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Abstract

Enterovirus 71 (EV-A71) is a major public health problem, causing a range of illnesses from hand-foot-and-mouth disease to severe neurological manifestations. EV-A71 strains have been phylogenetically classified into eight genogroups (A to H), based on their capsid-coding genomic region. Genogroups B and C have caused large outbreaks worldwide and represent the two canonical circulating EV-A71 subtypes. Little is known about the antigenic diversity of new genogroups as compared to the canonical ones. Here, we compared the antigenic features of EV-A71 strains that belong to the canonical B and C genogroups and to genogroups E and F, which circulate in Africa. Analysis of the peptide sequences of EV-A71 strains belonging to different genogroups revealed a high level of conservation of the capsid residues involved in known linear and conformational neutralization antigenic sites. Using a published crystal structure of the EV-A71 capsid as a model, we found that most of the residues that are seemingly specific to some genogroups were mapped outside known antigenic sites or external loops. These observations suggest a cross-neutralization activity of anti-genogroup B or C antibodies against strains of genogroups E and F. Neutralization assays were performed with diverse rabbit and mouse anti-EV-A71 sera, anti-EV-A71 human standards and a monoclonal neutralizing antibody. All the batches of antibodies that were tested successfully neutralized all available isolates, indicating an overall broad cross-neutralization between the canonical genogroups B and C and genogroups E and F. A panel constituted of more than 80 individual human serum samples from Cambodia with neutralizing antibodies against EV-A71 subgenogroup C4 showed quite similar cross-neutralization activities between isolates of genogroups C4, E and F. Our results thus indicate that the genetic drift underlying the separation of EV-A71 strains into genogroups A, B, C, E and F does not correlate with the emergence of antigenically distinct variants.

Funding
This study was supported by the:
  • Total Foundation (Award S-CM15010-05B)
    • Principle Award Recipient: FrancisDelpeyroux
  • Institut Pasteur (Award Roux-Howard-Cantarini postdoctoral fellowship)
    • Principle Award Recipient: RomainVolle
  • Institut Pasteur (Award Programme transversal de recherche PTR484)
    • Principle Award Recipient: FrancisDelpeyroux
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/content/journal/jgv/10.1099/jgv.0.001911
2023-11-01
2024-06-13
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References

  1. Zhu P, Ji W, Li D, Li Z, Chen Y et al. Current status of hand-foot-and-mouth disease. J Biomed Sci 2023; 30:15 [View Article] [PubMed]
    [Google Scholar]
  2. Chang L-Y, Lin H-Y, Gau SS-F, Lu C-Y, Hsia S-H et al. Enterovirus A71 neurologic complications and long-term sequelae. J Biomed Sci 2019; 26:57 [View Article] [PubMed]
    [Google Scholar]
  3. Xing J, Wang K, Wang G, Li N, Zhang Y. Recent advances in enterovirus A71 pathogenesis: a focus on fatal human enterovirus A71 infection. Arch Virol 2022; 167:2483–2501 [View Article] [PubMed]
    [Google Scholar]
  4. Kinobe R, Wiyatno A, Artika IM, Safari D. Insight into the enterovirus A71: a review. Rev Med Virol 2022; 32:e2361 [View Article] [PubMed]
    [Google Scholar]
  5. 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 2019; 26:75 [View Article] [PubMed]
    [Google Scholar]
  6. Cabrerizo M, Tarragó D, Muñoz-Almagro C, Del Amo E, Domínguez-Gil M et al. Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect 2014; 20:150–156 [View Article] [PubMed]
    [Google Scholar]
  7. Midgley SE, Nielsen AG, Trebbien R, Poulsen MW, Andersen PH et al. Co-circulation of multiple subtypes of enterovirus A71 (EV- A71) genotype C, including novel recombinants characterised by use of whole genome sequencing (WGS), Denmark 2016. Euro Surveill 2017; 22:30565 [View Article] [PubMed]
    [Google Scholar]
  8. Mirand A, Schuffenecker I, Henquell C, Billaud G, Jugie G et al. Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries. J Gen Virol 2010; 91:2263–2277 [View Article] [PubMed]
    [Google Scholar]
  9. Schuffenecker I, Mirand A, Antona D, Henquell C, Chomel J-J et al. Epidemiology of human enterovirus 71 infections in France, 2000-2009. J Clin Virol 2011; 50:50–56 [View Article] [PubMed]
    [Google Scholar]
  10. van der S, Koopmans M, Uslu G, van der H. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol 2009; 47:2826–2833 [View Article]
    [Google Scholar]
  11. González-Sanz R, Casas-Alba D, Launes C, Muñoz-Almagro C, Ruiz-García MM et al. Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016. Euro Surveill 2019; 24:1800089 [View Article] [PubMed]
    [Google Scholar]
  12. McMinn PC. Recent advances in the molecular epidemiology and control of human enterovirus 71 infection. Curr Opin Virol 2012; 2:199–205 [View Article] [PubMed]
    [Google Scholar]
  13. Yu H, Chen W, Chang H, Tang R, Zhao J et al. Genetic analysis of the VP1 region of enterovirus 71 reveals the emergence of genotype A in central China in 2008. Virus Genes 2010; 41:1–4 [View Article] [PubMed]
    [Google Scholar]
  14. Zhu J, Luo Z, Wang J, Xu Z, Chen H et al. Phylogenetic analysis of enterovirus 71 circulating in Beijing, China from 2007 to 2009. PLoS ONE 2013; 8:e56318 [View Article]
    [Google Scholar]
  15. Saxena VK, Sane S, Nadkarni SS, Sharma DK, Deshpande JM. Genetic diversity of enterovirus A71, India. Emerg Infect Dis 2015; 21:123–126 [View Article] [PubMed]
    [Google Scholar]
  16. Bessaud M, Pillet S, Ibrahim W, Joffret M-L, Pozzetto B et al. Molecular characterization of human enteroviruses in the Central African Republic: uncovering wide diversity and identification of a new human enterovirus A71 genogroup. J Clin Microbiol 2012; 50:1650–1658 [View Article] [PubMed]
    [Google Scholar]
  17. Sadeuh-Mba SA, Bessaud M, Massenet D, Joffret M-L, Endegue M-C et al. High frequency and diversity of species C enteroviruses in Cameroon and neighboring countries. J Clin Microbiol 2013; 51:759–770 [View Article] [PubMed]
    [Google Scholar]
  18. Fernandez-Garcia MD, Kebe O, Fall AD, Dia H, Diop OM et al. Enterovirus A71 genogroups C and E in children with acute flaccid paralysis, West Africa. Emerg Infect Dis 2016; 22:753–755 [View Article] [PubMed]
    [Google Scholar]
  19. Bessaud M, Razafindratsimandresy R, Nougairède A, Joffret M-L, Deshpande JM et al. Molecular comparison and evolutionary analyses of VP1 nucleotide sequences of new African human enterovirus 71 isolates reveal a wide genetic diversity. PLoS One 2014; 9:e90624 [View Article] [PubMed]
    [Google Scholar]
  20. Majumdar M, Celma C, Pegg E, Polra K, Dunning J et al. Detection and typing of human enteroviruses from clinical samples by entire-capsid next generation sequencing. Viruses 2021; 13:641 [View Article] [PubMed]
    [Google Scholar]
  21. Huang M-L, Chiang P-S, Chia M-Y, Luo S-T, Chang L-Y et al. Cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children: implications for vaccine development. PLoS Negl Trop Dis 2013; 7:e2067 [View Article] [PubMed]
    [Google Scholar]
  22. Huang Y-P, Lin T-L, Lin T-H, Wu H-S. Antigenic and genetic diversity of human enterovirus 71 from 2009 to 2012, Taiwan. PLoS One 2013; 8:e80942 [View Article] [PubMed]
    [Google Scholar]
  23. Mizuta K, Aoki Y, Suto A, Ootani K, Katsushima N et al. Cross-antigenicity among EV71 strains from different genogroups isolated in Yamagata, Japan, between 1990 and 2007. Vaccine 2009; 27:3153–3158 [View Article] [PubMed]
    [Google Scholar]
  24. Horwood PF, Andronico A, Tarantola A, Salje H, Duong V et al. Seroepidemiology of human enterovirus 71 infection among children, Cambodia. Emerg Infect Dis 2016; 22:92–95 [View Article] [PubMed]
    [Google Scholar]
  25. Cooper G, Mao Q, Crawt L, Wang Y, Dougall T et al. Establishment of the 1st WHO International Standard for anti-EV71 serum (Human). Biologicals 2018; 53:39–50 [View Article] [PubMed]
    [Google Scholar]
  26. van der Sanden S, van der Avoort H, Lemey P, Uslu G, Koopmans M. Evolutionary trajectory of the VP1 gene of human enterovirus 71 genogroup B and C viruses. J Gen Virol 2010; 91:1949–1958 [View Article] [PubMed]
    [Google Scholar]
  27. Ku Z, Shi J, Liu Q, Huang Z. Development of murine monoclonal antibodies with potent neutralization effects on enterovirus 71. J Virol Methods 2012; 186:193–197 [View Article] [PubMed]
    [Google Scholar]
  28. Ye X, Fan C, Ku Z, Zuo T, Kong L et al. Structural basis for recognition of human enterovirus 71 by a bivalent broadly neutralizing monoclonal antibody. PLoS Pathog 2016; 12:e1005454 [View Article] [PubMed]
    [Google Scholar]
  29. Razafindratsimandresy R, Joffret M-L, Andriamandimby SF, Andriamamonjy S, Rabemanantsoa S et al. Enterovirus detection in different regions of Madagascar reveals a higher abundance of enteroviruses of species C in areas where several outbreaks of vaccine-derived polioviruses occurred. BMC Infect Dis 2022; 22:821 [View Article] [PubMed]
    [Google Scholar]
  30. Wang X, Peng W, Ren J, Hu Z, Xu J et al. A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol 2012; 19:424–429 [View Article] [PubMed]
    [Google Scholar]
  31. Huang K-Y. Structural basis for neutralization of enterovirus. Curr Opin Virol 2021; 51:199–206 [View Article] [PubMed]
    [Google Scholar]
  32. Yuan J, Shen L, Wu J, Zou X, Gu J et al. Enterovirus A71 proteins: structure and function. Front Microbiol 2018; 9:286 [View Article] [PubMed]
    [Google Scholar]
  33. Liu C-C, Chou A-H, Lien S-P, Lin H-Y, Liu S-J et al. Identification and characterization of a cross-neutralization epitope of enterovirus 71. Vaccine 2011; 29:4362–4372 [View Article] [PubMed]
    [Google Scholar]
  34. Foo DGW, Alonso S, Phoon MC, Ramachandran NP, Chow VTK et al. Identification of neutralizing linear epitopes from the VP1 capsid protein of enterovirus 71 using synthetic peptides. Virus Res 2007; 125:61–68 [View Article] [PubMed]
    [Google Scholar]
  35. Zhao M, Bai Y, Liu W, Xiao X, Huang Y et al. Immunization of N terminus of enterovirus 71 VP4 elicits cross-protective antibody responses. BMC Microbiol 2013; 13:287 [View Article] [PubMed]
    [Google Scholar]
  36. Xu L, He D, Li Z, Zheng J, Yang 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 2014; 4:498–513 [View Article] [PubMed]
    [Google Scholar]
  37. Anasir MI, Poh CL. Advances in antigenic peptide-based vaccine and neutralizing antibodies against viruses causing hand, foot, and mouth disease. Int J Mol Sci 2019; 20:1256 [View Article] [PubMed]
    [Google Scholar]
  38. Kiener TK, Jia Q, Meng T, Chow VTK, 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 2014; 8:e2895 [View Article] [PubMed]
    [Google Scholar]
  39. Huang K-YA, Zhou D, Fry EE, Kotecha A, Huang P-N et al. Structural and functional analysis of protective antibodies targeting the threefold plateau of enterovirus 71. Nat Commun 2020; 11:5253 [View Article]
    [Google Scholar]
  40. Arthur Huang K-Y, Chen M-F, Huang Y-C, Shih S-R, Chiu C-H et al. Epitope-associated and specificity-focused features of EV71-neutralizing antibody repertoires from plasmablasts of infected children. Nat Commun 2017; 8:762 [View Article]
    [Google Scholar]
  41. Dang M, Wang X, Wang Q, Wang Y, Lin J et al. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein Cell 2014; 5:692–703 [View Article] [PubMed]
    [Google Scholar]
  42. Foo DGW, Macary PA, Alonso S, Poh CL. Identification of human CD4 T-cell epitopes on the VP1 capsid protein of enterovirus 71. Viral Immunol 2008; 21:215–224 [View Article] [PubMed]
    [Google Scholar]
  43. Kiener TK, Jia Q, Lim XF, He F, Meng T et al. Characterization and specificity of the linear epitope of the enterovirus 71 VP2 protein. Virol J 2012; 9:55 [View Article] [PubMed]
    [Google Scholar]
  44. Ku Z, Ye X, Huang X, Cai Y, Liu Q et al. Neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71 genotype C4 inhibit infection at pre- and post-attachment steps. PLoS One 2013; 8:e57601 [View Article] [PubMed]
    [Google Scholar]
  45. Lee H, Cifuente JO, Ashley RE, Conway JF, Makhov AM et al. A strain-specific epitope of enterovirus 71 identified by cryo-electron microscopy of the complex with fab from neutralizing antibody. J Virol 2013; 87:11363–11370 [View Article] [PubMed]
    [Google Scholar]
  46. Miyamura K, Nishimura Y, Abo M, Wakita T, Shimizu H. Adaptive mutations in the genomes of enterovirus 71 strains following infection of mouse cells expressing human P-selectin glycoprotein ligand-1. J Gen Virol 2011; 92:287–291 [View Article] [PubMed]
    [Google Scholar]
  47. Nishimura Y, Lee H, Hafenstein S, Kataoka C, Wakita T et al. Enterovirus 71 binding to PSGL-1 on leukocytes: VP1-145 acts as a molecular switch to control receptor interaction. PLoS Pathog 2013; 9:e1003511 [View Article] [PubMed]
    [Google Scholar]
  48. Plevka P, Lim P-Y, Perera R, Cardosa J, Suksatu A et al. Neutralizing antibodies can initiate genome release from human enterovirus 71. Proc Natl Acad Sci U S A 2014; 111:2134–2139 [View Article] [PubMed]
    [Google Scholar]
  49. Ren J, Wang X, Zhu L, Hu Z, Gao Q et al. Structures of coxsackievirus A16 capsids with native antigenicity: implications for particle expansion, receptor binding, and immunogenicity. J Virol 2015; 89:10500–10511 [View Article] [PubMed]
    [Google Scholar]
  50. Duong V, Mey C, Eloit M, Zhu H, Danet L et al. Molecular epidemiology of human enterovirus 71 at the origin of an epidemic of fatal hand, foot and mouth disease cases in Cambodia. Emerg Microbes Infect 2016; 5:e104 [View Article] [PubMed]
    [Google Scholar]
  51. Bello AM, Roshorm YM. Recent progress and advances towards developing enterovirus 71 vaccines for effective protection against human hand, foot and mouth disease (HFMD). Biologicals 2022; 79:1–9 [View Article] [PubMed]
    [Google Scholar]
  52. Chong P, Liu C-C, Chow Y-H, Chou A-H, Klein M. Review of enterovirus 71 vaccines. Clin Infect Dis 2015; 60:797–803 [View Article] [PubMed]
    [Google Scholar]
  53. Huang K-YA, Lin J-J, Chiu C-H, Yang S, Tsao K-C et al. A potent virus-specific antibody-secreting cell response to acute enterovirus 71 infection in children. J Infect Dis 2015; 212:808–817 [View Article]
    [Google Scholar]
  54. van der Sanden SMG, Koen G, van Eijk H, Koekkoek SM, de Jong MD et al. Prediction of protection against Asian enterovirus 71 outbreak strains by cross-neutralizing capacity of serum from dutch donors, The Netherlands. Emerg Infect Dis 2016; 22:1562–1569 [View Article] [PubMed]
    [Google Scholar]
  55. Chia M-Y, Chung W-Y, Chiang P-S, Chien Y-S, Ho M-S et al. Monitoring antigenic variations of enterovirus 71: implications for virus surveillance and vaccine development. PLOS Negl Trop Dis 2014; 8:e3044 [View Article] [PubMed]
    [Google Scholar]
  56. Liu P, Yuan Y, Cui B, Huo Y, Bian L et al. Cross-antigenicity between EV71 sub-genotypes: implications for vaccine efficacy. Viruses 2021; 13:720 [View Article] [PubMed]
    [Google Scholar]
  57. Lee M-S, Lin T-Y, Chiang P-S, Li W-C, Luo S-T et al. An investigation of epidemic enterovirus 71 infection in Taiwan, 2008: clinical, virologic, and serologic features. Pediatr Infect Dis J 2010; 29:1030–1034 [View Article] [PubMed]
    [Google Scholar]
  58. Chen Y, Li C, He D, Cheng T, Ge S et al. Antigenic analysis of divergent genotypes human enterovirus 71 viruses by a panel of neutralizing monoclonal antibodies: current genotyping of EV71 does not reflect their antigenicity. Vaccine 2013; 31:425–430 [View Article] [PubMed]
    [Google Scholar]
  59. Page GS, Mosser AG, Hogle JM, Filman DJ, Rueckert RR et al. Three-dimensional structure of poliovirus serotype 1 neutralizing determinants. J Virol 1988; 62:1781–1794 [View Article] [PubMed]
    [Google Scholar]
  60. Blondel B, Crainic R, Fichot O, Dufraisse G, Candrea A et al. Mutations conferring resistance to neutralization with monoclonal antibodies in type 1 poliovirus can be located outside or inside the antibody-binding site. J Virol 1986; 57:81–90 [View Article] [PubMed]
    [Google Scholar]
  61. Domingo E, Martin V, Perales C, Escarmis C. Coxsackieviruses and quasispecies theory: evolution of enteroviruses. Curr Top Microbiol Immunol 2008; 323:3–32 [View Article] [PubMed]
    [Google Scholar]
  62. Bordería AV, Rozen-Gagnon K, Vignuzzi M. Fidelity variants and RNA quasispecies. Curr Top Microbiol Immunol 2016; 392:303–322 [View Article] [PubMed]
    [Google Scholar]
  63. Klasse PJ. Molecular determinants of the ratio of inert to infectious virus particles. Prog Mol Biol Transl Sci 2015; 129:285–326 [View Article] [PubMed]
    [Google Scholar]
  64. Bessaud M, Joffret M-L, Holmblat B, Razafindratsimandresy R, Delpeyroux F. Genetic relationship between cocirculating Human enteroviruses species C. PLoS One 2011; 6:e24823 [View Article] [PubMed]
    [Google Scholar]
  65. Lukashev AN. Recombination among picornaviruses. Rev Med Virol 2010; 20:327–337 [View Article]
    [Google Scholar]
  66. Xu L, Qi M, Ma C, Yang M, Huang P et al. Natural intertypic and intratypic recombinants of enterovirus 71 from mainland China during 2009-2018: a complete genome analysis. Virus Genes 2021; 57:172–180 [View Article] [PubMed]
    [Google Scholar]
  67. Shih SR, Ho MS, Lin KH, Wu SL, Chen YT et al. Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in Taiwan, 1998. Virus Res 2000; 68:127–136 [View Article] [PubMed]
    [Google Scholar]
  68. Volle R, Razafindratsimandresy R, Joffret M-L, Bessaud M, Rabemanantsoa S et al. High permissiveness for genetic exchanges between enteroviruses of species A, including enterovirus 71, favors evolution through intertypic recombination in Madagascar. J Virol 2019; 93:e01667-18 [View Article] [PubMed]
    [Google Scholar]
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