Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys

Dong, Chuan; Liu, Long-ding; Zhao, Hang; Wang, Jingjing; Liao, Yun; Zhang, Xuemei; Na, Ruixiong; Liang, Yan; Wang, Lichun; Li, Qihan

doi:10.1016/j.vaccine.2011.06.044

Cited by 66 publications

(55 citation statements)

References 26 publications

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“…In several laboratories, neonatal mice have been used as models for studying EV71 pathogenesis and for the development of vaccines and antiviral drugs (17,18,(45)(46)(47). However, EV71 infection in the neonatal mouse model is significantly different from that in humans as the major viral replication sites in the mouse system include muscle and adipose tissues.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

Fujii¹,

Nagata

Sato

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

141

150

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Enterovirus 71 (EV71) typically causes mild hand-foot-and-mouth disease in children, but it can also cause severe neurological disease. Recently, epidemic outbreaks of EV71 with significant mortality have been reported in the Asia-Pacific region, and EV71 infection has become a serious public health concern worldwide. However, there is little information available concerning EV71 neuropathogenesis, and no vaccines or anti-EV71 drugs have been developed. Previous studies of this disease have used monkeys and neonatal mice that are susceptible to some EV71 strains as models. The monkey model is problematic for ethical and economical reasons, and mice that are more than a few weeks old lose their susceptibility to EV71. Thus, the development of an appropriate small animal model would greatly contribute to the study of this disease. Mice lack EV71 susceptibility due to the absence of a receptor for this virus. Previously, we identified the human scavenger receptor class B, member 2 (hSCARB2) as a cellular receptor for EV71. In the current study, we generated a transgenic (Tg) mouse expressing hSCARB2 with an expression profile similar to that in humans. Tg mice infected with EV71 exhibited ataxia, paralysis, and death. The most severely affected cells were neurons in the spinal cord, brainstem, cerebellum, hypothalamus, thalamus, and cerebrum. The pathological features in these Tg mice were generally similar to those of EV71 encephalomyelitis in humans and experimentally infected monkeys. These results suggest that this Tg mouse could represent a useful animal model for the study of EV71 infection.picornavirus | neurotropism | viral receptor E nterovirus 71 (EV71) is a human enterovirus species A of the genus Enterovirus within the Picornaviridae family, and it is known to be one of the causative agents of hand-foot-and-mouth disease (HFMD) (1, 2). HFMD is generally considered to be a mild exanthematous disease. However, in some infants and young children, after a few days of prodromal illness, HFMD caused predominantly by EV71 can be complicated by neurological manifestations, including ataxia, tremor, myoclonus, polio-like paralysis, encephalomyelitis, cardiopulmonary failure, and death (3, 4). In humans with fatal EV71 encephalomyelitis, inflammation and viral antigens in neurons were observed mainly in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus, and cerebrum (5, 6). Since the 1970s, HFMD outbreaks with significant mortality have been reported throughout the world, including in Bulgaria in 1975 [44 deaths (7) Appropriate animal models are needed to better understand EV71 neuropathogenesis and to facilitate the development of effective vaccines and drugs. EV71-infected cynomolgus monkeys developed neurological complications similar to those observed in human cases, including ataxia, tremor, and flaccid paralysis (11-15), and pathological lesions were observed in the spinal cord, brainstem, cerebellar dentate nucleus, and other parts of the brain (14,15). However, the use of monkeys to mod...

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Section: Discussionmentioning

confidence: 99%

Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

Fujii¹,

Nagata

Sato

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

141

150

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“…Given the aseptic meningitis and rhombencephalitis caused by CA16 in humans and the validity of the EV71 mouse model of i.c. inoculation (3,5,9), i.c. inoculation was finally selected to establish this CA16 mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, EV71, with very close gene homology and clinical symptoms to CA16, is also sensitive to suckling mice (1,9). Thus, the maternal antibody protection method for the evaluation of EV71 vaccines was successfully used (1, 6-9, 47, 53), in which dams were immunized and specific maternal antibody vertically transferred from dams to pups demonstrated excellent protection against EV71 challenge in the pups.…”

Section: Discussionmentioning

confidence: 99%

A Neonatal Mouse Model of Coxsackievirus A16 for Vaccine Evaluation

Mao

Wang

Gao

et al. 2012

J Virol

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cTo evaluate vaccine efficacy in protecting against coxsackievirus A16 (CA16), which causes human hand, foot, and mouth disease (HFMD), we established the first neonatal mouse model. In this article, we report data concerning CA16-induced pathological changes, and we demonstrate that anti-CA16 antibody can protect mice against lethal challenge and that the neonatal mouse model could be used to evaluate vaccine efficacy. To establish a mouse model, a BJCA08/CA16 strain (at 260 50% lethal doses [LD 50 ]) was isolated from a patient and used to intracerebrally (i.c.) inoculate neonatal mice. The infection resulted in wasting, hind-limb paralysis, and even death. Pathological examination and immunohistochemistry (IHC) staining indicated that BJCA08 had a strong tropism to muscle and caused severe necrosis in skeletal and cardiac muscles. We then found that BJCA08 pretreated with goat anti-G10/CA16 serum could significantly lose its lethal effect in neonatal mice. When the anti-G10 serum was intraperitoneally (i.p.) injected into the neonatal mice and, within 1 h, the same mice were intracerebrally inoculated with BJCA08, there was significant passive immunization protection. In a separate experiment, female mice were immunized with formaldehyde-inactivated G10/CA16 and BJCA08/CA16 and then allowed to mate 1 h after the first immunization. We found that there was significant protection against BJCA08 for neonatal mice born to the immunized dams. These data demonstrated that anti-CA16 antibody may block virus invasion and protect mice against lethal challenge, and that the neonatal mouse model was a viable tool for evaluating vaccine efficacy. C oxsackievirus A16 (CA16) belongs to the Enterovirus genus of the Picornaviridae family and is one of the major pathogens associated with human hand, foot, and mouth disease (HFMD) (4,16,19). CA16 was first isolated in 1951 (43). It is a single positive-stranded RNA virus and has an icosahedral symmetry structure. Its genome has approximately 7,410 nucleotides with one predominant serotype. Based on the VP4 nucleotide sequences, CA16 is classified into three distinct genetic lineages: A, B, and C. Before the 1990s, lineages A and B were the major epidemic strains in Asia (predominantly the B strain). After that, the CA16 gene gradually mutated to form lineage C, which replaced the B strain as the predominant epidemic strain (22).Epidemics of HFMD have been reported in England, Australia, Japan, Germany, Malaysia, Singapore, mainland China, and Taiwan (2,4,11,19,23,27,32,38,41,48). Recently, HFMD was highly epidemical in the west Pacific region, resulting in severe illness and fatalities (15, 23). The HFMD epidemics were mainly caused by CA16 and human enterovirus 71 (EV71), which circulated alternatively or together in the epidemic area (19,22,23,25,37). Because the most severe or fatal cases were caused by EV71, studies have mainly focused on EV71 but not CA16. However, in England, the largest HFMD outbreak (in 1994) was caused by CA16 (2). Similarly, in Taiwan the leading cau...

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“…24,26,34,56,57 The virus titer of EV71 strain (KJ508817) 4.5 £ 10 5 PFU/ml and CVA16 strain (JQ180468.1) 6.6 £ 10 6 PFU/ml were determined using a plaque assay on RDS cells. The newborn mice (age < 24 h) were selected (n D 10-20 per group) and intracerebrally (i.c.)…”

Section: Total Specific Igg Antibodies and Cross-reactive Igg Antibodiesmentioning

confidence: 99%

Evaluation of monovalent and bivalent vaccines against lethalEnterovirus71 andCoxsackievirusA16 infection in newborn mice

Sun

Jiang

Liang

et al. 2014

Human Vaccines & Immunotherapeutics

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Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) have caused severe epidemics of hand, foot and mouth disease (HFMD) in the Asia Pacific in recent years, particularly in infants and young children. This disease has become a serious public health problem, as no vaccines or antiviral drugs have been approved for EV71 and CA16 infections. In this study, we compared four monovalent vaccines, including formalin-inactivated EV71 virus (iEV71), EV71 virus-like particles (VLPs) (vEV71), formalin-inactivated CVA16 virus (iCVA16) and CVA16 VLPs (vCVA16), along with two bivalent vaccines, including equivalent doses of formalin-inactivated EV71CCVA16 virus (iEV71CiCVA16) and EV71CCVA16 VLPs (vEV71CvCVA16). The IgG titers and neutralization antibodies titers demonstrated that there are no immune interference exists between the two immunogens of EV71 and CVA16. IgG subclass isotyping revealed that IgG1 and IgG2b were induced primarily in all vaccine groups. Furthermore, cross-neutralization antibodies were elicited in mouse sera against other sub-genotypes of EV71 and CVA16. In vivo challenge experiments showed that the immune sera from vaccinated animals could confer passive protection to newborn mice against lethal challenge with 14 LD 50 of EV71 and 50 LD 50 of CVA16. Our results indicated that bivalent vaccination is promising for HFMD vaccine development. With the advantage of having a better safety profile than inactivated virus vaccines, VLPs should be used to combine both EV71 and CVA16 antigens as a candidate vaccine for prevention of HFMD virus transmission.

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Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys

Cited by 66 publications

References 26 publications

Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

A Neonatal Mouse Model of Coxsackievirus A16 for Vaccine Evaluation

Evaluation of monovalent and bivalent vaccines against lethalEnterovirus71 andCoxsackievirusA16 infection in newborn mice

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