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Enterovirus A71 priorities, challenges, and future opportunities in humoral immunity and vaccine development

  • Brouwer, L., Moreni, G., Wolthers, K.C. & Pajkrt, D. World-wide prevalence and genotype distribution of enteroviruses. Viruses 13, 434 (2021).

  • Royston, L. & Tapparel, C. Rhinoviruses and respiratory enteroviruses: not as simple as ABC. Viruses 8, 16 (2016).

  • Xie, Z., Khamrin, P., Maneekarn, N. & Kumthip, K. Epidemiology of enterovirus genotypes in association with human diseases. Viruses 16, 1165 (2024).

  • Tapparel, C., Siegrist, F., Petty, T. J. & Kaiser, L. Picornavirus and enterovirus diversity with associated human diseases. Infect. Genet. Evol. 14, 282–293 (2013).

    PubMed 

    Google Scholar
     

  • Liu, Y. et al. A novel subgenotype C6 Enterovirus A71 originating from the recombination between subgenotypes C4 and C2 strains in mainland China. Sci. Rep. 12, 593 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chan, Y. F., Sam, I. C. & AbuBakar, S. Phylogenetic designation of enterovirus 71 genotypes and subgenotypes using complete genome sequences. Infect. Genet. Evol. 10, 404–412 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • Aswathyraj, S., Arunkumar, G., Alidjinou, E. K. & Hober, D. Hand, foot and mouth disease (HFMD): emerging epidemiology and the need for a vaccine strategy. Med. Microbiol. Immunol. 205, 397–407 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Huang, K. A. Structural basis for neutralization of enterovirus. Curr. Opin. Virol. 51, 199–206 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • Kok, C. C., Phuektes, P., Bek, E. & McMinn, P. C. Modification of the untranslated regions of human enterovirus 71 impairs growth in a cell-specific manner. J. Virol. 86, 542–552 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Du, J. et al. Analysis of enterovirus 68 strains from the 2014 North American outbreak reveals a new clade, indicating viral evolution. PLoS ONE 10, e0144208 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, K. A. et al. Structural and functional analysis of protective antibodies targeting the threefold plateau of enterovirus 71. Nat. Commun. 11, 5253 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Plevka, P., Perera, R., Cardosa, J., Kuhn, R. J. & Rossmann, M. G. Crystal structure of human enterovirus 71. Science 336, 1274 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dang, M. et al. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein Cell 5, 692–703 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ku, Z. et al. Single Neutralizing monoclonal antibodies targeting the VP1 GH loop of enterovirus 71 inhibit both virus attachment and internalization during viral entry. J. Virol. 89, 12084–12095 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, L. et al. Neutralization mechanisms of two highly potent antibodies against human enterovirus 71. mBio 9, e01013–18 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lyu, K. et al. Crystal structures of enterovirus 71 (EV71) recombinant virus particles provide insights into vaccine design. J. Biol. Chem. 290, 3198–3208 (2015).

    PubMed 

    Google Scholar
     

  • Kiener, T. K., Jia, Q., Meng, T., Chow, V. T. & Kwang, J. A novel universal neutralizing monoclonal antibody against enterovirus 71 that targets the highly conserved “knob” region of VP3 protein. PLoS Negl. Trop. Dis. 8, e2895 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baggen, J., Thibaut, H. J., Strating, J. & van Kuppeveld, F. J. M. The life cycle of non-polio enteroviruses and how to target it. Nat. Rev. Microbiol. 16, 368–381 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • Yamayoshi, S., Fujii, K. & Koike, S. Receptors for enterovirus 71. Emerg. Microbes Infect. 3, e53 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, M. et al. Enhanced human enterovirus 71 infection by endocytosis inhibitors reveals multiple entry pathways by enterovirus causing hand-foot-and-mouth diseases. Virol. J. 15, 1 (2018).

  • Hussain, K. M., Leong, K. L., Ng, M. M. & Chu, J. J. The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71. J. Biol. Chem. 286, 309–321 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • Diarimalala, R. O., Hu, M., Wei, Y. & Hu, K. Recent advances of enterovirus 71 [Formula: see text] targeting Inhibitors. Virol. J. 17, 173 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thompson, S. R. & Sarnow, P. Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved. Virology 315, 259–266 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • Tan, C. W., Lai, J. K., Sam, I. C. & Chan, Y. F. Recent developments in antiviral agents against enterovirus 71 infection. J. Biomed. Sci. 21, 14 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wei, Y. et al. Recent advances in enterovirus A71 infection and antiviral agents. Lab. Invest. 104, 100298 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Horwood, P. F. et al. Seroepidemiology of Human Enterovirus 71 Infection among Children, Cambodia. Emerg. Infect. Dis. 22, 92–95 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, J. et al. Seroepidemiology of enterovirus A71 infection in prospective cohort studies of children in southern China, 2013–2018. Nat. Commun. 13, 7280 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hagiwara, A., Tagaya, I. & Komatsu, T. Seroepidemiology of enterovirus 71 among healthy children near Tokyo. Microbiol. Immunol. 23, 121–124 (1979).

    CAS 
    PubMed 

    Google Scholar
     

  • Ooi, M. H. et al. Human enterovirus 71 disease in Sarawak, Malaysia: a prospective clinical, virological, and molecular epidemiological study. Clin. Infect. Dis. 44, 646–656 (2007).

    PubMed 

    Google Scholar
     

  • Ooi, E. E., Phoon, M. C., Ishak, B. & Chan, S. H. Seroepidemiology of human enterovirus 71, Singapore. Emerg. Infect. Dis. 8, 995–997 (2002).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, T. Y., Twu, S. J., Ho, M. S., Chang, L. Y. & Lee, C. Y. Enterovirus 71 outbreaks, Taiwan: occurrence and recognition. Emerg. Infect. Dis. 9, 291–293 (2003).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Linsuwanon, P. et al. Epidemiology and seroepidemiology of human enterovirus 71 among Thai populations. J. Biomed. Sci. 21, 16 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tran, C. B. et al. The seroprevalence and seroincidence of enterovirus71 infection in infants and children in Ho Chi Minh City, Viet Nam. PLoS ONE 6, e21116 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shi, Y., Chen, P., Bai, Y., Xu, X. & Liu, Y. Seroprevalence of coxsackievirus A6 and enterovirus A71 infection in humans: a systematic review and meta-analysis. Arch. Virol. 168, 37 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. T. et al. Enterovirus 71 seroepidemiology in Taiwan in 2017 and comparison of those rates in 1997, 1999 and 2007. PLoS ONE 14, e0224110 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chang, L. Y. et al. Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan. Pediatrics 109, e88 (2002).

    PubMed 

    Google Scholar
     

  • Ang, L. W. et al. Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007. Ann. Acad. Med. Singap. 38, 106–112 (2009).

    PubMed 

    Google Scholar
     

  • Riller, Q., Schmutz, M., Fourgeaud, J., Fischer, A. & Neven, B. Protective role of antibodies in enteric virus infections: Lessons from primary and secondary immune deficiencies. Immunol. Rev. 328, 243–264 (2024).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kassab, S. et al. Fatal case of enterovirus 71 infection and rituximab therapy, france, 2012. Emerg. Infect. Dis. 19, 1345–1347 (2013).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Halliday, E., Winkelstein, J. & Webster, A. D. Enteroviral infections in primary immunodeficiency (PID): a survey of morbidity and mortality. J. Infect. 46, 1–8 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • Ahmed, R. et al. Enterovirus 71 meningoencephalitis complicating rituximab therapy. J. Neurol. Sci. 305, 149–151 (2011).

    PubMed 

    Google Scholar
     

  • Weng, K. F. et al. Variant enterovirus A71 found in immune-suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice. Cell Rep. 42, 112389 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Puenpa, J., Wanlapakorn, N., Vongpunsawad, S. & Poovorawan, Y. The history of enterovirus A71 outbreaks and molecular epidemiology in the Asia-Pacific region. J. Biomed. Sci. 26, 75 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xing, W. et al. Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. Lancet Infect. Dis. 14, 308–318 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guo, T. et al. Seasonal Distribution and Meteorological Factors Associated with Hand, Foot, and Mouth Disease among Children in Xi’an, Northwestern China. Am. J. Trop. Med. Hyg. 102, 1253–1262 (2020).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zeng, M. et al. Seroepidemiology of Enterovirus 71 infection prior to the 2011 season in children in Shanghai. J. Clin. Virol. 53, 285–289 (2012).

    PubMed 

    Google Scholar
     

  • Ang, L. W. et al. The changing seroepidemiology of enterovirus 71 infection among children and adolescents in Singapore. BMC Infect. Dis. 11, 270 (2011).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harvala, H. et al. Recommendations for enterovirus diagnostics and characterisation within and beyond Europe. J. Clin. Virol. 101, 11–17 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • Organization, T.W.H. A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD), (World Health Organization, Manila, Philippines, 2011).

  • Zhou, Y. et al. Diagnostic performance of different specimens in detecting enterovirus A71 in children with hand, foot and mouth disease. Virol. Sin. 38, 268–275 (2023).

    CAS 
    PubMed 

    Google Scholar
     

  • Wang, C. et al. A novel method to diagnose the infection of enterovirus A71 in children by detecting IgA from saliva. J. Med. Virol. 92, 1059–1064 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • Nguyen, T. H. T. et al. Methods to discriminate primary from secondary dengue during acute symptomatic infection. BMC Infect. Dis. 18, 375 (2018).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ooi, M. H. et al. Evaluation of different clinical sample types in diagnosis of human enterovirus 71-associated hand-foot-and-mouth disease. J. Clin. Microbiol. 45, 1858–1866 (2007).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ooi, M. H., Wong, S. C., Lewthwaite, P., Cardosa, M. J. & Solomon, T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 9, 1097–1105 (2010).

    PubMed 

    Google Scholar
     

  • McMinn, P. C. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol. Rev. 26, 91–107 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • Ma, E. et al. Estimation of the basic reproduction number of enterovirus 71 and coxsackievirus A16 in hand, foot, and mouth disease outbreaks. Pediatr. Infect. Dis. J. 30, 675–679 (2011).

    PubMed 

    Google Scholar
     

  • Shen, J. et al. Relationship between serologic response and clinical symptoms in children with enterovirus 71-infected hand-foot-mouth disease. Int. J. Clin. Exp. Pathol. 8, 11608–11614 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cheng, H. Y. et al. The correlation between the presence of viremia and clinical severity in patients with enterovirus 71 infection: a multi-center cohort study. BMC Infect. Dis. 14, 417 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qiu, Q. et al. Kinetics of the neutralising antibody response in patients with hand, foot, and mouth disease caused by EV-A71: a longitudinal cohort study in Zhengzhou during 2017-2019. EBioMedicine 68, 103398 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, Y. et al. Comparison of neutralizing antibody response kinetics in patients with hand, foot, and mouth disease caused by coxsackievirus A16 or enterovirus A71: a longitudinal cohort study of Chinese Children, 2017–2019. J. Immunol. 209, 280–287 (2022).

    CAS 
    PubMed 

    Google Scholar
     

  • Xu, F. et al. Performance of detecting IgM antibodies against enterovirus 71 for early diagnosis. PLoS ONE 5, e11388 (2010).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, K., Magri, G., Grasset, E. K. & Cerutti, A. Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat. Rev. Immunol. 20, 427–441 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, F. et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N. Engl. J. Med. 370, 818–828 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • Nguyen, T. T. et al. Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 399, 1708–1717 (2022).

    CAS 
    PubMed 

    Google Scholar
     

  • Sun, S. et al. Immunogenicity and protective efficacy of an EV71 virus-like particle vaccine against lethal challenge in newborn mice. Hum. Vaccin Immunother. 11, 2406–2413 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lim, P. Y. et al. Immunogenicity and performance of an enterovirus 71 virus-like-particle vaccine in nonhuman primates. Vaccine 33, 6017–6024 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • Seikrit, C. & Pabst, O. The immune landscape of IgA induction in the gut. Semin. Immunopathol. 43, 627–637 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mathias, A. & Corthesy, B. N-Glycans on secretory component: mediators of the interaction between secretory IgA and gram-positive commensals sustaining intestinal homeostasis. Gut Microbes 2, 287–293 (2011).

    PubMed 

    Google Scholar
     

  • Mbani, C. J. et al. Enterovirus antibodies: friends and foes. Rev. Med. Virol. 34, e70004 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Ye, X. et al. Structural basis for recognition of human enterovirus 71 by a bivalent broadly neutralizing monoclonal antibody. PLoS Pathog. 12, e1005454 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Plevka, P. et al. Neutralizing antibodies can initiate genome release from human enterovirus 71. Proc. Natl. Acad. Sci. USA 111, 2134–2139 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thomas, A. A., Vrijsen, R. & Boeye, A. Relationship between poliovirus neutralization and aggregation. J. Virol. 59, 479–485 (1986).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Watkinson, R. E., McEwan, W. A., Tam, J. C., Vaysburd, M. & James, L. C. TRIM21 promotes cGAS and RIG-I sensing of viral genomes during infection by antibody-opsonized virus. PLoS Pathog. 11, e1005253 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Du, R. et al. Non-neutralizing monoclonal antibody targeting VP2 EF loop of Coxsackievirus A16 can protect mice from lethal attack via Fc-dependent effector mechanism. Emerg. Microbes Infect. 12, 2149352 (2023).

    PubMed 

    Google Scholar
     

  • Behzadi, M. A. et al. A cross-reactive mouse monoclonal antibody against rhinovirus mediates phagocytosis in vitro. Sci. Rep. 10, 9750 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao, F. et al. Enterovirus 71 viral capsid protein linear epitopes: identification and characterization. Virol. J. 9, 26 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aw-Yong, K. L., Sam, I. C., Koh, M. T. & Chan, Y. F. Immunodominant IgM and IgG epitopes recognized by antibodies induced in enterovirus A71-associated hand, foot and mouth disease patients. PLoS ONE 11, e0165659 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, H. et al. Genome-wide linear B-cell epitopes of enterovirus 71 in a hand, foot and mouth disease (HFMD) population. J. Clin. Virol. 105, 41–48 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • Xu, L. et al. Protection against lethal enterovirus 71 challenge in mice by a recombinant vaccine candidate containing a broadly cross-neutralizing epitope within the VP2 EF loop. Theranostics 4, 498–513 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aw-Yong, K. L., NikNadia, N. M. N., Tan, C. W., Sam, I. C. & Chan, Y. F. Immune responses against enterovirus A71 infection: implications for vaccine success. Rev. Med. Virol. 29, e2073 (2019).

    PubMed 

    Google Scholar
     

  • Protein Data Bank. https://www.rcsb.org/search?request=%7B%22query%22%3A%7B%22type%22%3A%22group%22%2C%22nodes%22%3A%5B%7B%22type%22%3A%22group%22%2C%22nodes%22%3A%5B%7B%22type%22A71%20FAB%22%7D%7D%5D%2C%22logical_operator%22%3A%22and%22%7D%5D%2C%22logical_operator%22%3A%22and%22%2C%22label%22%3A%22full_text%22%7D%5D (2025).

  • You, L. et al. Antibody signatures in hospitalized hand, foot and mouth disease patients with acute enterovirus A71 infection. PLoS Pathog. 19, e1011420 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, L. et al. Bioinformatics-based prediction of conformational epitopes for Enterovirus A71 and Coxsackievirus A16. Sci. Rep. 11, 5701 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saarinen, N.V.V. et al. Multiplexed high-throughput serological assay for human enteroviruses. Microorganisms 8, 1426 (2020).

  • Vatti, A. et al. Original antigenic sin: a comprehensive review. J. Autoimmun. 83, 12–21 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Tsuchiya, H., Furukawa, M., Matsui, M., Katsuki, K. & Inouye, S. Original antigenic sin’ phenomenon in neutralizing antibody responses in children with enterovirus meningitis. J. Clin. Virol. 19, 205–207 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • Han, J. F. et al. Antibody dependent enhancement infection of enterovirus 71 in vitro and in vivo. Virol. J. 8, 106 (2011).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hawkes, R. A. Enhancement of the infectivity of arboviruses by specific antisera produced in domestic fowls. Aust. J. Exp. Biol. Med. Sci. 42, 465–482 (1964).

    CAS 
    PubMed 

    Google Scholar
     

  • Halstead, S. B. Neutralization and antibody-dependent enhancement of dengue viruses. Adv. Virus Res. 60, 421–467 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • Takada, A. & Kawaoka, Y. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev. Med. Virol. 13, 387–398 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • Shukla, R., Ramasamy, V., Shanmugam, R. K., Ahuja, R. & Khanna, N. Antibody-dependent enhancement: a challenge for developing a safe dengue vaccine. Front. Cell Infect. Microbiol. 10, 572681 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Narayan, R. & Tripathi, S. Intrinsic ADE: the dark side of antibody dependent enhancement during dengue infection. Front. Cell Infect. Microbiol. 10, 580096 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thomas, S. et al. Antibody-dependent enhancement (ADE) and the role of complement system in disease pathogenesis. Mol. Immunol. 152, 172–182 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nicholson-Weller, A. & Klickstein, L. B. C1q-binding proteins and C1q receptors. Curr. Opin. Immunol. 11, 42–46 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • Guillon, C., Schutten, M., Boers, P. H., Gruters, R. A. & Osterhaus, A. D. Antibody-mediated enhancement of human immunodeficiency virus type 1 infectivity is determined by the structure of gp120 and depends on modulation of the gp120-CCR5 interaction. J. Virol. 76, 2827–2834 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, K., Onintsoa Diarimalala, R., Yao, C., Li, H. & Wei, Y. EV-A71 mechanism of entry: receptors/co-receptors, related pathways and inhibitors. Viruses 15, 785 (2023).

  • He, Y. et al. Structures of foot-and-mouth disease virus with neutralizing antibodies derived from recovered natural host reveal a mechanism for cross-serotype neutralization. PLoS Pathog. 17, e1009507 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, S. M. et al. Enterovirus 71 infection of monocytes with antibody-dependent enhancement. Clin. Vaccin. Immunol. 17, 1517–1523 (2010).

    CAS 

    Google Scholar
     

  • Coudere, K. et al. Neutralising antibodies against enterovirus and parechovirus in IVIG reflect general circulation: a tool for sero-surveillance. Viruses 13, 1028 (2021).

  • Cao, R. et al. Presence of high-titer neutralizing antibodies against enterovirus 71 in intravenous immunoglobulin manufactured from Chinese donors. Clin. Infect. Dis. 50, 125–126 (2010).

    PubMed 

    Google Scholar
     

  • Chen, I. C., Wang, S. M., Yu, C. K. & Liu, C. C. Subneutralizing antibodies to enterovirus 71 induce antibody-dependent enhancement of infection in newborn mice. Med. Microbiol. Immunol. 202, 259–265 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Cao, R. Y. et al. Human IgG subclasses against enterovirus Type 71: neutralization versus antibody dependent enhancement of infection. PLoS ONE 8, e64024 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sauter, P. & Hober, D. Mechanisms and results of the antibody-dependent enhancement of viral infections and role in the pathogenesis of coxsackievirus B-induced diseases. Microbes Infect. 11, 443–451 (2009).

    CAS 
    PubMed 

    Google Scholar
     

  • Elmastour, F. et al. Immunoglobulin G-dependent enhancement of the infection with Coxsackievirus B4 in a murine system. Virulence 7, 527–535 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kishimoto, C., Kurokawa, M. & Ochiai, H. Antibody-mediated immune enhancement in coxsackievirus B3 myocarditis. J. Mol. Cell Cardiol. 34, 1227–1238 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • Yu, J. Z. et al. Secondary heterotypic versus homotypic infection by Coxsackie B group viruses: impact on early and late histopathological lesions and virus genome prominence. Cardiovasc. Pathol. 8, 93–102 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • Aswathyraj, S. et al. Serum-derived IgG from coxsackievirus A6-infected patients can enhance the infection of peripheral blood mononuclear cells with coxsackievirus A6. Microb. Pathog. 125, 7–11 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • Chehadeh, W., Bouzidi, A., Alm, G., Wattre, P. & Hober, D. Human antibodies isolated from plasma by affinity chromatography increase the coxsackievirus B4-induced synthesis of interferon-alpha by human peripheral blood mononuclear cells in vitro. J. Gen. Virol. 82, 1899–1907 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • Alidjinou, E. K., Sane, F., Engelmann, I. & Hober, D. Serum-dependent enhancement of coxsackievirus B4-induced production of IFNalpha, IL-6 and TNFalpha by peripheral blood mononuclear cells. J. Mol. Biol. 425, 5020–5031 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Morvan, C., Nekoua, M. P., Debuysschere, C., Alidjinou, E. K. & Hober, D. Antibody-dependent enhancement and neutralization against CVB4 investigated in vitro and in silico through an agent-based model. J. Med. Virol. 96, e29399 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Che, Z. et al. Antibody-mediated neutralization of human rhinovirus 14 explored by means of cryoelectron microscopy and X-ray crystallography of virus-Fab complexes. J. Virol. 72, 4610–4622 (1998).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiao, W. et al. The effectiveness of different doses of intravenous immunoglobulin on severe hand, foot and mouth disease: a meta-analysis. Med. Princ. Pract. 28, 256–263 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, R. et al. An inactivated enterovirus 71 vaccine in healthy children. N. Engl. J. Med. 370, 829–837 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • Liu, L. et al. Immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy Chinese children: a report of further observations. BMC Med. 13, 226 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, Y. et al. Five-year immunity persistence following immunization with inactivated enterovirus 71 type (EV71) vaccine in healthy children: a further observation. Hum. Vaccin. Immunother. 14, 1517–1523 (2018).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, F. C. et al. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 381, 2024–2032 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Yang, T. et al. Safety and immunogenicity of an experimental live combination vaccine against enterovirus 71 and coxsackievirus A16 in rhesus monkeys. Hum. Vaccin. Immunother. 16, 1586–1594 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, H. J. et al. Efficient expression of enterovirus 71 based on virus-like particles vaccine. PLoS ONE 14, e0210477 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maje Bello, A., Chaimongkolnukul, K., Poomputsa, K., Mekvichitsaeng, P. & Maprang Roshorm, Y. Immunogenicity and immunodominant linear B-cell epitopes of a new DNA-based tetravalent vaccine against four major enteroviruses causing hand, foot, and mouth disease. Vaccine 42, 3733–3743 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Yee, P. T. & Poh, C. L. Development of novel miRNA-based vaccines and antivirals against enterovirus 71. Curr. Pharm. Des. 22, 6694–6700 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Liu, Z. et al. A novel polypeptide vaccine and adjuvant formulation of EV71. Pathog. Dis. 79, ftab057 (2022).

  • Chen, H. F., Chang, M. H., Chiang, B. L. & Jeng, S. T. Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71. Vaccine 24, 2944–2951 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • Hu, Q. et al. Effectiveness of EV-A71 vaccine and its impact on the incidence of hand, foot and mouth disease: a systematic review. Vaccines 12, 1028 (2024).

  • Wei, M. et al. 2-Year efficacy, immunogenicity, and safety of vigoo enterovirus 71 vaccine in healthy chinese children: a randomized open-label study. J. Infect. Dis. 215, 56–63 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Ye, L. et al. Vaccination coverage estimates and utilization patterns of inactivated enterovirus 71 vaccine post vaccine introduction in Ningbo, China. BMC Public Health 21, 1118 (2021).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zheng, D. et al. Effect of EV71 vaccination on transmission dynamics of hand, foot, and mouth disease and its epidemic prevention threshold. Vaccines 12, 1166 (2024).

  • Liu, Y. et al. Effectiveness of the enterovirus A71 vaccine on hand, foot and mouth disease: a real-world study in China. Clin. Microbiol. Infect. 31, 258–265 (2024).

  • Jiang, H. et al. The epidemiological characteristics of enterovirus infection before and after the use of enterovirus 71 inactivated vaccine in Kunming, China. Emerg. Microbes Infect. 10, 619–628 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, M. et al. The spatial-temporal distribution and etiological characteristics of hand-foot-and-mouth disease before and after EV‑A71 vaccination in Kunming, China, 2017-2020. Sci. Rep. 12, 17028 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duan, X. et al. Effectiveness of enterovirus A71 vaccine against pediatric HFMD and disease profile of post-vaccination infection. Vaccine 42, 2317–2325 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Lizasoain, A., Mir, D., Martinez, N. & Colina, R. Coxsackievirus A10 causing hand-foot-and-mouth disease in Uruguay. Int. J. Infect. Dis. 94, 1–3 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • Mao, Q. et al. The cross-neutralizing activity of enterovirus 71 subgenotype c4 vaccines in healthy chinese infants and children. PLoS ONE 8, e79599 (2013).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, J. X. et al. Two-year efficacy and immunogenicity of Sinovac Enterovirus 71 vaccine against hand, foot and mouth disease in children. Expert Rev. Vaccines 15, 129–137 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, H. et al. Emergence of a non vaccine-cognate enterovirus A71 genotype C1 in mainland China. J. Infect. 82, 407–413 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • Xiao, J. et al. The impact of enterovirus A71 vaccination program on hand, foot, and mouth disease in Guangdong, China: a longitudinal surveillance study. J. Infect. 85, 428–435 (2022).

    CAS 
    PubMed 

    Google Scholar
     

  • Liu, H. B. et al. A 5-year molecular epidemiology survey of human enterovirus 71 before vaccine application in Yunnan Province, China. J. Med. Virol. 92, 1085–1092 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • Chou, A. H. et al. Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLoS ONE 8, e79783 (2013).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, L. M. et al. Immunogenicity, safety, cross-reaction, and immune persistence of an inactivated enterovirus A71 vaccine in children aged from two months to 11 years in Taiwan. Vaccine 37, 1827–1835 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • Cheng, A. et al. A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine. Vaccine 31, 2471–2476 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Yi, E. J. et al. A bivalent inactivated vaccine prevents enterovirus 71 and coxsackievirus A16 infections in the Mongolian Gerbil. Biomol. Ther.31, 350–358 (2023).

    CAS 

    Google Scholar
     

  • Lin, C. W. et al. Immunogenicity studies of bivalent inactivated virions of EV71/CVA16 formulated with submicron emulsion systems. Biomed. Res. Int. 2014, 670506 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Caine, E. A., Fuchs, J., Das, S. C., Partidos, C. D. & Osorio, J. E. Efficacy of a trivalent hand, foot, and mouth disease vaccine against enterovirus 71 and coxsackieviruses A16 and A6 in mice. Viruses 7, 5919–5932 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barcena, J., Zamora-Ceballos, M. & Blanco, E. Design of novel vaccines based on virus-like particles. Subcell. Biochem. 105, 785–821 (2024).

    PubMed 

    Google Scholar
     

  • Li, H. Y., Han, J. F., Qin, C. F. & Chen, R. Virus-like particles for enterovirus 71 produced from Saccharomyces cerevisiae potently elicits protective immune responses in mice. Vaccine 31, 3281–3287 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Zhao, H. et al. Novel recombinant chimeric virus-like particle is immunogenic and protective against both enterovirus 71 and coxsackievirus A16 in mice. Sci. Rep. 5, 7878 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Issaro, N. et al. Induction of immune responses by a novel recombinant fusion protein of enterovirus A71 in BALB/c mice. Mol. Immunol. 105, 1–8 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • Meng, T., Kolpe, A. B., Kiener, T. K., Chow, V. T. & Kwang, J. Display of VP1 on the surface of baculovirus and its immunogenicity against heterologous human enterovirus 71 strains in mice. PLoS ONE 6, e21757 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kolpe, A. B., Kiener, T. K., Grotenbreg, G. M. & Kwang, J. Display of enterovirus 71 VP1 on baculovirus as a type II transmembrane protein elicits protective B and T cell responses in immunized mice. Virus Res. 168, 64–72 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • Lin, X. et al. A novel peptide from VP1 of EV-D68 exhibits broad-spectrum antiviral activity against human enteroviruses. Biomolecules 14, 1331 (2024).

  • Zhao, M. et al. Immunization of N terminus of enterovirus 71 VP4 elicits cross-protective antibody responses. BMC Microbiol. 13, 287 (2013).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, L. et al. A broadly cross-protective vaccine presenting the neighboring epitopes within the VP1 GH loop and VP2 EF loop of enterovirus 71. Sci. Rep. 5, 12973 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, T. Y. et al. The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin. Infect. Dis. 34, S52–57 (2002).

    PubMed 

    Google Scholar
     

  • Liu, C. C. et al. Identification and characterization of a cross-neutralization epitope of enterovirus 71. Vaccine 29, 4362–4372 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • Yee, P. T. I. et al. Development of live attenuated Enterovirus 71 vaccine strains that confer protection against lethal challenge in mice. Sci. Rep. 9, 4805 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, N. & Zhang, B. The strategies used by animal viruses to antagonize host antiviral innate immunity: new clues for developing live attenuated vaccines (LAVs). Vaccines (Basel) 13, 46 (2025).

  • Sadeghipour, S., Bek, E. J. & McMinn, P. C. Ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture. J. Virol. 87, 1759–1769 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vignuzzi, M., Wendt, E. & Andino, R. Engineering attenuated virus vaccines by controlling replication fidelity. Nat. Med. 14, 154–161 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • Vignuzzi, M., Stone, J. K., Arnold, J. J., Cameron, C. E. & Andino, R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439, 344–348 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • Barnes, D., Kunitomi, M., Vignuzzi, M., Saksela, K. & Andino, R. Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines. Cell Host Microbe 4, 239–248 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mendoza, E. J., Racine, T. & Kobinger, G. P. The ongoing evolution of antibody-based treatments for Ebola virus infection. Immunotherapy 9, 435–450 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Zhu, R. et al. Broadly therapeutic antibody provides cross-serotype protection against enteroviruses via Fc effector functions and by mimicking SCARB2. Nat. Microbiol. 9, 2939–2953 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Li, Y., Yu, J., Qi, X. & Yan, H. Monoclonal antibody against EV71 3D(pol) inhibits the polymerase activity of RdRp and virus replication. BMC Immunol. 20, 6 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, Z. et al. In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model. PLoS ONE 9, e109391 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, B. et al. A bispecific broadly neutralizing antibody against enterovirus 71 and coxsackievirus A16 with therapeutic potential. Antivir. Res. 161, 28–35 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • Xu, L. et al. Monoclonal antibodies for diagnosis of enterovirus 71. Monoclon. Antib. Immunodiagn. Immunother. 32, 386–394 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, X. et al. The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection. Protein Cell 8, 590–600 (2017).

  • Lum, L. C. et al. Fatal enterovirus 71 encephalomyelitis. J. Pediatr. 133, 795–798 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • Lim, X. F. et al. Characterization of an isotype-dependent monoclonal antibody against linear neutralizing epitope effective for prophylaxis of enterovirus 71 infection. PLoS ONE 7, e29751 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, W. et al. Dual blockages of a broad and potent neutralizing IgM antibody targeting GH loop of EV-As. Immunology 169, 292–308 (2023).

    CAS 
    PubMed 

    Google Scholar
     

  • Zhu, W. et al. A broad and potent IgM antibody against tetra-EV-As induced by EVA71 and CVA16 co-immunization. Vaccine 39, 6510–6519 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • Ledford, H. Antibody therapies could be a bridge to a coronavirus vaccine — but will the world benefit? (Nature, 2020).

  • O’Hagan, S., Galway, N., Shields, M. D., Mallett, P. & Groves, H. E. Review of the safety, efficacy and tolerability of palivizumab in the prevention of severe respiratory syncytial virus (RSV) disease. Drug Health Patient Saf. 15, 103–112 (2023).


    Google Scholar
     

  • Rayaprolu, V. et al. Structure of the Inmazeb cocktail and resistance to Ebola virus escape. Cell Host Microbe 31, 260–272.e267 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Muslin, C., Mac Kain, A., Bessaud, M., Blondel, B. & Delpeyroux, F. Recombination in enteroviruses, a multi-step modular evolutionary process. Viruses 11, 859 (2019).

  • Rosenfeld, A. B. et al. Cross-Reactive Antibody Responses against Nonpoliovirus Enteroviruses. mBio 13, e0366021 (2022).

    PubMed 

    Google Scholar
     

  • Wegman, A. D. et al. DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection. PLoS Pathog. 19, e1011616 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nekoua, M. P., Alidjinou, E. K. & Hober, D. Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 18, 503–516 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Op de Beeck, A. & Eizirik, D. L. Viral infections in type 1 diabetes mellitus-why the beta cells?. Nat. Rev. Endocrinol. 12, 263–273 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Harkonen, T. et al. Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. J. Med. Virol. 69, 426–440 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • Bubba, L. et al. Circulation of non-polio enteroviruses in 24 EU and EEA countries between 2015 and 2017: a retrospective surveillance study. Lancet Infect. Dis. 20, 350–361 (2020).

    PubMed 

    Google Scholar
     

  • Liu, J. N. et al. Combined peptides of human enterovirus 71 protect against virus infection in mice. Vaccine 28, 7444–7451 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • Martinez-Gualda, B. et al. Scaffold simplification strategy leads to a novel generation of dual human immunodeficiency virus and enterovirus-A71 entry inhibitors. J. Med. Chem. 63, 349–368 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • Foo, D. G. et al. Identification of neutralizing linear epitopes from the VP1 capsid protein of Enterovirus 71 using synthetic peptides. Virus Res. 125, 61–68 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • Lidbury, B. A. & Mahalingam, S. Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection. J. Virol. 74, 8376–8381 (2000).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mahalingam, S. & Lidbury, B. A. Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kappa B) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc. Natl. Acad. Sci. USA 99, 13819–13824 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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