A new EV71 VP3 epitope in norovirus P particle vector displays neutralizing activity and protection in vivo in mice

Jiang, Liping; Fan, Rong; Sun, Shiqi; Fan, Peihu; Su, Weiheng; Zhou, Yan; Gao, Feng; Xu, Fengyuan; Kong, Wei; Jiang, Chunlai

doi:10.1016/j.vaccine.2015.10.104

Cited by 28 publications

(26 citation statements)

References 62 publications

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“…The mutation sites of the viral escape mutants of the two antibodies are adjacent to each other in the 3D structure. Besides these epitopes in the “knob” region, there are other neutralizing epitopes identified on VP328. Unlike VP1, which is predominantly immunogenic29 but exhibits considerable variation among different genotypes, VP3 is well-conserved among different EV71 genotypes with amino acid identity of >97%, thus representing a good target of broadly neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 99%

Effective in vivo therapeutic IgG antibody against VP3 of enterovirus 71 with receptor-competing activity

Jia

Chin

et al. 2017

Sci Rep

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Passive immunization is an effective option for treatment against hand, foot and mouth disease caused by EV71, especially with cross-neutralizing IgG monoclonal antibodies. In this study, an EV71-specific IgG2a antibody designated 5H7 was identified and characterized. 5H7 efficiently neutralizes the major EV71 genogroups (A, B4, C2, C4). The conformational epitope of 5H7 was mapped to the highly conserved amino acid position 74 on VP3 capsid protein using escape mutants. Neutralization with 5H7 is mediated by the inhibition of viral attachment, as revealed by virus-binding and post-attachment assays. In a competitive pull-down assay with SCARB2, 5H7 blocks the receptor-binding site on EV71 for virus neutralization. Passive immunization of chimeric 5H7 protected 100% of two-week-old AG129 mice from lethal challenge with an EV71 B4 strain for both prophylactic and therapeutic treatments. In contrast, 10D3, a previously reported neutralizing antibody that takes effect after virus attachment, could only confer prophylactic protection. These results indicate that efficient interruption of viral attachment is critical for effective therapeutic activity with 5H7. This report documents a novel universal neutralizing IgG antibody for EV71 therapeutics and reveals the underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

Effective in vivo therapeutic IgG antibody against VP3 of enterovirus 71 with receptor-competing activity

Jia

Chin

et al. 2017

Sci Rep

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“…Preclinical animal trials of these vaccine candidates revealed high antibody titers specific to the inserted antigen/epitopes and the P particle platform, respectively, and protected the vaccinated mice against infection of RV, 27 influenza virus, 30,43 and EV71. 45 These data indicated that the huNoV P particle is an excellent platform for combination vaccine development.…”

Section: Combination Subunit Vaccines Against Different Pathogens or mentioning

confidence: 94%

“…For example, NoV P particle contains 3 surface loops that has been shown to be able to hold a foreign antigen or epitopes without compromising the stability of the chimeric P particles. 27,32 The RV neutralizing antigen VP8 Ã , 27 the M2e epitope 30 and the HA2 antigen 43 of influenza virus, the 4E10 and 10E8 epitopes of human immunodeficiency virus (HIV), 44 and the VP3 epitope of enterovirus 71 (EV71) 45 were inserted onto the surface loops of the P particles as chimeric P particle vaccines. Preclinical animal trials of these vaccine candidates revealed high antibody titers specific to the inserted antigen/epitopes and the P particle platform, respectively, and protected the vaccinated mice against infection of RV, 27 influenza virus, 30,43 and EV71.…”

Section: Combination Subunit Vaccines Against Different Pathogens or mentioning

confidence: 99%

Recent advancements in combination subunit vaccine development

Tan

Jiang

2017

Human Vaccines & Immunotherapeutics

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Viral structural proteins share a common nature of homotypic interactions that drive viral capsid formation. This natural process has been mimicked in vitro through recombinant technology to generate various virus-like particles (VLPs) and small subviral particles that exhibit similar structural and antigenic properties of their authentic viruses. Therefore, such self-assembled, polyvalent, and highly immunogenic VLPs and small subviral particles are excellent subunit vaccines against individual viruses, such as the VLP vaccines against the hepatitis B virus, human papilloma virus, and hepatitis E virus, which have already been in the markets. In addition, various antigens and epitopes can be fused with VLPs, small subviral particles, or protein polymers, forming chimeric mono-, bi-, or trivalent vaccines. Owing to their easy-production, uninfectiousness, and polyvalence, the recombinant, chimeric vaccines offer a new approach for development of safe, low-cost, and high efficient subunit vaccines against a single or more pathogens or diseases. While the first VLP-based combination vaccine against malaria has been approved for human use, many others are under development with promising future, which are summarized in this commentary.

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“…Identification of neutralization epitopes are also important for therapeutic, vaccine, and diagnostics development. Several studies have identified neutralization epitopes, mainly in animals, and two recent studies described B‐cell epitopes in humans . The major neutralizing epitope is found on the capsid protein VP1, spanning amino acids at positions 208‐222, and recent studies have also identified neutralizing epitopes on VP2, VP3, and VP4 capsid proteins .…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of neutralization epitopes at VP2 and VP1 of enterovirus A71

NikNadia

Tan

Ong

et al. 2018

Journal of Medical Virology

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Enterovirus A71 (EV-A71) neutralization escape mutants were generated with monoclonal antibody MAB979 (Millipore). The VP2-T141I and VP1-D14N substitutions were identified. Using reverse genetics, infectious clones with these substitutions were constructed and tested by neutralization assay with immune sera from mice and humans. The N-terminus VP1-14 is more important than EF loop VP2-141 in acute human infection, mainly because it recognised IgM present in acute infection. The N-terminus VP1 could be a useful target for diagnostics and therapeutic antibodies in acute infection.

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A new EV71 VP3 epitope in norovirus P particle vector displays neutralizing activity and protection in vivo in mice

Cited by 28 publications

References 62 publications

Effective in vivo therapeutic IgG antibody against VP3 of enterovirus 71 with receptor-competing activity

Effective in vivo therapeutic IgG antibody against VP3 of enterovirus 71 with receptor-competing activity

Recent advancements in combination subunit vaccine development

Identification and characterization of neutralization epitopes at VP2 and VP1 of enterovirus A71

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