title: Adaptation of enterovirus 71 to adult interferon deficient mice.
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.
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. ecaine@wisc.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Caine
authors.forename: Charalambos D
authors.initials: CD
authors.lastname: Partidos
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Santangelo
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Osorio
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000235:genetics / Q000502:physiology*; D006232:Hand, Foot and Mouth Disease / Q000276:immunology* / Q000821:virology; D007106:Immune Sera / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009500:Neutralization Tests; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012692:Serial Passage / Q000379:methods*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D007106:Immune Sera; D014765:Viral Vaccines; D053633:Receptor, Interferon alpha-beta