A virus-like particle based bivalent vaccine confers dual protection against enterovirus 71 and coxsackievirus A16 infections in mice

Ku, Zhiqiang; Li, Renjie; Ye, Xiaohua; Cai, Yuepiao; Wang, Xiaoli; Shi, Jinping; Li, Dapeng; Jin, Xia; An, Wenqi; Huang, Zhong

doi:10.1016/j.vaccine.2014.06.025

Cited by 70 publications

(57 citation statements)

References 42 publications

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“…The animal studies were approved by the Institutional Animal Care and Use Committee at the Institut Pasteur of Shanghai, and the animals were cared for in accordance with the institutional guidelines. The 9B5 anti-CVA16 monoclonal antibodies were generated in-house from mice immunized with inactivated CVA16 as described previously (44).…”

Section: Methodsmentioning

confidence: 99%

Beta-Propiolactone Inactivation of Coxsackievirus A16 Induces Structural Alteration and Surface Modification of Viral Capsids

Chen

et al. 2017

J Virol

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Beta-propiolactone (BPL) is an inactivating agent that is widely used in the vaccine industry. However, its effects on vaccine protein antigens and its mechanisms of action remain poorly understood. Here we present cryo-electron microscopy (cryo-EM) structures of BPL-treated coxsackievirus A16 (CVA16) mature virions and procapsids at resolutions of 3.9 Å and 6.5 Å, respectively. Notably, both particles were found to adopt an expanded conformation resembling the 135S-like uncoating intermediate, with characteristic features including an opened 2-fold channel, the externalization of the N terminus of VP1 capsid protein, and the absence of pocket factor. However, major neutralizing epitopes are very well preserved on these particles. Further biochemical analyses revealed that BPL treatment impairs the abilities of CVA16 particles to bind to the attachment receptor heparan sulfate and to a conformation-dependent monoclonal antibody in a BPL dose-dependent manner, indicating that BPL is able to modify surface-exposed amino acid residues. Taken together, our results demonstrate that BPL treatment may induce alteration of the overall structure and surface properties of a nonenveloped viral capsid, thus revealing a novel mode of action of BPL.IMPORTANCE Beta-propiolactone (BPL) is commonly used as an inactivating reagent to produce viral vaccines. It is recognized that BPL inactivates viral infectivity through modification of viral nucleic acids. However, its effect on viral proteins remains largely unknown. Here, we present high-resolution cryo-EM structures of BPLtreated coxsackievirus A16 (CVA16) mature virions and procapsids, which reveals an expanded overall conformation and characteristic features that are typical for the 135S-like uncoating intermediate. We further show that the BPL concentration affects the binding of inactivated CVA16 particles to their receptor/antibody. Thus, BPL treatment can alter the overall structure and surface properties of viral capsids, which may lead to antigenic and immunogenic variations. Our findings provide important information for future development of BPL-inactivated vaccines.KEYWORDS Beta-propiolactone, coxsackievirus A16, cryo-EM structure, structural alteration, surface modification E nterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the two major causative agents of hand, foot, and mouth disease (HFMD), which has been prevalent in young children in the Asia-Pacific region (1). According to a recent survey, EV71 and CVA16 were associated with 50.4% and 38.3% of the 266 laboratory-confirmed HFMD

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Section: Methodsmentioning

confidence: 99%

Beta-Propiolactone Inactivation of Coxsackievirus A16 Induces Structural Alteration and Surface Modification of Viral Capsids

Chen

et al. 2017

J Virol

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“…170 Maternal immunization with a VLP-based bivalent vaccine produced in the baculovirus system and adjuvanted with alum conferred full protection to newborns against lethal challenge either with EV-A71 or CV-A16. 172 Crystallographic studies revealed that the EV-A71 BC loop could serve as an ideal insertion site for the display of foreign neutralization epitopes without perturbing the capsid structure, 93 thus providing the mean to engineer potential EV-A71/CV-A16 hybrid immunogens. Along a similar concept, antisera raised in mice vaccinated with a novel chimeric EV-A71-based VLP in which the autologous neutralization epitope SP70 had been replaced by that of CV-A16 conferred protection in neonates against lethal challenge in a passive transfer experiment.…”

Section: Development Of a Bivalent Ev-a71/cv-a16 Vaccinementioning

confidence: 99%

“…In this regard, the introduction of a protective bivalent EV-A71/CV-A16 vaccine on the market should markedly reduce the number of HFMD cases. [170][171][172][173][174] CV-A16 strains of the B genotype that have elicited both homologous and heterologous protection against genotypes A and B in pre-clinical studies are potential candidates for a multivalent HFMD vaccine. [166][167][168] The selection of CV-A6, CV-A10, CV-B3, CV-B5 and E-30 vaccine strains will have to be based on comprehensive epidemiological information to identify the most prevalent circulating genotype(s) for each enterovirus serotype.…”

Section: Cross-protective Ability Of a Multivalent Vaccine And Selectmentioning

confidence: 99%

“…157 Importantly, the risk of subneutralizing antibody levels exposing to antibody-dependent enhancement of disease described for EV-A71, CV-A16 and CV-B3 should be prevented. 172,176,184 In an early Phase II trial, 773 participants who had received at least 1 dose of EV-A71 vaccine were enrolled to receive a booster dose. 185 A 10-fold increase at least in neutralizing antibody responses was induced by the booster injection.…”

Section: Duration Of Humoral Immunity Role Of Cellular Responses Andmentioning

confidence: 99%

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Is a multivalent hand, foot, and mouth disease vaccine feasible?

Klein¹,

Chong

2015

Human Vaccines & Immunotherapeutics

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Keywords: bivalent and multivalent vaccines, coxsackievirus A16, coxsackieviruses B3 and B5, echovirus 30, epidemiology, enterovirus A (EV-A), enterovirus A71, hand, foot and mouth diseases, inactivated whole virion vaccines, monovalent, EV-A71 vaccine Enterovirus A infections are the primary cause of hand, foot and mouth disease (HFMD) in infants and young children. Although enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are the predominant causes of HFMD epidemics worldwide, EV-A71 has emerged as a major neurovirulent virus responsible for severe neurological complications and fatal outcomes. HFMD is a serious health threat and economic burden across the Asia-Pacific region. Inactivated EV-A71 vaccines have elicited protection against EV-A71 but not against CV-A16 infections in large efficacy trials. The current development of a bivalent inactivated EV-A71/CV-A16 vaccine is the next step toward that of multivalent HFMD vaccines. These vaccines should ultimately include other prevalent pathogenic coxsackieviruses A (CV-A6 and CV-A10), coxsackieviruses B (B3 and B5) and echovirus 30 that often co-circulate during HFMD epidemics and can cause severe HFMD, aseptic meningitis and acute viral myocarditis. The prospect and challenges for the development of such multivalent vaccines are discussed.

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“…Bivalent EV-A71/CV-A16 vaccines based on inactivated viruses or VLPs can elicit high titres of neutralizing antibodies in immunized mice and protect from EV-A71 and CV-A16 infections [146]. Yet broader protection is desired to mitigate other HFMD contributors, such as coxsackievirus A6 (CV-A6) [147], and one trivalent EV-A71/CV-A16/CV-A6 inactivated vaccine candidate protecting mice from lethal challenge with these viruses was reported [148].…”

Section: Neutralization Of Picornaviruses Neutralization Of Ev-a71 Anmentioning

confidence: 99%

Human picornaviruses associated with neurological diseases and their neutralization by antibodies

Anastasina

Domanska

Palm

et al. 2017

Journal of General Virology

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Picornaviruses are the most commonly encountered infectious agents in mankind. They typically cause mild infections of the gastrointestinal or respiratory tract, but sometimes also invade the central nervous system. There, they can cause severe diseases with long-term sequelae and even be lethal. The most infamous picornavirus is poliovirus, for which significant epidemics of poliomyelitis were reported from the end of the nineteenth century. A successful vaccination campaign has brought poliovirus close to eradication, but neurological diseases caused by other picornaviruses have increasingly been reported since the late 1990s. In this review we focus on enterovirus 71, coxsackievirus A16, enterovirus 68 and human parechovirus 3, which have recently drawn attention because of their links to severe neurological diseases. We discuss the clinical relevance of these viruses and the primary role of humoral immunity in controlling them, and summarize current knowledge on the neutralization of such viruses by antibodies.

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A virus-like particle based bivalent vaccine confers dual protection against enterovirus 71 and coxsackievirus A16 infections in mice

Cited by 70 publications

References 42 publications

Beta-Propiolactone Inactivation of Coxsackievirus A16 Induces Structural Alteration and Surface Modification of Viral Capsids

Beta-Propiolactone Inactivation of Coxsackievirus A16 Induces Structural Alteration and Surface Modification of Viral Capsids

Is a multivalent hand, foot, and mouth disease vaccine feasible?

Human picornaviruses associated with neurological diseases and their neutralization by antibodies

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