A virus-like particle vaccine for coxsackievirus A16 potently elicits neutralizing antibodies that protect mice against lethal challenge

Li, Renjie; Yan, Kexia; Feng, Yanni; Huang, Xulin; Ku, Zhiqiang; Cai, Yuepiao; Liu, Fei; Shi, Jinping; Huang, Zhong

doi:10.1016/j.vaccine.2012.08.071

Cited by 68 publications

(58 citation statements)

References 22 publications

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“…CA16 strain SZ05 (GenBank accession no. EU262658) has been described previously (19). All viruses were propagated in RD cells as described previously (18,19).…”

Section: Cells and Virusesmentioning

confidence: 99%

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Chimeric Virus-Like Particle Vaccines Displaying Conserved Enterovirus 71 Epitopes Elicit Protective Neutralizing Antibodies in Mice through Divergent Mechanisms

et al. 2014

J Virol

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Enterovirus 71 (EV71) is a major causative agent of hand, food, and mouth disease, which frequently occurs in young children. Since there are 11 subgenotypes (A, B1 to B5, and C1 to C5) within EV71, an EV71 vaccine capable of protecting against all of these subgenotypes is desirable. We report here the vaccine potential and protective mechanism of two chimeric virus-like particles (VLPs) presenting conserved neutralizing epitopes of EV71. We show that fusions of hepatitis B core antigen (HBc) with the SP55 or SP70 epitope of EV71, designated HBcSP55 and HBcSP70, respectively, can be rapidly generated and self-assembled into VLPs with the epitopes displayed on the surface. Immunization with the chimeric VLPs induced carrier-and epitope-specific antibody responses in mice. Anti-HBcSP55 and anti-HBcSP70 sera, but not anti-HBc sera, were able to neutralize in vitro multiple genotypes and strains of EV71. Importantly, passive immunization with anti-HBcSP55 or anti-HBcSP70 sera protected neonatal mice against lethal EV71 infections. Interestingly, anti-HBcSP70 sera could inhibit EV71 attachment to susceptible cells, whereas anti-HBcSP55 sera could not. However, both antisera were able to neutralize EV71 infection in vitro at the postattachment stage. The divergent mechanism of neutralization and protection conferred by anti-SP70 and anti-SP55 sera is in part attributed to their respective ability to bind authentic viral particles. Collectively, our study not only demonstrates that chimeric VLPs displaying the SP55 and SP70 epitopes are promising candidates for a broad-spectrum EV71 vaccine but also reveals distinct mechanisms of neutralization by the SP55-and SP70-targeted antibodies. E nterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease, which is prevalent in the Asia-Pacific region. EV71 infection may result in severe neurological complications and even death (1-3). However, there is currently no available EV71 vaccine (4, 5).EV71 is a member of the enterovirus genus of the Picornaviridae family. It possesses a single-stranded, positive-sense RNA genome, which is encapsidated within an icosahedral capsid consisting of 60 copies of each of VP1, VP2, VP3, and VP4 subunit proteins. Based on the VP1 sequence, EV71 is categorized into three genotypes (A, B, and C), which can be further divided into eleven subgenotypes (A, B1 to B5, and C1 to C5) (reviewed in references 1 and 2). Thus, an EV71 vaccine capable of protecting against all of these subgenotypes is desirable.Increasing evidence has established that neutralizing antibodies play a key role in in vivo protection against lethal EV71 infection (reviewed in references 4 and 5). For example, Foo et al. showed that passive transfer of neutralizing antisera protects recipient mice against lethal EV71 challenge (6). Inactivated wholevirus and recombinant EV71 virus-like particles (VLPs) containing all capsid subunit proteins could elicit potent neutralizing antibodies (reviewed in references 4 and 5). Besides intact capsids, VP1 has been sh...

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“…CA16 strain SZ05 (GenBank accession no. EU262658) has been described previously (19). All viruses were propagated in RD cells as described previously (18,19).…”

Section: Cells and Virusesmentioning

confidence: 99%

“…EU262658) has been described previously (19). All viruses were propagated in RD cells as described previously (18,19). The virus titers were determined by the Reed and Muench method based on a typical cytopathic effect (CPE) developing in the infected RD cells and expressed in 50% tissue culture infectious doses (TCID 50 ).…”

Section: Cells and Virusesmentioning

confidence: 99%

Chimeric Virus-Like Particle Vaccines Displaying Conserved Enterovirus 71 Epitopes Elicit Protective Neutralizing Antibodies in Mice through Divergent Mechanisms

et al. 2014

J Virol

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“…Various candidates against EV71 or CA16 virus, including inactivated vaccines (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), live attenuated vaccines (23,24), subunit vaccines based on the VP1 protein (25), virus-like particle (VLP) vaccines (26)(27)(28)(29)(30)(31)(32)(33)(34), and epitopebased vaccines (35)(36)(37)(38)(39), were shown to possess various levels of efficacy in animal studies or human clinical trials. In particular, inactivated EV71 vaccines showed promising results against EV71-associated diseases in recent phase 3 clinical studies conducted in mainland China (20)(21)(22).…”

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confidence: 99%

“…Expression systems based on baculovirus-insect cells are often used for the production of VLP vaccines. Coexpression in insect cells of the P1 (encoding viral structural proteins) and 3CD (encoding viral proteases) genes mimics the early steps of the enteroviral life cycle, including proteolysis of polyprotein, assembly into empty capsid, and generation of VLPs (26,28,29,33). Both EV71 and CA16 VLPs consist of 60 copies for each of the capsid proteins, VP0, VP1, and VP3, which follow a P ϭ 3 icosahedral arrangement.…”

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confidence: 99%

Cryo-Electron Microscopy Study of Insect Cell-Expressed Enterovirus 71 and Coxsackievirus A16 Virus-Like Particles Provides a Structural Basis for Vaccine Development

Gong

Zhu

Zhou

et al. 2014

J Virol

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Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (HFMD), a childhood illness with occasional severe neurological complications. A number of vaccine candidates against EV71 or CA16 have been reported; however, no vaccine is currently available for clinical use. Here, we generated a secreted version of EV71 and CA16 virus-like particles (VLPs) using a baculovirus-insect cell expression system and reconstructed the three-dimensional (3D) structures of both VLPs by cryo-electron microscopy (cryo-EM) single-particle analysis at 5.2-Å and 5.5-Å resolutions, respectively. The reconstruction results showed that the cryo-EM structures of EV71 and CA16 VLPs highly resemble the recently published crystal structures for EV71 natural empty particles and CA16 135S-like expanded particles, respectively. Our cryo-EM analysis also revealed that the majority of previously identified linear neutralizing epitopes are well preserved on the surface of EV71 and CA16 VLPs. In addition, both VLPs were able to induce efficiently neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71-and CA16-associated HFMD. IMPORTANCEThe recent outbreaks of hand, foot, and mouth disease (HFMD) in the Asia Pacific region spurred the search for effective vaccines against EV71 and CA16 viruses, the two most common etiological agents responsible for HFMD. In this paper, we show that secreted versions of EV71 and CA16 VLPs generated in the baculovirus-insect cell expression system highly resemble the crystal structures of their viral conterparts and that the majority of previously identified linear neutralizing epitopes are well preserved on the VLP surfaces. In addition, the generated VLPs can efficiently induce neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71-and CA16-associated HFMD. Hand, foot, and mouth disease (HFMD) most frequently occurs in infants or children under 5 years old. Although most cases are mild and self-limited, HFMD can in some cases cause severe symptoms, such as myocarditis, pulmonary edema, and central nervous system complications ranging from flaccid paralysis to fatal encephalitis (1, 2). The recent epidemics of HFMD led to serious public health threats in the Asia Pacific region. In China, 1.16 million and 1.77 million cases of HFMD, including 353 and 905 deaths, were reported for 2009 and 2010, respectively (3). Etiologic studies revealed that enteroviruses, especially enterovirus 71 (EV71) and coxsackievirus A16 (CA16), are the most common causative agents responsible for HFMD epidemics (4-6). A clinical survey of the...

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“…9 As a result, inactivated or subunit vaccines are believed to be a feasible alternative for preventing CA16 infection due to their controllable safety compared with that of attenuated vaccines. [10][11][12] Recently, it has been reported that an experimental, inactivated CA16 vaccine candidate provides effective protection against CA16 infection by inducing a neutralizing antibody response in mice; this response was demonstrated using an immunological analysis (neutralizing antibodies assay and lethal challenge analysis). 12 Although some studies report that mice could be a candidate model for HFMD, the characterization of this immune response in different animal models (especially in primates, who share a close relationship to humans) would provide more support for these studies.…”

Section: Introductionmentioning

confidence: 99%

Comparative study of the immunogenicity in mice and monkeys of an inactivated CA16 vaccine made from a human diploid cell line

Yang

Chen

Zhang

et al. 2014

Human Vaccines & Immunotherapeutics

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A virus-like particle vaccine for coxsackievirus A16 potently elicits neutralizing antibodies that protect mice against lethal challenge

Cited by 68 publications

References 22 publications

Chimeric Virus-Like Particle Vaccines Displaying Conserved Enterovirus 71 Epitopes Elicit Protective Neutralizing Antibodies in Mice through Divergent Mechanisms

Chimeric Virus-Like Particle Vaccines Displaying Conserved Enterovirus 71 Epitopes Elicit Protective Neutralizing Antibodies in Mice through Divergent Mechanisms

Cryo-Electron Microscopy Study of Insect Cell-Expressed Enterovirus 71 and Coxsackievirus A16 Virus-Like Particles Provides a Structural Basis for Vaccine Development

Comparative study of the immunogenicity in mice and monkeys of an inactivated CA16 vaccine made from a human diploid cell line

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