Generation and characterization of a protective mouse monoclonal antibody against human enterovirus 71

Deng, Yong-Qiang; Ma, Jie; Xu, Lijuan; Li, Yuexiang; Zhao, Hui; Han, Jianfeng; Jiang, Tao; Li, Xiaofeng; Zhu, Shun-Ya; Qin, E-De; Qin, Cheng‐Feng

doi:10.1007/s00253-015-6652-8

Cited by 11 publications

(11 citation statements)

References 33 publications

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“…Monoclonal antibody therapy could be an alternative to IVIg. Monoclonal antibodies are highly specific and bind to highly conserved regions present in all subgenotypes of EV‐A71 . The identified neutralizing antibodies listed by Ng et al could also be further developed into humanized antibodies for therapeutic use.…”

Section: Prevention and Control: How Close We Are To Success?mentioning

confidence: 99%

“…Monoclonal antibodies are highly specific and bind to highly conserved regions present in all subgenotypes of EV-A71. [150][151][152][153][154][155] The identified neutralizing antibodies listed by Ng et al 147 could also be further developed into humanized antibodies for therapeutic use. Other immune modulators such as IFN-α and IL-18…”

Section: Il-6 Is An Interleukin Secreted By Macrophages and T Lymphocmentioning

confidence: 99%

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Immune responses against enterovirus A71 infection: Implications for vaccine success

Aw-Yong

NikNadia

Tan

et al. 2019

Reviews in Medical Virology

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Summary Enterovirus A71 (EV‐A71) from the Picornaviridae family is an important emerging pathogen causing hand, foot, and mouth disease (HFMD) outbreaks worldwide. EV‐A71 also caused fatal neurological complications in young children especially in Asia. On the basis of seroepidemiological studies from many Asian countries, EV‐A71 infection is very common. Children of very young age are particularly vulnerable. Large‐scale epidemics that occur every 3 to 4 years are associated with accumulation of an immunologically naive younger population. Capsid proteins especially VP1 with the presence of major B‐ and T‐cell epitopes are the most antigenic proteins. The nonstructural proteins mainly contribute to T‐cell epitopes that induce cross‐reactive immune responses against other enteroviruses. Dominant epitopes and their neutralization magnitudes differ in mice, rabbits, and humans. Neutralizing antibody is sufficient for immune protection, but poorer cellular immunity may lead to severe neurological complications and deaths. Some chemokines/cytokines are consistently found in severely ill patients, for example, IL‐6, IL‐10, IL‐17A, MCP‐1, IL‐8, MIG, IP‐10, IFN‐γ, and G‐CSF. An increase in white cell counts is a risk factor for severe HFMD. Recent clinical trials on EV‐A71 inactivated vaccine showed >90% efficacy and a robust neutralization response that was protective, indicating neutralizing antibody correlates for protection. No protection against other enteroviruses was observed. A comprehensive understanding of the immune responses to EV‐A71 infection will benefit the development of diagnostic tools, potential therapeutics, and subunit vaccine candidates. Future development of a multivalent enterovirus vaccine will require knowledge of correlates of protection, understanding of cross‐protection and memory T‐cell responses among enteroviruses.

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Section: Prevention and Control: How Close We Are To Success?mentioning

confidence: 99%

Section: Il-6 Is An Interleukin Secreted By Macrophages and T Lymphocmentioning

confidence: 99%

Immune responses against enterovirus A71 infection: Implications for vaccine success

Aw-Yong

NikNadia

Tan

et al. 2019

Reviews in Medical Virology

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“…The synthetic peptide SP70, located at amino acids 208–222 in VP1, has been identified as a neutralizing and protective EV-A71-specific B-cell epitope in animals [16,22,48]. Several studies have demonstrated that neutralizing mAbs generated by EV-A71-immunized mice can recognize SP70 [17–20,22]. In addition, VP2-28 (amino acids 136–150 in VP2) is a cross-neutralization epitope recognized by commercial mAb 979 and mAbs generated by immunized mice [22, 2,49].…”

Section: Discussionmentioning

confidence: 99%

Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

et al. 2016

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Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease (HFMD). Unlike other enteroviruses that cause HFMD, EV-A71 is more frequently associated with severe neurological complications and fatality. To date, no effective licensed antivirals are available to combat EV-A71 infection. Little is known about the immunogenicity of viral non-structural proteins in humans. Previous studies have mainly focused on characterization of epitopes of EV-A71 structural proteins by using immunized animal antisera. In this study, we have characterized human antibody responses against the structural and non-structural proteins of EV-A71. Each viral protein was cloned and expressed in either bacterial or mammalian systems, and tested with antisera by western blot. Results revealed that all structural proteins (VP1-4), and non-structural proteins 2A, 3C and 3D were targets of EV-A71 IgM, whereas EV-A71 IgG recognized all the structural and non-structural proteins. Sixty three synthetic peptides predicted to be immunogenic in silico were synthesized and used for the characterization of EV-A71 linear B-cell epitopes. In total, we identified 22 IgM and four IgG dominant epitopes. Synthetic peptide PEP27, corresponding to residues 142–156 of VP1, was identified as the EV-A71 IgM-specific immunodominant epitope. PEP23, mapped to VP1 41–55, was recognized as the EV-A71 IgG cross-reactive immunodominant epitope. The structural protein VP1 is the major immunodominant site targeted by anti-EV-A71 IgM and IgG antibodies, but epitopes against non-structural proteins were also detected. These data provide new understanding of the immune response to EV-A71 infection, which benefits the development of diagnostic tools, potential therapeutics and subunit vaccine candidates.

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“…However, there are disadvantages to using pooled human sera, such as the risk of transmitting human pathogens, availability of donors, and batch-to-batch variability [19]. Therefore, neutralizing monoclonal antibodies (mAbs) are considered a safe alternative for passive immunization against EV71.Over the years, several EV71-neutralizing antibodies have been reported [20][21][22][23][24][25][26]. Among these mAbs, D5 is one of the most promising mAb for development as prophylactic and therapeutic for EV71 infection.…”

mentioning

confidence: 99%

“…Over the years, several EV71-neutralizing antibodies have been reported [20][21][22][23][24][25][26]. Among these mAbs, D5 is one of the most promising mAb for development as prophylactic and therapeutic for EV71 infection.…”

mentioning

confidence: 99%

Plant-Produced Anti-Enterovirus 71 (EV71) Monoclonal Antibody Efficiently Protects Mice Against EV71 Infection

Rattanapisit

Zhang

Siriwattananon

et al. 2019

Plants

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Enterovirus 71 (EV71) is the main causative agent of severe hand-foot-mouth disease. EV71 affects countries mainly in the Asia-Pacific region, which makes it unattractive for pharmaceutical companies to develop drugs or vaccine to combat EV71 infection. However, development of these drugs and vaccines is vital to protect younger generations. This study aims to develop a specific monoclonal antibody (mAb) to EV71 using a plant platform, which is a cost-effective and scalable production technology. A previous report showed that D5, a murine anti-EV71 mAb, binds to VP1 protein of EV71, potently neutralizes EV71 in vitro, and effectively protects mice against EV71 infection. Herein, plant-produced chimeric D5 (cD5) mAb, variable regions of murine D5 antibody linked with constant regions of human IgG1, was transiently expressed in Nicotiana benthamiana using geminiviral vectors. The antibody was expressed at high levels within six days of infiltration. Plant-produced cD5 retained its in vitro high-affinity binding and neutralizing activity against EV71. Furthermore, a single dose (10 µg/g body weight) of plant-produced cD5 mAb offered 100% protection against infection in mice after a lethal EV71 challenge. Therefore, our results showed that plant-produced anti-EV71 mAb is an effective, safe, and affordable therapeutic option against EV71 infection.2 of 10 vaccines [16,17]. For EV71 post-exposure treatment in patients with severe infection, EV71-specific intravenous immunoglobulins are used [18]. However, there are disadvantages to using pooled human sera, such as the risk of transmitting human pathogens, availability of donors, and batch-to-batch variability [19]. Therefore, neutralizing monoclonal antibodies (mAbs) are considered a safe alternative for passive immunization against EV71.Over the years, several EV71-neutralizing antibodies have been reported [20][21][22][23][24][25][26]. Among these mAbs, D5 is one of the most promising mAb for development as prophylactic and therapeutic for EV71 infection. D5 mAb binds specifically to SP70 peptide on VP1 GH loop of EV71 and can potently neutralize EV71 infection by blocking viral attachment and internalization and by stabilizing the virus through a bivalent binding mode [26,27]. However, the antibody production in mammalian cell culture has limitations with high production costs and scalability.Recently, plants are being used as an alternative mAb production platform with unique advantages such as low production cost, speed of production, and scalability [28]. This platform offers a solution for developing countries to develop affordable medicines in the region. Previous studies demonstrated the efficacy of plant-produced mAbs for viral infections, such as West Nile virus [29], Ebola virus [30], Rabies virus [31], and others. The goal of this study is to investigate the protective effect of plant-produced EV71 specific mAb against EV71 challenge in mice.In this study, chimeric D5 (cD5) mAb was constructed and produced transiently in Nicotiana benthamiana leaves. After...

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Generation and characterization of a protective mouse monoclonal antibody against human enterovirus 71

Cited by 11 publications

References 33 publications

Immune responses against enterovirus A71 infection: Implications for vaccine success

Immune responses against enterovirus A71 infection: Implications for vaccine success

Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

Plant-Produced Anti-Enterovirus 71 (EV71) Monoclonal Antibody Efficiently Protects Mice Against EV71 Infection

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