Abstract
Non-polio enteroviruses, including enterovirus 71 (EV71), have caused severe and fatal cases of hand, foot and mouth disease (HFMD) in the Asia-Pacific region. The development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. In this study, a mouse adapted EV71 strain was produced by conducting serial passages through A129 (α/β interferon (IFN) receptor deficient) and AG129 (α/β, γ IFN receptor deficient) mice. A B2 sub genotype of EV71 was inoculated intraperitoneally (i.p.) into neonatal AG129 mice and brain-harvested virus was subsequently passaged through 12 and 15 day-old A129 mice. When tested in 10 week-old AG129 mice, this adapted strain produced 100% lethality with clinical signs including limb paralysis, eye irritation, loss of balance, and death. This virus caused only 17% mortality in same age A129 mice, confirming that in the absence of a functional IFN response, adult AG129 mice are susceptible to infection by adapted EV71 isolates. Subsequent studies in adult AG129 and young A129 mice with the adapted EV71 virus examined the efficacy of an inactivated EV71 candidate vaccine and determined the role of humoral immunity in protection. Passive transfer of rabbit immune sera raised against the EV71 vaccine provided protection in a dose dependent manner in 15 day-old A129 mice. Intramuscular injections (i.m.) in five week-old AG129 mice with the alum adjuvanted vaccine also provided protection against the mouse adapted homologous strain. No clinical signs of disease or mortality were observed in vaccinated animals, which received a prime-and-boost, whereas 71% of control animals were euthanized after exhibiting systemic clinical signs (P<0.05). The development of this animal model will facilitate studies on EV71 pathogenesis, antiviral testing, the evaluation of immunogenicity and efficacy of vaccine candidates, and has the potential to establish correlates of protection studies.
Highlights
Hand, foot and mouth disease (HFMD) is an emerging humanviral disease causing significant public health concerns across the Asia-Pacific region
3.1 Adaptation of enterovirus 71 (EV71) Virus in Adult AG129 Mice Blind serial passages of EV71 MS/7423/87 resulted in the generation of an adapted virus that was lethal in adult AG129 mice
A trial inoculation of the P3 EV71 virus in 10 weekold AG129 mice (n = 4) resulted in clinical disease with three mice being euthanized between days 10–12 p.i., and one mouse showing no signs of disease
Summary
Foot and mouth disease (HFMD) is an emerging humanviral disease causing significant public health concerns across the Asia-Pacific region. In 2010, a HFMD outbreak in China caused at least 1.7 million cases and 905 deaths [4]. In 2011, severe outbreaks were reported in many Asian countries including Japan (346,000 cases), and Vietnam (110,000 cases and 160 deaths) [5]. It has been reported in Singapore, Europe, Australia, Middle East and the United States [2]. Epidemiological studies in the beginning of 2012 have shown the number of HFMD cases rising in China and Singapore, remaining steady in Japan and Vietnam, and causing a recent outbreak in Cambodia [5,8]
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