fax: +61-2-93829180
Received: October 4, 2014
Peer-review started: October 5, 2014
First decision: October 28, 2014
Revised: November 21, 2014
Accepted: February 9, 2015
Article in press: February 11, 2015
Published online: May 12, 2015


Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved.

Key Words: Human enterovirus 71, Infection, Therapy, Prevention, Drugs, Vaccine

Core tip: This review focuses on therapeutic and prevention strategies for the control of human enterovirus 71 infection. Therapeutic strategies highlighted include natural products, synthetic antivirals, immunotherapy, and the use of olignucleotides. Prevention strategies such as surveillance, physical prevention, and vaccine development form the second part of the review.


Human enterovirus 71 (HEV71) is a member of the human enterovirus A species within the genus Enterovirus of the family Picornaviridae. It is a positive-stranded RNA virus of approximately 7500 nucleotides. The viral genome contains an open reading frame (ORF) encoding a polyprotein of 2194 amino acids. The ORF is divided into three regions: P1 encodes four structural proteins (VP1-VP4); P2 (2A-2C) and P3 (3A-3D) encode seven non-structural proteins. The ORF is flanked by 5’ and 3’ untranslated regions. A poly-A tail of variable length is covalently attached to the 3´ terminus of the genome[1].

Since its discovery in 1969, HEV71 has been iden tified as the cause of epidemics of hand-foot-and-mouth disease (HFMD) associated with severe neurological complications, including aseptic meningitis, brainstem encephalitis, acute flaccid paralysis and neurogenic pulmonary oedema, in children under five years of age[1]. There has been a large increase in HEV71 epidemic activity throughout the Asia-Pacific region since 1997. A large epidemic occurred in Taiwan in 1998, with 1.3 × 105 cases of HFMD, 405 cases of severe neurological disease and 78 fatalities attributed to HEV71 infection[2-4]. In 1999, a large HFMD outbreak occurred in Perth, Western Australia, with approximately 6 × 103 cases reported and 29 cases of severe neurological disease identified[5]. From 2008 to 2011, circulating HFMD outbreaks occurred throughout mainland China, increasing the annual number of HFMD cases from 488955 (126 deaths) to 1619706 (509 deaths)[6]. In 2010, the largest recorded outbreak of HEV71-associated HFMD occurred in the country, comprising more than 1.7 million cases, including 27000 patients who exhibited severe neurological complications, and 905 deaths[7]. Smaller epidemics have been detected in the United States and European countries, such as Austria, Germany, France, Norway, United Kingdom, Hungary and Greece[8-14].

The reasons for the emergence of HEV71 as a cause of large epidemics of HFMD and acute neurological disease in the Asia-Pacific region remain elusive. Upon successful completion of the WHO-sponsored eradication of poliomyelitis, HEV71 will become the extant neurotropic enterovirus of highest global public health significance. However there are currently no effective clinical therapies or vaccine for HEV71 associated HFMD. Symptoms such as fever, encephalitis and meningitis are eased by supportive medication. In some cases viral infections are treated with broad-spectrum antiviral drugs, including Ribavirin, Ganciclovir, and Acyclovir[15]. These common remedies only partially alleviate the symptoms instead of controlling the infections, and usually come with high cytotoxicity. Although ribavirin has been reported to inhibit virus production in vivo, a very high dose is used for treat ment, which may raise safety concerns. Other than symptomatic treatment, intravenous immunoglobulin (IVIG) is clinically used to neutralise the virus and to non-specifically suppress inflammation. Considering the morbidity and mortality caused by the disease, it is important to develop new specialised drugs and ultimately a safe and effective vaccine for the control of HEV71 infection. This review focuses on the efforts and progress towards development of effective therapeutic and prevention strategies.


In recent years, significant amount of effort has been made to develop antiviral drugs for the treatment of HEV71 associated HFMD. Promising candidates have been identified through the screening of natural therapeutic products, repositioning of existing antiviral drugs, as well as the development of new synthetic compounds. Many of these drugs show anti-HEV71 activity in vitro, and some have been evaluated in animal models. However, clinical application of these drugs is not yet available.

Natural therapeutic products

Natural therapeutic products have been used in many countries in Asia for centuries, and have gradually been adopted by Western medical treatment and health care[16,17]. The WHO estimates that approximately 80% of the global population still relies on traditional medicine for primary health care[18]. As such, the search for new bioactive molecules in plants is still an active part of pharmaceutical research in many key therapeutic areas, including immunosuppression and infectious disease[19]. Antiviral activities have been identified in several hundred natural compounds worldwide. Compared to synthetic pharmaceutical drugs, an advantage of natural molecules is the exclusion of extra chemical synthesis. This may reduce the cost of production, which is particularly attractive to affected patient population from low income countries.

Most natural therapeutic products work as a mixture, and thus it is difficult to characterise the detailed antiviral mechanisms and to further develop into effective clinical drugs. Up till recently, no single compound has been identified to potently inhibit HEV71. However, during the HFMD outbreaks in China, traditional Chinese medicines have demonstrated therapeutic efficacy by ameliorating the symptoms of the disease and/or shortening the course of the disease[20]. Most of the herbs with reported therapeutic effectiveness have been used traditionally or folklorically for inflammatory and/or infectious diseases. As disease outbreaks become more common in China, a significant increase of research in this area followed. Table 1 compares natural therapeutic products that have been well studied.

Table 1 Natural therapeutic products tested for anti-human enterovirus 71 activity.
Natural product (Group)TestedPossible mechanismAdvantagesDisadvantagesRef.
Hydrolysable Ellagitanninsin vitro/in vivoInhibit viral absorption/penetrationNo obvious side effectsWeak oral activity[21-30]
Flavonoidsin vitroInhibit viral RNA/protein synthesisLow escape mutantsMechanism not clear[18,31–35]
Alkaloidsin vitro/in vivoInhibit protein synthesisNo obvious side effectsMechanism not clear[36-38]
Deferoxaminein vitro/in vivoUpregulation of B cellsPrevious US FDA approval forN/A[39,40]
treatment of iron overload

Hydrolysable ellagitannins: The most widely published natural molecules in association with HEV71 infection are ellagitannins, from the family of hydrolysable tannins. Ellagitannins are characterised by the presence of one or more hexahydroxydiphenoyl (HHDP) unit(s) on a glucopyranose core. The HHDP group is biosynthetically formed through intramolecular, oxidative C-C bond formation between neighboring galloyl groups in galloylglucoses[21]. They are easily hydrolysed, either enzymatically or with acid, to liberate a stable ellagic acid as the dilactone form of hexahydroxydiphenic acid. Hydrolysable ellagitannins have previously shown medicinal values and antiviral effects[22-25].

Treatment with hydrolysable ellagitannins such as corilagin[26], geraniin[27], punicalagin[25] and chebulagic acid[28] enhanced the survival of HEV71-infected cells in vitro with low cytotoxicity. Further, geraniin, punicalagin and chebulagic acid was shown to greatly prolong the survival time and reduce mortality of HEV71-infected mice. Virus replication in the muscle of treated mice was shown to be significantly inhibited. In general, treatment did not cause any obvious side effects in the mice and full recovery was observed after two weeks. The antiviral mechanism of chebulagic acid against herpes simplex virus-1 (HSV-1) was previously published[22]. It was found to block interactions between cell surface glycosaminoglycans and HSV-1 glycoproteins, and could prevent binding, entry, and cell-to-cell spread, as well as secondary infection. Based on these observations, it is possible that chebulagic acid activity against HEV71 is related to the inhibition of viral absorption and/or entry. Further studies are required to elucidate the anti-HEV71 mechanism of hydrolysable ellagitannins, but results thus far suggest that they constitute a potential source for antiviral discovery, particularly in the field of HEV71 infection. Interestingly another hydrolysable tannin, punicalin, did not demonstrate obvious antiviral efficacy. This prompted the suggestion of key structural requirements for anti-HEV71 activity[28]. Although the in vitro antiviral activity of corilagin seemed promising, oral administration of corilagin was not shown to induce significant biological activity[29,30]. On the contrary, intraperitoneally administrated geraniin, punicalagin and chebulagic acid demonstrated good inhibitory effects on HEV71[25,27,28]. This may have been due to the difficulty in the absorption and metabolism of corilagin by intestinal microflora. The incubation of tannins with anaerobic microflora in faeces of animal led to the hydrolysis of the compound into metabolites including gallic acid and ellagic acid[30]. To circumvent this problem, in vivo studies using intravenous or intraperitoneal administration may be required.

Flavonoids: Another group of compounds commonly tested for anti-HEV71 activity are the flavonoids. Flavonoids are a broad class of low molecular weight secondary metabolites that are present in all vascular plants. The flavonoid structure is usually characterised by a C6-C3-C6 carbon skeleton[31]. These phenolic compounds are known to be responsible for the bioactivities of plant crude extracts to confer protection against UV radiation, pathogens, and herbivores[32]. Their relatively low toxicity and strong bioactive potential to increase human health prompted many studies in the field of pharmaceutical drug development.

Chrysosplenetin and penduletin[33], 7-hydro xyisoflavone[34], chrysin and its phosphate esther[18], epigenin and its analog luteoline[35], are flavonoids that have all been shown to exhibit in vitro anti-HEV71 activity. Experimental evidence indicated that these compounds could inhibit viral RNA and protein synthesis. To understand the mechanism of action, Zhu et al[33] attempted to select chrysosplenetin- and penduletin-resistant HEV71 through continuous passage in the presence of the compounds. However, after 13 passages, HEV71 remained sensitive to the compounds. Although the mechanism of action is still unclear, time-of-addition studies suggested that flavonoids function in post virus-attachment, during the early stages of virus infection[33-35].

Alkaloids: Alkaloids have also been shown to possess anti-HEV71 activities. Liu et al[36] found that lycorine, one of the most abundant alkaloids of Amaryllidaceae, inhibited HEV71 replication in cultured cells, and lycorine treatment significantly enhanced the survival rate of HEV71-infected mice. Further investigation suggested that the drug inhibits the elongation of viral polyprotein during protein synthesis, and may lead to imbalanced synthesis of viral proteins and interrupted packaging of the virus. Matrine, a quinolizidine alkaloid, is one of the main active components of the root of Chinese Sophora herb plants[37]. It proved effective in reducing the mortality rate of HEV71-infected mice[38]. Treatment with matrine delayed the appearance of paralysis, reduced the clinical scores and prevented other symptoms of the infected mice compared with that of the placebo. Virus replication in mouse muscle tissues was significantly decreased and no obvious side effects were observed.

Deferoxamine: Besides plants, marine microorganisms are also a major source for natural products[39]. Deferoxamine (DFO), a marine natural product derived from Streptomyces pilosus, was found to compensate for the decreased levels of B cells caused by HEV71 infection in mice, and to improve the levels of the neutralising antibodies against the virus[40]. The clinical symptoms, muscle damage and mortality were ameliorated by DFO treatment. Interestingly DFO did not significantly inhibit viral replication in Rhabdomyosarcoma (RD) cells. In contrast, viral replication in the muscle tissues of DFO-treated mice was slightly inhibited. These results suggested that the possible mechanism of DFO activity against HEV71 in infected mice was through the upregulation of B cells, and not the direct inhibition of HEV71.

Other natural products: Other natural products shown to exhibit antiviral activity against HEV71 include Glycyrrhiza spp. and its active component glycyrrhizic acid[20,41], Fructus gardenia and its primary component geniposide[42], chlorogenic acid[43], the Ganoderma lucidum triterpenoids, Lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy and Ganoderic acid Y[15], and hederasaponin B[44]. Whilst the in vitro results of these compounds looked promising, in vivo studies were not performed.

Synthetic antiviral compounds

A growing body of literature on synthetic anti-HEV71 drug development has been published in recent years, but most of these drugs are still in the early phase of development and need further optimisation of their pharmacokinetics and absorption, distribution, metabolism, excretion, and toxicity profiles. Ribavirin, a wide spectrum synthetic antiviral, was reported to reduce mortality caused by HEV71 in Institute for Cancer Research (ICR) mice[45]. However, the dosage used was much higher than the clinical recommended dosage prescribed to adults with Hepatitis C Virus (HCV) infection. Given that most HEV71 infections affect children younger than 5 years old, high dose of ribavirin may raise serious safety concerns.

The life cycle of HEV71 generally involves virus attachment, uncoating and entry, polyprotein translation and cleavage, viral RNA replication, and virus assembly. These critical steps are currently considered targets for synthetic antiviral development. Lead compounds that inhibit virus attachment, uncoating and entry are being actively pursued and may be used as potential prophylactic against HEV71, whereas inhibitors of post-infection stages may be suitable for treatment. Both pre- and post-infection inhibitors of HEV71 are discussed in detail below and further summarised in Table 2.

Table 2 Synthetic antiviral compounds tested for anti- human enterovirus 71 activity.
Synthetic antiviralsTestedMechanismAdvantagesDisadvantagesRef.
PleconarilIn vivoPrevents attachment by binding to viral capsidHigh oral availabilityVaried capacity of inhibition[47-49]
BPROZIn vitroPrevents attachment by binding to viral capsidHigh oral availabilityResistant mutants[49-54]
Soluble andIn vitroPrevents attachmentN/AN/A[55-57]
LactoferrinIn vitro / in vivoPrevents entry by binding to VP1/ cellular receptorNo obvious side effects (animal)Mechanism not clear[58-62]
SuraminIn vitroPrevents attachmentMay inhibit other multiple stages ofMechanism not clear[63]
HEV71 life cycle
Peptides (SP40)In vitroPrevents attachment by bindingSmall size, high activity/specificity,Low bioavailability[64-66]
to glycosaminoglycanslow toxicity
RupintrivirIn vitro /in vivoInhibits viral 3C proteinLow quantity, low toxicity,Lack efficacy in natural infection[67,68]
high barrier for drug resistace
DTrip-22In vitroInhibits viral 3D polymerase activityBroad spectrum activityN/A[69]
Aurintricarboxylic acidIn vitroInhibits viral 3D polymerase activityN/AN/A[76-81]
NITD008In vitro / in vivoInhibits viral 3D polymerase activityMore potent than ribavirin in vivoMay have toxicity issue, resistant mutants[82,83]
SorafenibIn vitroBlock virus induced activation of ERK/p38Licensed for cancer treatmentN/A[84,85]
signalling pathways

Pre-infection inhibitors: The most widely studied chemical structures amongst capsid binding molecules as antiviral agents for HEV71 are the series of “WIN” compounds[46]. Pleconaril (WIN 61893) was the first of a new generation of metabolically stable capsid function inhibitors. In a mouse model of infection following intracranial inoculation of enteroviruses, pleconaril reduced viral titres in all affected organs and prevented death in animals. Furthermore, there was high oral bioavailability in humans and other animals[47,48]. However, the HEV71 inhibition capacity of pleconaril could vary for different isolates of the virus. It was nearly ineffective in neutralising HEV71 isolates from the outbreak in Taiwan[49]. Using pleconaril as a template for computational drug design, a Taiwanese group succeeded in discovering a new class of pyridyl imidazolidinones with anti-HEV71 activity. A series of imidazolidinone derivatives, designated BPROZ (e.g., BPROZ-194, BPROZ-103 and BPROZ-074), demonstrated effectiveness against HEV71 infec tion[49-54]. Their therapeutic potential is still under active investigation.

The soluble form of HEV71 receptors, SCARB2 and PSGL-1, has been shown to block virus-host interaction[55,56]. It was proposed that these soluble receptors could act as molecular decoys of cell-associated receptors[57]. Antibodies against these receptors have also been shown to inhibit in vitro virus infection[55,56]. However, further studies are required to determine the potential of these molecules as therapeutic antivirals. In their study, Weng et al[58] demonstrated that lactoferrin (LF) inhibited HEV71 infection in vitro and in vivo by binding to the VP1 protein of HEV71, as well as to host cells. The anti-HEV71 mechanism of LF is unclear, but may relate to the prevention of viral entry by blocking cellular receptors and/or by direct binding to the virus particles, as suggested by the above finding. Binding of LF to several different cell ligands such as heparan sulfate, chondroitin sulphate and nucleolin has been reported[59-61]. However, antiviral activity of LF analogues is only partly related to their affinity for heparin sulfate[62]. Although lactoferrin has not been approved for therapeutic purposes, it could be considered an agent for preventing virus entry. Another group of researchers screened a library of compounds and identified suramin as having the ability to inhibit HEV71 proliferation by blocking the attachment of HEV71 to host cells, as well as affect other steps of the HEV71 life cycle[63].

Peptides have also been used as therapeutic agents to block viral attachment or entry into host cells. A major advantage is their small size and their high activity and specificity when compared to antibodies and other larger molecules. Peptides accumulate in lesser quantity in tissues, and have very low cell toxicity when compared to synthetic molecules[64]. A 15-mer peptide spanning from position 118 to 132 in the VP1 capsid region, SP40, exhibited antiviral activity in all three genotypes of HEV71 (genotypes A, B and C), coxsackievirus A16 (CVA16) and poliovirus Mahoney (PV1)[65]. It also reduced viral induced CPE and viral RNA synthesis in Vero, HeLa and HT-29 cell lines in a dose-dependent manner. Data from further research suggested that the SP40 peptide could have interacted with cell surface glycosaminoglycans and prevented HEV71 attachment. A major disadvantage of peptides is their low bioavailability due to their rapid degradation in the gastrointestinal system. To circumvent this issue, new formulations such as the D-isomer peptide[64], addition of N-terminal pyroglutamate and C-terminal homoserine lactone to the peptide, are being developed to improve the resistance to peptidase[66].

Attachment and entry inhibitors stop the virus from entering cells, and therefore may be useful as prophylactic agents. However, a major obstacle of this approach is for it to be cost-effective for resource-limited countries where large outbreaks frequently occur. Furthermore, the effectiveness of the drug itself would be highly dependent on the timing of the treatment provided. It is a challenge to deliver a sufficient amount of the inhibitor to the targeted site early enough to prevent disease progression, or to prevent the spread of infection to others.

Post-infection inhibitors: Various synthetic antiviral compounds were designed to target post-entry stages of the HEV71 life-cycle. The anti-HEV71 activity of rupintrivir, an irreversible peptidomimetic inhibitor of viral 3C protein, has been evaluated in a mouse model[67]. Complete protection against HEV71-induced cell death was observed at low nanomolar concentrations, with very little cell toxicity. Consistent with the symptoms, a significant decline in viral RNA was witnessed in intestine, lung, muscle, brain stem, and cardiac muscle when rupintrivir was administered in vivo. Rupintrivir also significantly improved the integrity of limb muscle structure and suppressed the expression of VP1 in infected mouse muscle. Another potential clinical advantage is the high barrier for emergence of drug resistance, as tested by the researchers[67]. However, it is worth noting that a previous clinical trial for rupintrivir for the treatment of human rhinovirus infection was halted due to a lack of efficacy in natural infection studies[68].

Several compounds were found to inhibit the 3D polymerase. DTriP-22, a piperazine-containing pyrazolo [3,4-d] pyrimidine derivative, was shown to inhibit HEV71 RNA accumulation during virus infection, but not IRES-driven translation[69]. It may interfere with 3D activity by obstructing the nucleoside triphosphate entry cavity of 3D polymerase but not by incorporation into the growing RNA chains. This compound is considered novel because most other polymerase inhibitors that exhibit anti-enterovirus activity are nucleoside analogues[70-75]. DTrip-22 has a broad spectrum activity against RNA viruses, including different genotypes of HEV71, coxsackieviruses A and B, and echovirus 9[69]. Aurintricarboxylic acid (ATA), a polyanionic compound originally reported to be an inhibitor for the replication of HIV, HCV and SARS-CoV[76-80], also exhibited the ability to inhibit HEV71 3D polymerase[81]. Results showed that ATA slows down viral RNA synthesis at early stages after a single round of viral replication in HEV71-infected cells. However, ATA did not inhibit the activity of HEV71 viral 2A/3C protease activity. A nucleoside analog, NITD008, has been reported to selectively inhibit viruses within the family Flaviviridae[82]. Although NITD008 showed efficacy in a dengue mouse model, it was not further developed due to the adverse findings observed in a preclinical toxicity study[83]. Deng et al[83] reported that NITD008 potently inhibits HEV71 in cell culture and in a mouse model, and demonstrated the feasibility that this compound could potentially be developed for HEV71 therapy, if the toxicity issue is resolved. Their data further showed that mutations in viral 3A and 3D polymerase regions could confer resistance against NITD008, suggesting an intimate crosstalk between 3A and 3D during viral replication.

Sorafenib, previously known as BAY 43-9006 and marketed commercially as Nexavar, is a multi-target tyrosine and serine-threonine kinase inhibitor currently used in cancer therapy[84]. A significant reduction of infectious HEV71 titres and viral RNA was observed in infected cells when sorafenib was added 1 and 3 h post-infection. However, no difference was seen compared to non-treated cells when sorafenib was added 2 h pre-infection and during virus adsorption. Experimental data indicated that sorafenib treatment was able to block the HEV71 mediated CPE through blocking of virus induced activation of the ERK and p38 signaling pathways. A previous study has shown that HEV71 infection induced cyclooxygenase-2 (COX-2)/prostaglandins (PG) E2 expression via mitogen-activated protein kinases (MAPKs) including ERK and p38, and further that inhibition of HEV71-induced COX-2/PGE2 expression may reduce CNS inflammation[85]. Thus it was proposed that sorafenib treatment may alleviate HEV71-induced inflammatory responses[84]. Further in vivo studies are required to validate the effectiveness of the drug.

Other therapeutic strategies

Immunoglobulin: A number of animal studies have shown that neutralising antibodies stimulated by immunisation with inactivated virus, virus-like proteins, or VP1 subunit vaccines, are cross-protective against heterologous strains of HEV71 and can passively protect mice and monkeys (see section on vaccine development). Further, studies on patients have indicated that HEV71 infection is cleared by humoral immunity, and clinical trials have shown the presence of neutralising antibodies in the serum of immunised healthy adults and children[86-88]. The significant involvement of neutralising antibody responses in the control of HEV71 infection in humans would render IVIG treatment an ideal complimentary therapeutic agent. In fact since the year 2000, IVIG has been used in China as the last resort for treatment of severe cases of HEV71 infection, with some measure of success[89].

However, treatment of patients with IVIG has its disadvantages. Besides the risk of transmitting human pathogens using pooled human sera, necessitating screening and treatment, it also requires donor availability. Other disadvantages include batch to batch variability, and the presence in the serum of virus specific but non-neutralising antibodies[90]. A phenomenon termed antibody-dependent enhancement (ADE) was recently confirmed in experimental and clinical settings[91,92], in which sub-neutralising concentration of antibodies was evidenced to enhance HEV71 infection in Fc receptor-bearing human monocytes and contributed to exacerbation of HEV71 infection in mice. The wide existence of cross reactivity between enterovirus antibodies may also become the underlying risk for HEV71 ADE infections.

A solution would be to exploit future passive immunotherapy based on monoclonal antibodies (mAb) produced in cell culture. They offer a selective advantage over pooled human sera that are more commonly used in IVIG treatment by reducing the risks mentioned above. Based on the success of a United States Food and Drug Administration (FDA) approved humanised mAb for respiratory syncytial virus infection of the lower respiratory tract[93], a similar approach was taken to develop neutralising anti-HEV71 mAb for the treatment of severe HFMD caused by HEV71[89]. Using previously identified peptides containing amino acids of the VP1 region known to be potent in eliciting neutralising antibody[94,95], a mAb (clone 22A12) with strong neutralising activity against HEV71 in an in vitro neutralisation assay was successfully generated. Because clone 22A12 is a murine antibody, further work for the chimerisation and/or humanisation of the antibody is currently underway to reduce human anti-mouse antibody response for therapeutic application. Another group of researchers generated and characterised several mAbs by immunising mice with purified HEV71 virus, strain Henan2[96]. They identified a mAb, clone 4E8, with strong neutralising activity against HEV71 and that specifically reacted with synthetic peptides containing amino acids 240-250 and 250-260 of VP1 by Enzyme-Linked Immunosorbent Assay (ELISA) assay. Clone 4E8 partially protected mice against the lethal challenge of HEV71 strain Henan2. Kiener et al[90] succeeded in isolating a novel mAb against HEV71 that targets a conformational neutralisation epitope outside of VP1. The mAb 10D3 targets the highly conserved “knob” region of VP3. The protective efficacy of mAb 10D3 was evaluated and verified by an animal challenge experiment using a lethal dose of HEV71. All mice prophylactically treated with mAb 10D3 survived the lethal challenge without showing any disease symptoms.

Several factors have to be considered when using mAbs instead of polyclonal serum. First, due to the antigenic variability of circulating strains, the mAb must cross-neutralise all existing subtypes to be useful. Second, there is a risk of escape mutations, which may be circumvented by administering two or more antiviral mAbs against non-overlapping epitopes. A combination of synergistic mAbs may also reduce the required dosage[97,98].

The use of non-human immunoglobulins in the treatment of HEV71 infection has also been investigated. Immunoglobulin Y (IgY) antibodies are the predominant serum immunoglobulin in birds, reptiles, and amphibians, and are transferred from serum to egg yolk in the females to confer passive immunity to their embryos and neonates[99]. The potential of orally administered IgY for the prevention and treatment of many pathogens has been widely reported[100-103]. It was found that chicken as bio-factory can produce a higher yield of IgY antibodies compared to the production of IgG in mammals. In HEV71-infected ICR mice, a survival rate of 98.3% was achieved when the challenged mice were given intraperitoneal injection 1 to 3 d post-infection for 3 consecutive days with a purified IgY antibody at neutralisation titre of 128 or more[104]. Oral administration at a higher dose also conferred protection to infected mice. The study suggested that IgY in the form of an egg-yolk-added drink, yolk powder tablet, or capsule, can potentially be used to prevent the early infection of HEV71.

Adoptive transfer of macrophage: The adoptive transfer or activation of macrophages has been used in the immunotherapy of cancer, liver ischemia, reperfusion injury and pneumonia[105-108]. Liu et al[109] showed that the adoptive transfer of macrophage cells from adult mice can partly protect young mice from lethal HEV71 infection. The macrophages displayed anti-HEV71 activity in vitro and could alleviate the pathology of infected mice, possibly by engulfing the virus directly through phagocytosis. The application of macrophages in antiviral therapy via adoptive transfer is a novel proposal. Unlike human macrophage, murine macrophage can be easily obtained either from the peritoneal cavity or grown from bone marrow precursor cells. Technology for the isolation or growth of large scale human macrophage is still unavailable. Future studies using activated macrophage derived from peripheral blood monocytes of adults were proposed.

Interferons: The effectiveness of interferons (IFNs) in the treatment of HEV71 infection has been studied with contradictory findings. Liu et al[110] demonstrated that early treatment of HEV71-infected newborn mice with a recombinant murine IFN-α resulted in an increased survival rate. However another study demonstrated that HEV71 2Apro could be an IFN antagonist, because it reduces the expression level of the type I IFN receptor[111], making it questionable whether type I IFN will be active against HEV71 infection. There are about 20 different human type I IFNs identified to date[112]. Although they are highly homologous in amino acid sequence and share the same receptors, the biological effect of each IFN is apparently different. It has been shown that the anti-HEV71 activities of various IFN subtypes differ from each other[113]. Based on their antiviral activities, they can be divided into three subgroups: IFNs with high anti-HEV71 activities at low concentrations, IFNs with moderate anti-HEV71 activity at high concentrations, and IFNs with nearly no antiviral activities. Hung et al[114] showed that the 3Cpro of HEV71 was able to cleave IRF9, a host protein involved in the signaling cascade triggered by type I IFN. They found that HEV71 could be effectively inhibited by a combination of IFN-α and a 3Cpro inhibitor such as rupintrivir.

All-trans-retinoic-acid: Most HEV71-infected children present with vitamin A (VA) deficiency, which is associated with decreased immunity and more severe pathogenic conditions[115]. It was shown that serum IFN-α levels were markedly reduced and positively related to the lack of VA in HEV71-infected children. The active VA metabolite, all-trans-retinoic acid (ATRA), is the natural ligand for the retinoic acid receptors (RAR). In various in vitro systems, ATRA has been shown to regulate the expression of a number of IFN-stimulated genes, including retinoid-induced gene I (RIG-I), a pattern recognition receptor involved in the innate immune response of the host[116-118]. It was proposed that the inhibition of RIG-I-mediated type I IFN responses may contribute to the pathogenesis of HEV71 infection[119]. Chen et al[120] demonstrated that ATRA is a potent IFN inducer that effectively inhibits HEV71 and significantly regulates the RIG-I signalling pathway in the human monocytic cell line. They proposed that the antiviral effect of ATRA occurred through a RAR-α pathway, and further suggested that ATRA may directly contribute to anti-HEV71 infection by reinforcing innate immunity.

Oligonucleotides: Previous reports have described the antiviral effects of RNA-based therapeutics, such as siRNA,shRNA and miRNA, targeting the VP1, 3D, 2C genes, or the 3’ UTR of the HEV71 genome, resulting in antiviral activity[121-128]. However, whilst plasmid-derived shRNAs are widely used for laboratory studies, they are not suitable for antiviral therapy. Further, the limitations of RNAs are short half-life and the requirement of a delivery agent that may be toxic to the host. There is currently no approved marketed siRNA drug. On the contrary, the use of antisense oligodeoxynucleotide (ASODN) technology to inhibit pathogen replication has shown promising results. Since the United States FDA approved the first antisense drug, Fomivirsen, for the treatment of cytomegalovirus (CMV) retinitis in 1998, more than 30 types of ASODNs have been evaluated in clinical trials[129].

Unmodified oligonucleotides are highly unstable in vivo due to rapid nuclease digestion. In order to circumvent this problem, a number of chemically modified oligonucleotides such as classic phosphorothioate oligonucleotides, phosphorodiamidate morpholino oligomers, locked nucleic acids, and gene-silencing oligonucleotides have been developed[130].

Liu et al[131] designed and tested 5 antisense phosphorothioate oligonucleotides targeting the 5’-terminal conserved sequence found in HEV71 RNA. One of the oligonucleotides, EV5, effectively inhibited HEV71 amplification both in vitro and in vivo in a sequence-specific and dose-dependent manner. It was also capable of providing effective protection to HEV71-infected mice and inhibited virus replication in the lungs, intestines, muscle, but not brain, of infected mice. Tan et al[132] tested 3 octoguanidium dendrimer conjugated-morpholino oligomers (vivo-MOs) that are complementary to the HEV71 IRES (vivo-MO-1 and -2) and 3D polymerase (vivo-MO-3). Vivo-MO-1 and -2 showed significantly reduced plaque numbers, viral RNA copies, and viral capsid expression in RD cells in a dose-dependent manner. In contrast, vivo-MO-3 exhibited less antiviral activity. Both vivo-MO-1 and 2 remained active when administered within 4 h before or 6 h after HEV71 infection. Resistant mutants arose after serial passages in the presence of vivo-MO-1, but not vivo-MO-2. Thus vivo-MO-2 was proposed to be a favourable candidate for further development as an antiviral agent.


HEV71 is highly contagious and can be isolated from throat swabs, rectal swabs, and stool specimens of sick children. Virus shedding can persist for nearly 4-5 wk in the respiratory tract and through faeces[133,134]. As a result, HEV71 transmission may occur not only through direct contact with infected people, but also contact with respiratory secretions or faeces of an infected person. The virus can subsequently spread from one person to another through the faecal-oral route by contaminated hands or objects[135], rapidly causing outbreaks. Due to the long periods of viral shedding in children, HEV71 is frequently transmitted in families, kindergartens, and schools[136]. Therefore to successfully control the devastating outcome of HEV71 epidemics, prevention of infection remains the top priority.


Until a vaccine becomes available, the best way to prevent HEV71 infection is through infection control practices such as hand-washing, disinfection and social distancing during epidemics[137]. Early intervention can lessen the spread of the virus. For these actions to be effective, adequate clinical and laboratory surveillance of HEV71 activity and identity in the community is essential to provide early warning of impending epidemics. As such many countries in the Asia-Pacific region, including Japan, Malaysia, Singapore, Taiwan, Vietnam and China, have implemented heightened surveillance for HEV71[138-142]. HFMD has now become a notifiable disease in many countries in the region. However, since other enteroviruses such as CVA8, CVA10, and CVA16 can also cause HFMD, concurrent virological surveillance may provide invaluable molecular epidemiological data to help track the spread of the virus across the region[143]. In some instances surveillance programs have provided information that resulted in early control of HEV71 epidemics and reduced the total number of cases of acute neurological disease[144].

Physical prevention

Transmission of the viruses responsible for HFMD, including HEV71 and CVA16, is mainly through the faecal-oral route. Therefore the first line of defense is to contain the disease causing agent. Infected children are quarantined and non-infected children are also kept from crowds. During the 2000 outbreak in Singapore, spread of viruses was prevalent in child-care centres. One of the measures taken to break the chain of transmission was a 2-wk nationwide closure of preschool centres[145]. However, it was suggested that even though such controls may decrease the peak incidence of disease, the outbreak may be prolonged, and therefore the overall number of cases may not be lowered[143].

Health education plays an important role to inform and educate parents about the virus infection and prevention strategies. It should focus on observance of good personal hygiene, and cleaning and disinfection of premises and articles. Alcohols are widely used as active ingredients in many hand disinfectants. However, their effectiveness is largely dependent on the type and concentration used. A recent study showed that 95% ethanol instead of 70%-95% isopropanol has the most virucidal activity against HEV71, but did not result in complete inactivation of HEV71[146]. Further, high concentration of ethanol may cause skin irritation and a decrease in antibacterial activity. New formulations are needed for routine use to prevent the spread of enteroviruses.

Vaccine development

Similarities between HEV71 and poliovirus in many virological and clinical aspects have strongly suggested that a vaccine strategy, similar to that against poliovirus infection, could be effectively adopted to control HEV71 infection. Because it mainly threatens the children in developing countries, an ideal HEV71 vaccine would have to be inexpensive, safe, convenient to administer, and acceptable to parents. In addition, a successful vaccine strain would also provide cross-protection to different HEV71 genotypes.

Live-attenuated vaccine: Based on the similarities between PV and HEV71, Arita et al[147] developed a HEV71 attenuated strain carrying mutations in the 5’-and 3’-untranslated regions and 3D polymerase, based on the temperature-sensitive determinants of poliovirus Sabin 1 vaccine strain. The EV71 (S1-3’) strain, which belongs to HEV71 genotype A, was characterised by attenuated neurovirulence and limited spread of virus. In a subsequent study, cynomolgus monkeys inoculated with EV71 (S1-3’) via the intravenous route had a mild neurological symptom in the form of tremor, but survived lethal challenge by virulent HEV71 (BrCr-TR) without exacerbation of the symptom[148]. The immunised monkey sera demonstrated a broad spectrum of cross-genotype neutralising activity, including genotypes A, B1, B4, C2, and C4. Although EV71 (S1-3’) demonstrated promise as a live attenuated vaccine against HEV71, the vaccine itself was not completely attenuated, as evidenced by mild neurological symptoms and isolation of virus from the spinal cord.

Due to the lack of proof-reading activity by enteroviral 3D polymerase, a high incidence of error leading to random mutations occur during replication. This phenomenon makes it easier for the reversion of mutants to wild-type virus. To overcome this issue, researchers have explored the possibility of replacement or deletion of bigger fragments. Replacement of the PV internal ribosome entry site (IRES), with that of a non-neurotropic human rhinovirus (HRV), was found to stably attenuate PV in animal models[149,150]. In HEV71, it was shown that deletion of stem-loop domain Z within the 3’-untranslated region attenuates the growth of a HEV71-HRV2-IRES chimera in neuroblastoma cells[151]. Another strategy employed to generate stably attenuated vaccine strains is to increase the replication fidelity of the 3D polymerase. Mutations at amino acid positions G64R and S264L in the HEV71 3D polymerase have recently been shown to increase replication fidelity and the genetic stability of the HEV71 genome by greater than ten-fold during growth in cell culture[152]. Further, the HEV71 3D-G64R and 3D-S264L mutant virus populations were attenuated in a mouse model of HEV71 infection[153].

Inactivated vaccine: In response to the Bulgarian outbreak in 1975, a formalin-inactivated HEV71 vaccine was developed, but was not used to control the epidemic[154]. However since then, the value of inactivated vaccine for the effective control of HEV71 has been shown by various researchers. Suckling mice immunised with the adjuvant-carrying formaldehyde-inactivated mouse-adapted HEV71 vaccine were effectively protected from lethal virus challenge and disease[155]. Another experimentally inactivated vaccine produced using the FY-23K-B strain of HEV71 was capable of inducing an immune response and offered protection to rhesus monkeys against future virus attacks[156]. Additionally, passive transfer of serum from formalin-inactivated and heat-inactivated virus vaccine immunised adult mice, could provide protection against HEV71 challenge in neonatal mice[157,158]. The efficacy of this model of maternal vaccination-neonatal challenge is consistent with the results of other similar studies using maternal vaccination to protect offspring from infectious disease[159-162]. Bek et al[159] provided the first demonstration of cross-genotype protective efficacy of a candidate HEV71 vaccine which suggested that inactivated vaccines may confer broad protection against HEV71 infection. On the other hand, another study showed that HEV71 type specificity of neutralisation was unidirectional[163]. The antisera used against newly emerging subgenogroups could cross-neutralise their ancestor subgenogroups, but not vice versa. Chen et al[164] demonstrated that co-immunisation of a formaldehyde-inactivated HEV71 vaccine with a commercial pentavalent vaccine that contained inactivated polio vaccine, did not interfere in antibody production nor protective efficacy of the HEV71 vaccine. This indicates that the two vaccines are compatible after co-immunisation, and that formaldehyde-inactivated HEV71 vaccine may be used in designing multivalent vaccines.

Due to their inability to replicate, inactivated HEV71 vaccines are favoured over the live attenuated vaccines for safety reasons. However, the manufacturing costs of inactivated vaccines and potential supply problems cause substantial difficulties in practical implementation, particularly in developing countries. Further, viruses are sensitive to chemical treatment and neutralising epitopes could be destroyed during inactivation, as it is reported in formalin inactivated C4D HEV71 vaccine strain[165]. Nevertheless, research and development of HEV71 inactivated vaccines have progressed further than the other types of HEV71 vaccines, with some currently in phase III clinical trial[166].

Subunit vaccine: Like all enterovirus the antigenic diversity of HEV71 is caused by variations within capsid proteins VP1, VP2 and VP3, but the VP1 protein displays a number of important neutralising epitopes[157,167,168]. Key neutralising antibody determinants have been found in the N-terminal half of VP1 when tested with high titre human neutralising antibodies[169,170]. The potential safety advantage of subunit vaccines over conventional whole virus vaccines has prompted researchers to query whether the VP1 subunit of HEV71 is sufficient to provoke adequate protective immunity against viral infection. Different delivery systems have been tested for their suitability in expressing the VP1 and to stimulate immune response. They include recombinant VP1 protein expressed in Escherichia coli BL21[157], recombinant Newcastle disease virus capsid displaying VP1[171], and VP1 expressed in yeast Pischia pastoris[172]. All induced high levels of neutralising antibodies.

The mucosal immune system serves as the first line of defense against HEV71 as it initiates disease following implantation in the gut mucosa[173]. Thus an oral vaccine for immunisation against HEV71 has its advantages over injected vaccines. Oral subunit vaccines stimulate production of mucosal antibodies more effectively than is the usual case with injected vaccines[174]. Oral administration is also widely accepted in children who need a HEV71 vaccine. The use of attenuated Salmonella as a vector for the VP1 subunit demonstrated the advantages of oral vaccine vectors[175]. Yu et al[176] showed that VP1-expressing Bifidobacterium longum, a gastrointestinal probiotic, can confer protection from the mother to neonatal mice, suggesting the potential of this recombinant B. longum as an oral vaccine against HEV71 infection. Transgenic plants and animals are possible alternatives to prokaryotic and eukaryotic vectors. They offer a palatable oral delivery system that can elicit a good mucosal immune response as well as systemic humoral and cellular immune responses, making it particularly suitable for protecting against infectious agents intruding via the mucosal surface[177,178]. In one study, transgenic tomato fruit expressing the VP1 subunit was developed as a free-feeding oral vaccine[179]. Serum from immunised mice was able to neutralise the infection of HEV71 in RD cells. In another study, the bovine α-lactalbumin promoter and αS1-casein signal peptide sequence were fused with the VP1 cDNA to generate transgenic mice with mammary gland-specific VP1 expression[180]. Expression of the HEV71 VP1 capsid protein was shown to be highly specific to the mammary gland and was secreted in the milk of transgenic mice, reaching satisfactory expression level for oral vaccine development and is much higher than that achieved in bacterial or transgenic plant system[157,158,179,181,182].

Gastric acid and enzymatic digestion are major concerns for oral vaccines because they may interfere with vaccine conformation and absorption. Moreover, it is difficult to determine the precise dose of antigens for immunisation, since competition with food and microbial antigens interferes with the absorption rate of vaccine components. Many strategies have been employed to improve oral vaccine delivery, including the use of tissue-specific promoters, mucosal immune adjuvant, liposomes, and N-trimethyl chitosan nanoparticles[173,174]. New strategies are necessary to achieve a high level of expression of VP1 protein in the correct antigen conformation. If these prototypes can be refined to yield similar immunogenicity levels as inactivated vaccines, they could become strong preventive options.

Synthetic peptide: Epitope-based vaccination using synthetic peptides is another area under intense investigation for the delivery of precise vaccine components to the immune system. A series of overlapping synthetic peptides spanning the VP1 capsid protein of HEV71 was used to immunise BALB/c mice in order to identify neutralising linear epitopes[94]. Peptides containing amino acids 163–177 and 208–222 of the VP1 were capable of eliciting neutralising antibodies against HEV71. Additionally, mouse antisera raised against the peptide 208-222, designated SP70, demonstrated in vivo passive protective efficacy in BALB/c mice[183]. Hydrophobic profile assays showed that this highly conserved sequence is located within the major hydrophilic regions and is expected to be exposed at the surface of the protein, hence making it a promising and attractive candidate for synthetic peptide-based HEV71 vaccine[94]. Further, the amino acid sequence represented by SP70 was totally conserved amongst 25 HEV71 strains from subgenogroups A, B1-B5 and C1-C4, which suggested possible cross-protection against infectivity of all HEV71 strains. A different delivery approach for the synthetic peptide was explored using adenovirus (Ad) vectors[184]. Compared to the recombinant GST-fused SP70 protein, immunisation with the Ads containing SP70 elicited higher SP70-specific IgG titres, higher neutralisation titres, and conferred more effective protection to neonatal mice.

Nevertheless, mouse antisera raised against HEV71 whole virions provide higher in vivo passive protection to suckling mice against lethal HEV71 challenge when compared with the anti-SP70 antisera, possibly due to higher titres of neutralising antibodies elicited by several neutralising epitopes located on the virus other than that represented by the synthetic peptide SP70 alone. Further, the short epitopes can easily change to avoid antibody mediated neutralisation. To circumvent this issue, 6 peptides without cross-reactivity were selected and combined into three vaccine candidates and applied in further evaluation in neonatal mice[185]. The Vac6 comprising the peptides of P70–159, P140–249, P324–443 and P746–876 of the structural proteins could provide effective protection on pups against virus infection.

Virus-like particles: Another method of vaccine development is the construction of virus-like particles (VLPs). The baculovirus expression system is the most widely used platform for generating VLPs. To assemble the HEV71 VLPs, the P1 polyprotein needs to be cleaved by viral protease 3CD into individual structural proteins. Hu et al[186] developed VLPs by co-expressing the P1 and 3CD regions of HEV71 in the pFastBacTM Dual vector, which contains two strong baculovirus promoters, polyhedron (PPH) and p10 (Pp10). The P1 region was controlled by a strong baculovirus promoter, PPH, whilst the protease 3CD was controlled by weak promoters such as CMV promoter or baculovirus IE1 promoter. The expressed 3CD successfully cleaved P1 in vitro and in vivo. Also, the co-infection in insect cells resulted in crystalline virus-like particle structures morphologically resembling the authentic HEV71 aggregates. A patent for these recombinant baculoviruses has been applied for in Taiwan, the United States and mainland China[166].

In a study using monkeys, Lin et al[187] found that VLPs and formalin-inactivated vaccines generated comparable amount of HEV71-binding antibodies measured by ELISA, and induced memory T and B cell responses. However, monkeys immunised with inactivated HEV71 virus showed relatively greater neutralisation titre, proliferation, and cytokine production than those immunised with VLPs. This may be partially due to the conformation difference between VLPs and viral particles, which was not detected under the assays performed. Even though immunisation with VLPs has less of a response than inactivated vaccine, nevertheless they provide a safer method for preventing viral infection with regards to clinical treatment.

The main problem associated with VLPs is their stability, purification and cost. At present, the VLPs are mostly developed using insect cells and the strict culture conditions limit the required large scale of vaccine production. Thus, transgenic plants or yeast that can produce VLPs to be delivered by either oral administration or injection may prove to be promising platforms. Recently Li et al[188] coexpressed the P1 and 3CD regions in Saccharomyces cerevisiae to yield VLPs. The S. cerevisiae system is a low cost platform and it is easy to scale-up production. As a eukaryotic expression system, it benefits from the processes of protein expression, folding, and modification, which are lacking in prokaryotic expression systems. Compared to the insect cell expression systems, the use of stable yeast transformants avoid the generation of initial large quantities of recombinant baculoviruses. In laboratory conditions, however, the yield of S. cerevisiae-derived VLPs was not sufficient for clinical use. However the use of fermentation engineering and automation control, which have been used for the production of other types of VLPs[189], may overcome this issue. The patent for S. cerevisiae production of VLPs has been applied for in China[166].

DNA vaccine: DNA immunisation offers many advantages over the traditional forms of vaccination. It is able to induce the expression of antigens that resemble native viral epitopes more closely than standard vaccines do, since live attenuated and inactivated vaccines are often altered in their protein structure and antigenicity. Plasmid vectors can be constructed and produced quickly, at relatively lower cost, and the coding sequence can be manipulated in many ways. Further, DNA vaccines encoding several antigens or proteins can be delivered to the host in a single dose at low quantity to induce immune responses. They are also very temperature stable making storage and transport much easier.

Tung et al[190] developed a HEV71 DNA vaccine by inserting the VP1 gene into a eukaryotic expression vector and evaluated the immune response in mice. They showed that whilst anti-VP1 IgG level was increased in immunised mice, the level declined after boosting immunisation. Further, although the anti-VP1 IgG exhibited neutralising activity against HEV71, the neutralising effect of the sera of mice immunised with the VP1 DNA vaccine was much lower than that of HEV71-infected human serum. Another DNA vaccine was developed by inserting the entire VP1 gene into plasmid pcDNA3[157]. Intramuscular administration elicited a high and stable level of neutralisation titre in both ICR and BALB/c mice, which could be detected post-immunisation. However, it induced a weaker immune stimulation compared to whole virus particles.

Various strategies to increase the immune stimulation ability of DNA vaccines have been explored. Amongst these are the incorporation of immunostimulatory sequences in the backbone of the plasmid, co-expression of stimulatory molecules, use of localisation/secretory signals, and an appropriate delivery system, as well as adjuvants and optimisation of transgene expression[191-194]. While therapeutic and prophylactic DNA vaccine clinical trials are underway for a variety of infectious diseases and cancers, the scientific basis of DNA vaccines has yet to be clearly defined. If DNA vaccines pass all scientific and regulatory scrutiny, they promise to be products of the next generation. A comparison of DNA vaccine with other vaccine strategies is shown in Table 3.

Table 3 Comparison of human enterovirus 71 vaccine strategies.
Live-attenuated vaccineIn vitro / in vivoBroad spectrum, low costIncomplete attenuation[143-149]
Inactivated vaccineIn vitro / in vivo / clinical trialInability to replicateHigh cost[150-162]
Subunit vaccineIn vitro / in vivoSafe to useLow immunogenicity[153,154,163-178]
Synthetic peptidesIn vitro / in vivoSmall and safe to useLow immunogenicity, escape mutants[94,179-181]
Virus-like particlesIn vitro / in vivoSafe to useUnstable, need purification, high cost[162,182-185]
DNA vaccineIn vitro / in vivoMost resemble native virus, fast production, low cost, can be manipulatedLow neutralising effect[153,186-190]

During the past decade, HFMD and associated neurological complications caused by HEV71 infection have resulted in the loss of many paediatric lives in the Asia-Pacific region. Whilst a significant amount of research have been published in the field of HEV71 antivirals and vaccine development lately, an effective therapeutic and/or prevention strategy is still elusive. Various groups of natural compounds have demonstrated anti-HEV71 activities. However more work is needed to characterise the detailed antiviral mechanisms and to further develop into effective clinical drugs. The use of synthetic antiviral compounds in clinical setting has been hampered by potential adverse effects to the host and emergence of drug resistance mutants. New strategies such as computer-aided drug design, screening of licensed drugs against HEV71 infection, and combination therapy targeting different replication steps of HEV71, may play an important role in antiviral drug development.

The recent identification of HEV71 receptors SCARB2 and PSGL-1 will enable the development of humanised transgenic mice for testing of antivirals and vaccines. Vaccine candidates in the form of inactivated HEV71 have progressed into clinical trials and look most promising. However, the unit cost of inactivated HEV71 vaccines is likely to be high, restricting their usefulness in resource-limited countries in Southeast Asia. By contrast, self-propagating live attenuated vaccines can be produced at much lower unit cost and are thus likely to be more cost-effective for use in vaccine prevention programs in developing countries and in regional and global control strategies. However, in order for this potential to be realised, it will be necessary to design a HEV71 vaccine in which attenuation is fully defined and which possesses a demonstrably higher stability and safety profile than the oral polio vaccine. Together with a good surveillance program, these strategies will hopefully lead to the containment and eradication of HEV71.


P- Reviewer: Arriagada GL, Christodoulou CG, Chen SH, Qiu HJ, Tetsuya T S- Editor: Song XX L- Editor: A E- Editor: Jiao XK

1.  McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 2002;26:91-107.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Hsiung GD, Wang JR. Enterovirus infections with special reference to enterovirus 71. J Microbiol Immunol Infect. 2000;33:1-8.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Liao HT, Hung KL. Neurologic involvement in an outbreak of enterovirus 71 infection: a hospital-based study. Acta Paediatr Taiwan. 2001;42:27-32.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Liu CC, Tseng HW, Wang SM, Wang JR, Su IJ. An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol. 2000;17:23-30.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  McMinn P, Stratov I, Nagarajan L, Davis S. Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis. 2001;32:236-242.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 316]  [Cited by in F6Publishing: 331]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
6.  Yip CC, Lau SK, Woo PC, Yuen KY. Human enterovirus 71 epidemics: what’s next? Emerg Health Threats J. 2013;6:19780.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 124]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
7.  Zeng M, El Khatib NF, Tu S, Ren P, Xu S, Zhu Q, Mo X, Pu D, Wang X, Altmeyer R. Seroepidemiology of Enterovirus 71 infection prior to the 2011 season in children in Shanghai. J Clin Virol. 2012;53:285-289.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 77]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
8.  Bible JM, Iturriza-Gomara M, Megson B, Brown D, Pantelidis P, Earl P, Bendig J, Tong CY. Molecular epidemiology of human enterovirus 71 in the United Kingdom from 1998 to 2006. J Clin Microbiol. 2008;46:3192-3200.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 95]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
9.  Fowlkes AL, Honarmand S, Glaser C, Yagi S, Schnurr D, Oberste MS, Anderson L, Pallansch MA, Khetsuriani N. Enterovirus-associated encephalitis in the California encephalitis project, 1998-2005. J Infect Dis. 2008;198:1685-1691.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 75]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
10.  Kapusinszky B, Szomor KN, Farkas A, Takács M, Berencsi G. Detection of non-polio enteroviruses in Hungary 2000-2008 and molecular epidemiology of enterovirus 71, coxsackievirus A16, and echovirus 30. Virus Genes. 2010;40:163-173.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 47]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
11.  Mirand A, Schuffenecker I, Henquell C, Billaud G, Jugie G, Falcon D, Mahul A, Archimbaud C, Terletskaia-Ladwig E, Diedrich S. Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries. J Gen Virol. 2010;91:2263-2277.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
12.  Siafakas N, Attilakos A, Vourli S, Stefos E, Meletiadis J, Nikolaidou P, Zerva L. Molecular detection and identification of enteroviruses in children admitted to a university hospital in Greece. Mol Cell Probes. 2011;25:249-254.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
13.  van der Sanden S, Koopmans M, Uslu G, van der Avoort H. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol. 2009;47:2826-2833.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 118]  [Cited by in F6Publishing: 124]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
14.  Witsø E, Palacios G, Rønningen KS, Cinek O, Janowitz D, Rewers M, Grinde B, Lipkin WI. Asymptomatic circulation of HEV71 in Norway. Virus Res. 2007;123:19-29.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 60]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
15.  Zhang W, Tao J, Yang X, Yang Z, Zhang L, Liu H, Wu K, Wu J. Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection. Biochem Biophys Res Commun. 2014;449:307-312.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 59]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
16.  Li T, Peng T. Traditional Chinese herbal medicine as a source of molecules with antiviral activity. Antiviral Res. 2013;97:1-9.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 120]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
17.  Zhu YP, Woerdenbag HJ. Traditional Chinese herbal medicine. Pharm World Sci. 1995;17:103-112.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Wang J, Zhang T, Du J, Cui S, Yang F, Jin Q. Anti-enterovirus 71 effects of chrysin and its phosphate ester. PLoS One. 2014;9:e89668.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 49]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
19.  Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75:311-335.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3368]  [Cited by in F6Publishing: 3041]  [Article Influence: 253.4]  [Reference Citation Analysis (0)]
20.  Wang J, Chen X, Wang W, Zhang Y, Yang Z, Jin Y, Ge HM, Li E, Yang G. Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease. J Ethnopharmacol. 2013;147:114-121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 73]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
21.  Yoshida T, Amakura Y, Yoshimura M. Structural features and biological properties of ellagitannins in some plant families of the order Myrtales. Int J Mol Sci. 2010;11:79-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 96]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
22.  Lin LT, Chen TY, Chung CY, Noyce RS, Grindley TB, McCormick C, Lin TC, Wang GH, Lin CC, Richardson CD. Hydrolyzable tannins (chebulagic acid and punicalagin) target viral glycoprotein-glycosaminoglycan interactions to inhibit herpes simplex virus 1 entry and cell-to-cell spread. J Virol. 2011;85:4386-4398.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 119]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
23.  Lin LT, Chen TY, Lin SC, Chung CY, Lin TC, Wang GH, Anderson R, Lin CC, Richardson CD. Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry. BMC Microbiol. 2013;13:187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 117]  [Cited by in F6Publishing: 125]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
24.  Satomi H, Umemura K, Ueno A, Hatano T, Okuda T, Noro T. Carbonic anhydrase inhibitors from the pericarps of Punica granatum L. Biol Pharm Bull. 1993;16:787-790.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Yang Y, Xiu J, Zhang L, Qin C, Liu J. Antiviral activity of punicalagin toward human enterovirus 71 in vitro and in vivo. Phytomedicine. 2012;20:67-70.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 35]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
26.  Yeo SG, Song JH, Hong EH, Lee BR, Kwon YS, Chang SY, Kim SH, Lee SW, Park JH, Ko HJ. Antiviral effects of Phyllanthus urinaria containing corilagin against human enterovirus 71 and Coxsackievirus A16 in vitro. Arch Pharm Res. 2015;38:193-202.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 33]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
27.  Yang Y, Zhang L, Fan X, Qin C, Liu J. Antiviral effect of geraniin on human enterovirus 71 in vitro and in vivo. Bioorg Med Chem Lett. 2012;22:2209-2211.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 51]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
28.  Yang Y, Xiu J, Liu J, Zhang L, Li X, Xu Y, Qin C, Zhang L. Chebulagic Acid, a Hydrolyzable Tannin, Exhibited Antiviral Activity in Vitro and in Vivo against Human Enterovirus 71. Int J Mol Sci. 2013;14:9618-9627.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 35]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
29.  Park JH, Joo HS, Yoo KY, Shin BN, Kim IH, Lee CH, Choi JH, Byun K, Lee B, Lim SS. Extract from Terminalia chebula seeds protect against experimental ischemic neuronal damage via maintaining SODs and BDNF levels. Neurochem Res. 2011;36:2043-2050.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 43]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
30.  Shiota S, Shimizu M, Sugiyama J, Morita Y, Mizushima T, Tsuchiya T. Mechanisms of action of corilagin and tellimagrandin I that remarkably potentiate the activity of beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol. 2004;48:67-73.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry. 2000;55:481-504.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem. 2002;13:572-584.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Zhu QC, Wang Y, Liu YP, Zhang RQ, Li X, Su WH, Long F, Luo XD, Peng T. Inhibition of enterovirus 71 replication by chrysosplenetin and penduletin. Eur J Pharm Sci. 2011;44:392-398.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 47]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
34.  Wang HQ, Meng S, Li ZR, Peng ZG, Han YX, Guo SS, Cui XL, Li YH, Jiang JD. The antiviral effect of 7-hydroxyisoflavone against Enterovirus 71 in vitro. J Asian Nat Prod Res. 2013;15:382-389.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 18]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
35.  Lv X, Qiu M, Chen D, Zheng N, Jin Y, Wu Z. Apigenin inhibits enterovirus 71 replication through suppressing viral IRES activity and modulating cellular JNK pathway. Antiviral Res. 2014;109:30-41.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 43]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
36.  Liu J, Yang Y, Xu Y, Ma C, Qin C, Zhang L. Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol J. 2011;8:483.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 84]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
37.  Chen ZF, Mao L, Liu LM, Liu YC, Peng Y, Hong X, Wang HH, Liu HG, Liang H. Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) matrine with Ga(III), Au(III), Sn(IV) ions, and DNA binding studies. J Inorg Biochem. 2011;105:171-180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 43]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
38.  Yang Y, Xiu J, Zhang X, Zhang L, Yan K, Qin C, Liu J. Antiviral effect of matrine against human enterovirus 71. Molecules. 2012;17:10370-10376.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 55]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
39.  Xiong ZQ, Wang JF, Hao YY, Wang Y. Recent advances in the discovery and development of marine microbial natural products. Mar Drugs. 2013;11:700-717.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 109]  [Cited by in F6Publishing: 96]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
40.  Yang Y, Ma J, Xiu J, Bai L, Guan F, Zhang L, Liu J, Zhang L. Deferoxamine compensates for decreases in B cell counts and reduces mortality in enterovirus 71-infected mice. Mar Drugs. 2014;12:4086-4095.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 13]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
41.  Kuo KK, Chang JS, Wang KC, Chiang LC. Water extract of Glycyrrhiza uralensis inhibited enterovirus 71 in a human foreskin fibroblast cell line. Am J Chin Med. 2009;37:383-394.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 26]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
42.  Lin YJ, Lai CC, Lai CH, Sue SC, Lin CW, Hung CH, Lin TH, Hsu WY, Huang SM, Hung YL. Inhibition of enterovirus 71 infections and viral IRES activity by Fructus gardeniae and geniposide. Eur J Med Chem. 2013;62:206-213.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 34]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
43.  Li X, Liu Y, Hou X, Peng H, Zhang L, Jiang Q, Shi M, Ji Y, Wang Y, Shi W. Chlorogenic acid inhibits the replication and viability of enterovirus 71 in vitro. PLoS One. 2013;8:e76007.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 34]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
44.  Song J, Yeo SG, Hong EH, Lee BR, Kim JW, Kim J, Jeong H, Kwon Y, Kim H, Lee S. Antiviral Activity of Hederasaponin B from Hedera helix against Enterovirus 71 Subgenotypes C3 and C4a. Biomol Ther (Seoul). 2014;22:41-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 39]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
45.  Li ZH, Li CM, Ling P, Shen FH, Chen SH, Liu CC, Yu CK, Chen SH. Ribavirin reduces mortality in enterovirus 71-infected mice by decreasing viral replication. J Infect Dis. 2008;197:854-857.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 104]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
46.  Shang L, Xu M, Yin Z. Antiviral drug discovery for the treatment of enterovirus 71 infections. Antiviral Res. 2013;97:183-194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 89]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
47.  De Palma AM, Vliegen I, De Clercq E, Neyts J. Selective inhibitors of picornavirus replication. Med Res Rev. 2008;28:823-884.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 185]  [Cited by in F6Publishing: 196]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
48.  Pevear DC, Tull TM, Seipel ME, Groarke JM. Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother. 1999;43:2109-2115.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Shia KS, Li WT, Chang CM, Hsu MC, Chern JH, Leong MK, Tseng SN, Lee CC, Lee YC, Chen SJ. Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors. J Med Chem. 2002;45:1644-1655.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Chang CS, Lin YT, Shih SR, Lee CC, Lee YC, Tai CL, Tseng SN, Chern JH. Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives. J Med Chem. 2005;48:3522-3535.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 63]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
51.  Chen TC, Liu SC, Huang PN, Chang HY, Chern JH, Shih SR. Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants. J Biomed Sci. 2008;15:291-300.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 34]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
52.  Chern JH, Shia KS, Hsu TA, Tai CL, Lee CC, Lee YC, Chang CS, Tseng SN, Shih SR. Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidines: a novel class of potent enterovirus inhibitors. Bioorg Med Chem Lett. 2004;14:2519-2525.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 70]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
53.  Shih SR, Chen SJ, Hakimelahi GH, Liu HJ, Tseng CT, Shia KS. Selective human enterovirus and rhinovirus inhibitors: An overview of capsid-binding and protease-inhibiting molecules. Med Res Rev. 2004;24:449-474.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
54.  Shih SR, Tsai MC, Tseng SN, Won KF, Shia KS, Li WT, Chern JH, Chen GW, Lee CC, Lee YC. Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone. Antimicrob Agents Chemother. 2004;48:3523-3529.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 65]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
55.  Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med. 2009;15:794-797.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 300]  [Cited by in F6Publishing: 310]  [Article Influence: 20.7]  [Reference Citation Analysis (0)]
56.  Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, Koike S. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med. 2009;15:798-801.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 410]  [Cited by in F6Publishing: 397]  [Article Influence: 26.5]  [Reference Citation Analysis (0)]
57.  Tan CW, Lai JK, Sam IC, Chan YF. Recent developments in antiviral agents against enterovirus 71 infection. J Biomed Sci. 2014;21:14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 48]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
58.  Weng TY, Chen LC, Shyu HW, Chen SH, Wang JR, Yu CK, Lei HY, Yeh TM. Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells. Antiviral Res. 2005;67:31-37.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 64]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
59.  Legrand D, Vigié K, Said EA, Elass E, Masson M, Slomianny MC, Carpentier M, Briand JP, Mazurier J, Hovanessian AG. Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells. Eur J Biochem. 2004;271:303-317.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Marchetti M, Trybala E, Superti F, Johansson M, Bergström T. Inhibition of herpes simplex virus infection by lactoferrin is dependent on interference with the virus binding to glycosaminoglycans. Virology. 2004;318:405-413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 61]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
61.  van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral activities of lactoferrin. Antiviral Res. 2001;52:225-239.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Jenssen H, Andersen JH, Uhlin-Hansen L, Gutteberg TJ, Rekdal Ø. Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate. Antiviral Res. 2004;61:101-109.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Wang Y, Qing J, Sun Y, Rao Z. Suramin inhibits EV71 infection. Antiviral Res. 2014;103:1-6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 30]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
64.  Huther A, Dietrich U. The emergence of peptides as therapeutic drugs for the inhibition of HIV-1. AIDS Rev. 2007;9:208-217.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Tan CW, Chan YF, Sim KM, Tan EL, Poh CL. Inhibition of enterovirus 71 (EV-71) infections by a novel antiviral peptide derived from EV-71 capsid protein VP1. PLoS One. 2012;7:e34589.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
66.  Kajiwara K, Watanabe K, Tokiwa R, Kurose T, Ohno H, Tsutsumi H, Hata Y, Izumi K, Kodama E, Matsuoka M. Bioorganic synthesis of a recombinant HIV-1 fusion inhibitor, SC35EK, with an N-terminal pyroglutamate capping group. Bioorg Med Chem. 2009;17:7964-7970.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
67.  Zhang X, Song Z, Qin B, Zhang X, Chen L, Hu Y, Yuan Z. Rupintrivir is a promising candidate for treating severe cases of enterovirus-71 infection: evaluation of antiviral efficacy in a murine infection model. Antiviral Res. 2013;97:264-269.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 69]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
68.  Park KS, Choi YJ, Park JS. Enterovirus infection in Korean children and anti-enteroviral potential candidate agents. Korean J Pediatr. 2012;55:359-366.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 7]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
69.  Chen TC, Chang HY, Lin PF, Chern JH, Hsu JT, Chang CY, Shih SR. Novel antiviral agent DTriP-22 targets RNA-dependent RNA polymerase of enterovirus 71. Antimicrob Agents Chemother. 2009;53:2740-2747.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 60]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
70.  Chen TC, Weng KF, Chang SC, Lin JY, Huang PN, Shih SR. Development of antiviral agents for enteroviruses. J Antimicrob Chemother. 2008;62:1169-1173.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 71]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
71.  De Palma AM, Pürstinger G, Wimmer E, Patick AK, Andries K, Rombaut B, De Clercq E, Neyts J. Potential use of antiviral agents in polio eradication. Emerg Infect Dis. 2008;14:545-551.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 53]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
72.  Goris N, De Palma A, Toussaint JF, Musch I, Neyts J, De Clercq K. 2’-C-methylcytidine as a potent and selective inhibitor of the replication of foot-and-mouth disease virus. Antiviral Res. 2007;73:161-168.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 41]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
73.  Graci JD, Too K, Smidansky ED, Edathil JP, Barr EW, Harki DA, Galarraga JE, Bollinger JM, Peterson BR, Loakes D. Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues. Antimicrob Agents Chemother. 2008;52:971-979.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 41]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
74.  Harki DA, Graci JD, Galarraga JE, Chain WJ, Cameron CE, Peterson BR. Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases. J Med Chem. 2006;49:6166-6169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 38]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
75.  Kishimoto C, Crumpacker CS, Abelmann WH. Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets. J Am Coll Cardiol. 1988;12:1334-1341.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Chen Y, Bopda-Waffo A, Basu A, Krishnan R, Silberstein E, Taylor DR, Talele TT, Arora P, Kaushik-Basu N. Characterization of aurintricarboxylic acid as a potent hepatitis C virus replicase inhibitor. Antivir Chem Chemother. 2009;20:19-36.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 35]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
77.  De Clercq E. Potential antivirals and antiviral strategies against SARS coronavirus infections. Expert Rev Anti Infect Ther. 2006;4:291-302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 130]  [Cited by in F6Publishing: 122]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
78.  Santhosh KC, Paul GC, De Clercq E, Pannecouque C, Witvrouw M, Loftus TL, Turpin JA, Buckheit RW, Cushman M. Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores. J Med Chem. 2001;44:703-714.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Witvrouw M, Fikkert V, Pluymers W, Matthews B, Mardel K, Schols D, Raff J, Debyser Z, De Clercq E, Holan G. Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (reverse transcriptase/integrase) in the virus replicative cycle. Mol Pharmacol. 2000;58:1100-1108.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Yap Y, Zhang X, Andonov A, He R. Structural analysis of inhibition mechanisms of aurintricarboxylic acid on SARS-CoV polymerase and other proteins. Comput Biol Chem. 2005;29:212-219.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 32]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
81.  Hung HC, Chen TC, Fang MY, Yen KJ, Shih SR, Hsu JT, Tseng CP. Inhibition of enterovirus 71 replication and the viral 3D polymerase by aurintricarboxylic acid. J Antimicrob Chemother. 2010;65:676-683.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 53]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
82.  Yin Z, Chen YL, Schul W, Wang QY, Gu F, Duraiswamy J, Kondreddi RR, Niyomrattanakit P, Lakshminarayana SB, Goh A. An adenosine nucleoside inhibitor of dengue virus. Proc Natl Acad Sci USA. 2009;106:20435-20439.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 270]  [Cited by in F6Publishing: 274]  [Article Influence: 18.3]  [Reference Citation Analysis (0)]
83.  Deng CL, Yeo H, Ye HQ, Liu SQ, Shang BD, Gong P, Alonso S, Shi PY, Zhang B. Inhibition of enterovirus 71 by adenosine analog NITD008. J Virol. 2014;88:11915-11923.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 54]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
84.  Gao M, Duan H, Liu J, Zhang H, Wang X, Zhu M, Guo J, Zhao Z, Meng L, Peng Y. The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins. Antiviral Res. 2014;106:80-85.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
85.  Tung WH, Hsieh HL, Yang CM. Enterovirus 71 induces COX-2 expression via MAPKs, NF-kappaB, and AP-1 in SK-N-SH cells: Role of PGE(2) in viral replication. Cell Signal. 2010;22:234-246.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 71]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
86.  Li YP, Liang ZL, Gao Q, Huang LR, Mao QY, Wen SQ, Liu Y, Yin WD, Li RC, Wang JZ. Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, Phase I clinical trial. Vaccine. 2012;30:3295-3303.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 78]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
87.  Lin YW, Chang KC, Kao CM, Chang SP, Tung YY, Chen SH. Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. J Virol. 2009;83:6477-6483.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 80]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
88.  Meng FY, Li JX, Li XL, Chu K, Zhang YT, Ji H, Li L, Liang ZL, Zhu FC. Tolerability and immunogenicity of an inactivated enterovirus 71 vaccine in Chinese healthy adults and children: an open label, phase 1 clinical trial. Hum Vaccin Immunother. 2012;8:668-674.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 37]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
89.  Li X, Mao C, Ma S, Wang X, Sun Z, Yi Y, Guo M, Shen X, Sun L, Bi S. Generation of neutralizing monoclonal antibodies against Enterovirus 71 using synthetic peptides. Biochem Biophys Res Commun. 2009;390:1126-1128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 39]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
90.  Kiener TK, Jia Q, Meng T, Chow VT, Kwang J. A novel universal neutralizing monoclonal antibody against enterovirus 71 that targets the highly conserved “knob” region of VP3 protein. PLoS Negl Trop Dis. 2014;8:e2895.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
91.  Han JF, Cao RY, Deng YQ, Tian X, Jiang T, Qin ED, Qin CF. Antibody dependent enhancement infection of enterovirus 71 in vitro and in vivo. Virol J. 2011;8:106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 51]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
92.  Wang SM, Chen IC, Su LY, Huang KJ, Lei HY, Liu CC. Enterovirus 71 infection of monocytes with antibody-dependent enhancement. Clin Vaccine Immunol. 2010;17:1517-1523.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 44]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
93.  Palivizumab , a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics. 1998;102:531-537.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Foo DG, Alonso S, Phoon MC, Ramachandran NP, Chow VT, Poh CL. Identification of neutralizing linear epitopes from the VP1 capsid protein of Enterovirus 71 using synthetic peptides. Virus Res. 2007;125:61-68.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 170]  [Cited by in F6Publishing: 169]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
95.  Lal SK, Kumar P, Yeo WM, Kar-Roy A, Chow VT. The VP1 protein of human enterovirus 71 self-associates via an interaction domain spanning amino acids 66-297. J Med Virol. 2006;78:582-590.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 23]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
96.  Chang GH, Luo YJ, Wu XY, Si BY, Lin L, Zhu QY. Monoclonal antibody induced with inactived EV71-Hn2 virus protects mice against lethal EV71-Hn2 virus infection. Virol J. 2010;7:106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 40]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
97.  Prabakaran M, Prabhu N, He F, Hongliang Q, Ho HT, Qiang J, Meng T, Goutama M, Kwang J. Combination therapy using chimeric monoclonal antibodies protects mice from lethal H5N1 infection and prevents formation of escape mutants. PLoS One. 2009;4:e5672.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 50]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
98.  ter Meulen J, van den Brink EN, Poon LL, Marissen WE, Leung CS, Cox F, Cheung CY, Bakker AQ, Bogaards JA, van Deventer E. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 2006;3:e237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 514]  [Cited by in F6Publishing: 479]  [Article Influence: 26.6]  [Reference Citation Analysis (0)]
99.  Leslie GA, Clem LW. Phylogen of immunoglobulin structure and function. 3. Immunoglobulins of the chicken. J Exp Med. 1969;130:1337-1352.  [PubMed]  [DOI]  [Cited in This Article: ]
100.  Amaral JA, Tino De Franco M, Carneiro-Sampaio MM, Carbonare SB. Anti-enteropathogenic Escherichia coli immunoglobulin Y isolated from eggs laid by immunised Leghorn chickens. Res Vet Sci. 2002;72:229-234.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 22]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
101.  Kweon CH, Kwon BJ, Woo SR, Kim JM, Woo GH, Son DH, Hur W, Lee YS. Immunoprophylactic effect of chicken egg yolk immunoglobulin (Ig Y) against porcine epidemic diarrhea virus (PEDV) in piglets. J Vet Med Sci. 2000;62:961-964.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Shin JH, Yang M, Nam SW, Kim JT, Myung NH, Bang WG, Roe IH. Use of egg yolk-derived immunoglobulin as an alternative to antibiotic treatment for control of Helicobacter pylori infection. Clin Diagn Lab Immunol. 2002;9:1061-1066.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Yokoyama H, Umeda K, Peralta RC, Hashi T, Icatlo FC, Kuroki M, Ikemori Y, Kodama Y. Oral passive immunization against experimental salmonellosis in mice using chicken egg yolk antibodies specific for Salmonella enteritidis and S. typhimurium. Vaccine. 1998;16:388-393.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Liou JF, Chang CW, Tailiu JJ, Yu CK, Lei HY, Chen LR, Tai C. Passive protection effect of chicken egg yolk immunoglobulins on enterovirus 71 infected mice. Vaccine. 2010;28:8189-8196.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 23]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
105.  Andreesen R, Hennemann B, Krause SW. Adoptive immunotherapy of cancer using monocyte-derived macrophages: rationale, current status, and perspectives. J Leukoc Biol. 1998;64:419-426.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Hart ML, Mosier DA, Chapes SK. Toll-like receptor 4-positive macrophages protect mice from Pasteurella pneumotropica-induced pneumonia. Infect Immun. 2003;71:663-670.  [PubMed]  [DOI]  [Cited in This Article: ]
107.  Ke B, Shen XD, Gao F, Ji H, Qiao B, Zhai Y, Farmer DG, Busuttil RW, Kupiec-Weglinski JW. Adoptive transfer of ex vivo HO-1 modified bone marrow-derived macrophages prevents liver ischemia and reperfusion injury. Mol Ther. 2010;18:1019-1025.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 36]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
108.  Lang PA, Recher M, Honke N, Scheu S, Borkens S, Gailus N, Krings C, Meryk A, Kulawik A, Cervantes-Barragan L. Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice. Hepatology. 2010;52:25-32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 66]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
109.  Liu J, Li X, Fan X, Ma C, Qin C, Zhang L. Adoptive transfer of macrophages from adult mice reduces mortality in mice infected with human enterovirus 71. Arch Virol. 2013;158:387-397.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 5]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
110.  Liu ML, Lee YP, Wang YF, Lei HY, Liu CC, Wang SM, Su IJ, Wang JR, Yeh TM, Chen SH. Type I interferons protect mice against enterovirus 71 infection. J Gen Virol. 2005;86:3263-3269.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 121]  [Cited by in F6Publishing: 125]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
111.  Lu J, Yi L, Zhao J, Yu J, Chen Y, Lin MC, Kung HF, He ML. Enterovirus 71 disrupts interferon signaling by reducing the level of interferon receptor 1. J Virol. 2012;86:3767-3776.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 105]  [Cited by in F6Publishing: 110]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
112.  Jaks E, Gavutis M, Uzé G, Martal J, Piehler J. Differential receptor subunit affinities of type I interferons govern differential signal activation. J Mol Biol. 2007;366:525-539.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 159]  [Cited by in F6Publishing: 167]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
113.  Yi L, Lu J, Kung HF, He ML. The virology and developments toward control of human enterovirus 71. Crit Rev Microbiol. 2011;37:313-327.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 83]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
114.  Hung HC, Wang HC, Shih SR, Teng IF, Tseng CP, Hsu JT. Synergistic inhibition of enterovirus 71 replication by interferon and rupintrivir. J Infect Dis. 2011;203:1784-1790.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 73]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
115.  Chen S, Yang Y, Yan X, Chen J, Yu H, Wang W. Influence of vitamin A status on the antiviral immunity of children with hand, foot and mouth disease. Clin Nutr. 2012;31:543-548.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 13]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
116.  Dimberg A, Nilsson K, Oberg F. Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts. Blood. 2000;96:2870-2878.  [PubMed]  [DOI]  [Cited in This Article: ]
117.  Luo XM, Ross AC. Physiological and receptor-selective retinoids modulate interferon gamma signaling by increasing the expression, nuclear localization, and functional activity of interferon regulatory factor-1. J Biol Chem. 2005;280:36228-36236.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 23]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
118.  Soye KJ, Trottier C, Richardson CD, Ward BJ, Miller WH. RIG-I is required for the inhibition of measles virus by retinoids. PLoS One. 2011;6:e22323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
119.  Lei X, Liu X, Ma Y, Sun Z, Yang Y, Jin Q, He B, Wang J. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol. 2010;84:8051-8061.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 164]  [Cited by in F6Publishing: 163]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
120.  Chen S, Yang Y, Xu J, Su L, Wang W. Effect of all-trans-retinoic acid on enterovirus 71 infection in vitro. Br J Nutr. 2014;111:1586-1593.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 15]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
121.  Lu WW, Hsu YY, Yang JY, Kung SH. Selective inhibition of enterovirus 71 replication by short hairpin RNAs. Biochem Biophys Res Commun. 2004;325:494-499.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 35]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
122.  Sim AC, Luhur A, Tan TM, Chow VT, Poh CL. RNA interference against enterovirus 71 infection. Virology. 2005;341:72-79.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 46]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
123.  Tan EL, Tan TM, Chow VT, Poh CL. Enhanced potency and efficacy of 29-mer shRNAs in inhibition of Enterovirus 71. Antiviral Res. 2007;74:9-15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 22]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
124.  Tan EL, Tan TM, Tak Kwong Chow V, Poh CL. Inhibition of enterovirus 71 in virus-infected mice by RNA interference. Mol Ther. 2007;15:1931-1938.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 40]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
125.  Li Y, Xie J, Xu X, Wang J, Ao F, Wan Y, Zhu Y. MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1. Protein Cell. 2013;4:130-141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 77]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
126.  Wen BP, Dai HJ, Yang YH, Zhuang Y, Sheng R. MicroRNA-23b inhibits enterovirus 71 replication through downregulation of EV71 VPl protein. Intervirology. 2013;56:195-200.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 55]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
127.  Zheng Z, Ke X, Wang M, He S, Li Q, Zheng C, Zhang Z, Liu Y, Wang H. Human microRNA hsa-miR-296-5p suppresses enterovirus 71 replication by targeting the viral genome. J Virol. 2013;87:5645-5656.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 135]  [Cited by in F6Publishing: 143]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
128.  Zhang L, Chen X, Shi Y, Zhou B, Du C, Liu Y, Han S, Yin J, Peng B, He X. miR-27a suppresses EV71 replication by directly targeting EGFR. Virus Genes. 2014;49:373-382.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 25]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
129.  Rayburn ER, Zhang R. Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible? Drug Discov Today. 2008;13:513-521.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 142]  [Article Influence: 8.9]  [Reference Citation Analysis (0)]
130.  Jones D. The long march of antisense. Nat Rev Drug Discov. 2011;10:401-402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 28]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
131.  Liu J, Zhou Z, Li K, Han M, Yang J, Wang S. In vitro and in vivo protection against enterovirus 71 by an antisense phosphorothioate oligonucleotide. Arch Virol. 2014;159:2339-2347.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 7]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
132.  Tan CW, Chan YF, Quah YW, Poh CL. Inhibition of enterovirus 71 infection by antisense octaguanidinium dendrimer-conjugated morpholino oligomers. Antiviral Res. 2014;107:35-41.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 12]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
133.  Chung PW, Huang YC, Chang LY, Lin TY, Ning HC. Duration of enterovirus shedding in stool. J Microbiol Immunol Infect. 2001;34:167-170.  [PubMed]  [DOI]  [Cited in This Article: ]
134.  Han J, Ma XJ, Wan JF, Liu YH, Han YL, Chen C, Tian C, Gao C, Wang M, Dong XP. Long persistence of EV71 specific nucleotides in respiratory and feces samples of the patients with Hand-Foot-Mouth Disease after recovery. BMC Infect Dis. 2010;10:178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 52]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
135.  Chang LY. Enterovirus 71 in Taiwan. Pediatr Neonatol. 2008;49:103-112.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 86]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
136.  Chang LY, King CC, Hsu KH, Ning HC, Tsao KC, Li CC, Huang YC, Shih SR, Chiou ST, Chen PY. Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan. Pediatrics. 2002;109:e88.  [PubMed]  [DOI]  [Cited in This Article: ]
137.  Bek EJ, McMinn PC. The Pathogenesis and Prevention of Encephalitis due to Human Enterovirus 71. Curr Infect Dis Rep. 2012;14:397-407.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 12]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
138.  Ang LW, Koh BK, Chan KP, Chua LT, James L, Goh KT. Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007. Ann Acad Med Singapore. 2009;38:106-112.  [PubMed]  [DOI]  [Cited in This Article: ]
139.  Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY. Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in Taiwan, 1998-2005. Pediatrics. 2007;120:e244-e252.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 223]  [Cited by in F6Publishing: 223]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
140.  Mizuta K, Abiko C, Murata T, Matsuzaki Y, Itagaki T, Sanjoh K, Sakamoto M, Hongo S, Murayama S, Hayasaka K. Frequent importation of enterovirus 71 from surrounding countries into the local community of Yamagata, Japan, between 1998 and 2003. J Clin Microbiol. 2005;43:6171-6175.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 128]  [Cited by in F6Publishing: 135]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
141.  Podin Y, Gias EL, Ong F, Leong YW, Yee SF, Yusof MA, Perera D, Teo B, Wee TY, Yao SC. Sentinel surveillance for human enterovirus 71 in Sarawak, Malaysia: lessons from the first 7 years. BMC Public Health. 2006;6:180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 157]  [Cited by in F6Publishing: 164]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
142.  Yu SC, Hao YT, Zhang J, Xiao GX, Liu Z, Zhu Q, Ma JQ, Wang Y. Using interrupted time series design to analyze changes in hand, foot, and mouth disease incidence during the declining incidence periods of 2008-2010 in China. Biomed Environ Sci. 2012;25:645-652.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 7]  [Reference Citation Analysis (0)]
143.  Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10:778-790.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 912]  [Cited by in F6Publishing: 949]  [Article Influence: 67.8]  [Reference Citation Analysis (0)]
144.  Wu TN, Tsai SF, Li SF, Lee TF, Huang TM, Wang ML, Hsu KH, Shen CY. Sentinel surveillance for enterovirus 71, Taiwan, 1998. Emerg Infect Dis. 1999;5:458-460.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 48]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
145.  Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003;9:78-85.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 186]  [Article Influence: 8.9]  [Reference Citation Analysis (0)]
146.  Chang SC, Li WC, Huang KY, Huang YC, Chiu CH, Chen CJ, Hsieh YC, Kuo CY, Shih SR, Lin TY. Efficacy of alcohols and alcohol-based hand disinfectants against human enterovirus 71. J Hosp Infect. 2013;83:288-293.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 18]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
147.  Arita M, Shimizu H, Nagata N, Ami Y, Suzaki Y, Sata T, Iwasaki T, Miyamura T. Temperature-sensitive mutants of enterovirus 71 show attenuation in cynomolgus monkeys. J Gen Virol. 2005;86:1391-1401.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 124]  [Cited by in F6Publishing: 130]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
148.  Arita M, Nagata N, Iwata N, Ami Y, Suzaki Y, Mizuta K, Iwasaki T, Sata T, Wakita T, Shimizu H. An attenuated strain of enterovirus 71 belonging to genotype a showed a broad spectrum of antigenicity with attenuated neurovirulence in cynomolgus monkeys. J Virol. 2007;81:9386-9395.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 112]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
149.  Dobrikova EY, Goetz C, Walters RW, Lawson SK, Peggins JO, Muszynski K, Ruppel S, Poole K, Giardina SL, Vela EM. Attenuation of neurovirulence, biodistribution, and shedding of a poliovirus: rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis. J Virol. 2012;86:2750-2759.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 39]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
150.  Gromeier M, Alexander L, Wimmer E. Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants. Proc Natl Acad Sci USA. 1996;93:2370-2375.  [PubMed]  [DOI]  [Cited in This Article: ]
151.  Kok CC, Phuektes P, Bek E, McMinn PC. Modification of the untranslated regions of human enterovirus 71 impairs growth in a cell-specific manner. J Virol. 2012;86:542-552.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 22]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
152.  Sadeghipour S, Bek EJ, McMinn PC. Ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture. J Virol. 2013;87:1759-1769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 51]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
153.  Sadeghipour S, McMinn PC. A study of the virulence in mice of high copying fidelity variants of human enterovirus 71. Virus Res. 2013;176:265-272.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 12]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
154.  Chumakov M, Voroshilova M, Shindarov L, Lavrova I, Gracheva L, Koroleva G, Vasilenko S, Brodvarova I, Nikolova M, Gyurova S. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol. 1979;60:329-340.  [PubMed]  [DOI]  [Cited in This Article: ]
155.  Ong KC, Devi S, Cardosa MJ, Wong KT. Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease. J Virol. 2010;84:661-665.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 108]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
156.  Dong C, Wang J, Liu L, Zhao H, Shi H, Zhang Y, Jiang L, Li Q. Optimized development of a candidate strain of inactivated EV71 vaccine and analysis of its immunogenicity in rhesus monkeys. Hum Vaccin. 2010;6:1028-1037.  [PubMed]  [DOI]  [Cited in This Article: ]
157.  Wu CN, Lin YC, Fann C, Liao NS, Shih SR, Ho MS. Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1 vaccines and inactivated virus. Vaccine. 2001;20:895-904.  [PubMed]  [DOI]  [Cited in This Article: ]
158.  Yu CK, Chen CC, Chen CL, Wang JR, Liu CC, Yan JJ, Su IJ. Neutralizing antibody provided protection against enterovirus type 71 lethal challenge in neonatal mice. J Biomed Sci. 2000;7:523-528.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 93]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
159.  Bek EJ, Hussain KM, Phuektes P, Kok CC, Gao Q, Cai F, Gao Z, McMinn PC. Formalin-inactivated vaccine provokes cross-protective immunity in a mouse model of human enterovirus 71 infection. Vaccine. 2011;29:4829-4838.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 57]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
160.  Chen CS, Yao YC, Lin SC, Lee YP, Wang YF, Wang JR, Liu CC, Lei HY, Yu CK. Retrograde axonal transport: a major transmission route of enterovirus 71 in mice. J Virol. 2007;81:8996-9003.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 132]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
161.  Iiai T, Watanabe H, Seki S, Sugiura K, Hirokawa K, Utsuyama M, Takahashi-Iwanaga H, Iwanaga T, Ohteki T, Abo T. Ontogeny and development of extrathymic T cells in mouse liver. Immunology. 1992;77:556-563.  [PubMed]  [DOI]  [Cited in This Article: ]
162.  Paoletti LC, Pinel J, Kennedy RC, Kasper DL. Maternal antibody transfer in baboons and mice vaccinated with a group B streptococcal polysaccharide conjugate. J Infect Dis. 2000;181:653-658.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 32]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
163.  van der Sanden S, van der Avoort H, Lemey P, Uslu G, Koopmans M. Evolutionary trajectory of the VP1 gene of human enterovirus 71 genogroup B and C viruses. J Gen Virol. 2010;91:1949-1958.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 55]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
164.  Chen CW, Lee YP, Wang YF, Yu CK. Formaldehyde-inactivated human enterovirus 71 vaccine is compatible for co-immunization with a commercial pentavalent vaccine. Vaccine. 2011;29:2772-2776.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 31]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
165.  Chang JY, Chang CP, Tsai HH, Lee CD, Lian WC, Ih-Jen-Su IH, Liu CC, Chou AH, Lu YJ, Chen CY. Selection and characterization of vaccine strain for Enterovirus 71 vaccine development. Vaccine. 2012;30:703-711.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 51]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
166.  Kung YA, Hung CT, Liu YC, Shih SR. Update on the development of enterovirus 71 vaccines. Expert Opin Biol Ther. 2014;14:1455-1464.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 30]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
167.  Mateu MG. Antibody recognition of picornaviruses and escape from neutralization: a structural view. Virus Res. 1995;38:1-24.  [PubMed]  [DOI]  [Cited in This Article: ]
168.  Minor PD. Antigenic structure of picornaviruses. Curr Top Microbiol Immunol. 1990;161:121-154.  [PubMed]  [DOI]  [Cited in This Article: ]
169.  Sivasamugham LA, Cardosa MJ, Tan WS, Yusoff K. Recombinant Newcastle Disease virus capsids displaying enterovirus 71 VP1 fragment induce a strong immune response in rabbits. J Med Virol. 2006;78:1096-1104.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 26]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
170.  Tan CS, Cardosa MJ. High-titred neutralizing antibodies to human enterovirus 71 preferentially bind to the N-terminal portion of the capsid protein VP1. Arch Virol. 2007;152:1069-1073.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 36]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
171.  Ch’ng WC, Stanbridge EJ, Wong KT, Ong KC, Yusoff K, Shafee N. Immunization with recombinant enterovirus 71 viral capsid protein 1 fragment stimulated antibody responses in hamsters. Virol J. 2012;9:155.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
172.  Wang M, Jiang S, Wang Y. Recombinant VP1 protein expressed in Pichia pastoris induces protective immune responses against EV71 in mice. Biochem Biophys Res Commun. 2013;430:387-393.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 30]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
173.  Chen F, Zhang ZR, Yuan F, Qin X, Wang M, Huang Y. In vitro and in vivo study of N-trimethyl chitosan nanoparticles for oral protein delivery. Int J Pharm. 2008;349:226-233.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 102]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
174.  Zhao W, Wu W, Xu X. Oral vaccination with liposome-encapsulated recombinant fusion peptide of urease B epitope and cholera toxin B subunit affords prophylactic and therapeutic effects against H. pylori infection in BALB/c mice. Vaccine. 2007;25:7664-7673.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 46]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
175.  Chiu CH, Chu C, He CC, Lin TY. Protection of neonatal mice from lethal enterovirus 71 infection by maternal immunization with attenuated Salmonella enterica serovar Typhimurium expressing VP1 of enterovirus 71. Microbes Infect. 2006;8:1671-1678.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 73]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
176.  Yu Z, Huang Z, Sao C, Huang Y, Zhang F, Ma G, Chen Z, Zeng Z, Qiwen D, Zeng W. Oral immunization of mice using Bifidobacterium longum expressing VP1 protein from enterovirus 71. Arch Virol. 2013;158:1071-1077.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 18]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
177.  Cárdenas L, Clements JD. Oral immunization using live attenuated Salmonella spp. as carriers of foreign antigens. Clin Microbiol Rev. 1992;5:328-342.  [PubMed]  [DOI]  [Cited in This Article: ]
178.  Wang L, Coppel RL. Oral vaccine delivery: can it protect against non-mucosal pathogens? Expert Rev Vaccines. 2008;7:729-738.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 31]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
179.  Chen HF, Chang MH, Chiang BL, Jeng ST. Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71. Vaccine. 2006;24:2944-2951.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 90]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
180.  Chen HL, Huang JY, Chu TW, Tsai TC, Hung CM, Lin CC, Liu FC, Wang LC, Chen YJ, Lin MF. Expression of VP1 protein in the milk of transgenic mice: a potential oral vaccine protects against enterovirus 71 infection. Vaccine. 2008;26:2882-2889.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 83]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
181.  Carrillo C, Wigdorovitz A, Oliveros JC, Zamorano PI, Sadir AM, Gómez N, Salinas J, Escribano JM, Borca MV. Protective immune response to foot-and-mouth disease virus with VP1 expressed in transgenic plants. J Virol. 1998;72:1688-1690.  [PubMed]  [DOI]  [Cited in This Article: ]
182.  Shih SR, Li YS, Chiou CC, Suen PC, Lin TY, Chang LY, Huang YC, Tsao KC, Ning HC, Wu TZ. Expression of capsid [correction of caspid] protein VP1 for use as antigen for the diagnosis of enterovirus 71 infection. J Med Virol. 2000;61:228-234.  [PubMed]  [DOI]  [Cited in This Article: ]
183.  Foo DG, Alonso S, Chow VT, Poh CL. Passive protection against lethal enterovirus 71 infection in newborn mice by neutralizing antibodies elicited by a synthetic peptide. Microbes Infect. 2007;9:1299-1306.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 122]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
184.  Tian X, Su X, Li X, Li H, Li T, Zhou Z, Zhong T, Zhou R. Protection against enterovirus 71 with neutralizing epitope incorporation within adenovirus type 3 hexon. PLoS One. 2012;7:e41381.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 31]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
185.  Liu JN, Wang W, Duo JY, Hao Y, Ma CM, Li WB, Lin SZ, Gao XZ, Liu XL, Xu YF. Combined peptides of human enterovirus 71 protect against virus infection in mice. Vaccine. 2010;28:7444-7451.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 54]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
186.  Hu YC, Hsu JT, Huang JH, Ho MS, Ho YC. Formation of enterovirus-like particle aggregates by recombinant baculoviruses co-expressing P1 and 3CD in insect cells. Biotechnol Lett. 2003;25:919-925.  [PubMed]  [DOI]  [Cited in This Article: ]
187.  Lin YL, Yu CI, Hu YC, Tsai TJ, Kuo YC, Chi WK, Lin AN, Chiang BL. Enterovirus type 71 neutralizing antibodies in the serum of macaque monkeys immunized with EV71 virus-like particles. Vaccine. 2012;30:1305-1312.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 70]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
188.  Li HY, Han JF, Qin CF, Chen R. Virus-like particles for enterovirus 71 produced from Saccharomyces cerevisiae potently elicits protective immune responses in mice. Vaccine. 2013;31:3281-3287.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 68]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
189.  Rodríguez-Limas WA, Tyo KE, Nielsen J, Ramírez OT, Palomares LA. Molecular and process design for rotavirus-like particle production in Saccharomyces cerevisiae. Microb Cell Fact. 2011;10:33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 44]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
190.  Tung WS, Bakar SA, Sekawi Z, Rosli R. DNA vaccine constructs against enterovirus 71 elicit immune response in mice. Genet Vaccines Ther. 2007;5:6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 95]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
191.  Cui Z, Baizer L, Mumper RJ. Intradermal immunization with novel plasmid DNA-coated nanoparticles via a needle-free injection device. J Biotechnol. 2003;102:105-115.  [PubMed]  [DOI]  [Cited in This Article: ]
192.  Garmory HS, Brown KA, Titball RW. DNA vaccines: improving expression of antigens. Genet Vaccines Ther. 2003;1:2.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 94]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
193.  Greenland JR, Letvin NL. Chemical adjuvants for plasmid DNA vaccines. Vaccine. 2007;25:3731-3741.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 92]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
194.  Gurunathan S, Klinman DM, Seder RA. DNA vaccines: immunology, application, and optimization*. Annu Rev Immunol. 2000;18:927-974.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 893]  [Cited by in F6Publishing: 857]  [Article Influence: 35.7]  [Reference Citation Analysis (0)]