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Introduction
Enterovirus 71 (EV71), together with Coxsackievirus A16, is a common cause of hand, foot, and mouth disease (HFMD), and sometimes, albeit rarely, infection with this virus can result in neurological disorders induced by inflammation in the central nervous system (CNS). In Asian countries, including Korea, Japan, and China, there have been several outbreaks of HFMD, and thus it has become an important public health problem in this region [1] . HFMD caused by EV71 infection usually occurs in infants and children under 5 years of age and shows mild symptoms including blisters or ulcers on the hands, feet, and mouth with pharyngitis. However, CNS infection with EV71 sometimes results in aseptic meningitis, encephalitis, and acute flaccid paralysis with significant fatality rates. Unfortunately, there are currently no approved vaccines or antiviral therapeutics to prevent or treat EV71 infection [2] .
EV71 is a non-enveloped, positive-sense, single-stranded RNA virus belonging to the genus Enterovirus in the family Picornaviridae. The RNA genome of EV71 consists of about 7400 nucleotides, and the viral capsid includes 4 proteins: VP1, VP2, VP3, and VP4. Based on its antigenicity and the neutralization capacity of antibodies that are raised against it, VP1 is regarded as one of the major antigenic targets for the development of a subunit vaccine to prevent EV71 infection [3] . In addition, VP1 contains the most antigenic determinants for T cell responses that reinforce humoral immunity and that are known to be critical for preventing EV71 infection [4] . In this regard, recent study has suggested that recombinant VP1 protein produced by Escherichia coli would be a good EV71 vaccine candidate because of the strong humoral and cellular immunity induced in mice [3] . Although the antigenic characteristics of recombinant VP1 proteins expressed in E. coli[5] and Pichia pastoris[6] were evaluated in mice, the protective efficacy of these vaccine candidates was tested only by passive serum transfer in newborn mice, due to the lack of appropriate EV71-infection models. Similarly, it has been difficult to evaluate the protective efficacy of other types of EV71 vaccines based on virus-like particles and inactivated virus in existing mice model [5,7,8] .
Recently, randomized, double-blinded, placebo-controlled phase 3 trials of inactivated EV71 vaccines were conducted in China with healthy children, and...