Mapping Enterovirus A71 Antigenic Determinants from Viral Evolution.
Human enterovirus A71 (EV-A71) belongs to the Enterovirus A species in the Picornaviridae family. Several vaccines against EV-A71, a disease causing severe neurological complications or even death, are currently under development and being tested in clinical trials, and preventative vaccination programs are expected to start soon. To characterize the potential for antigenic change of EV-A71, we compared the sequences of two antigenically diverse genotype B4 and B5 strains of EV-A71 and identified substitutions at residues 98, 145, and 164 in the VP1 capsid protein as antigenic determinants. To examine the effects of these three substitutions on antigenicity, we constructed a series of recombinant viruses containing different mutation combinations at these three residues with a reverse genetics system and then investigated the molecular basis of antigenic changes with antigenic cartography. We found that a novel EV-A71 mutant, containing lysine, glutamine, and glutamic acid at the respective residues 98, 145, and 164 in the VP1 capsid protein, exhibited neutralization reduction against patients' antisera and substantially increased virus binding ability to human cells. These observations indicated that this low-neutralization-reactive EV-A71 VP1-98K/145Q/164E mutant potentially increases viral binding ability and that surveillance studies should look out for these mutants, which could compromise vaccine efficacy.


OBJECTIVE
Emerging and reemerging EV-A71 viruses can cause severe neurological etiology, primarily affecting children, especially around Asia-Pacific countries. We identified a set of mutations in EV-A71 that both reduced neutralization activity against humoral immunity in antisera of patients and healthy adults and greatly increased the viral binding ability to cells. These findings provide important insights for EV-A71 antigenic determinants and emphasize the importance of continuous surveillance, especially after EV-A71 vaccination programs begin.
Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
Sheng-Wen
SW
Huang
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
Ching-Hui
CH
Tai
University of Cambridge, Cambridge, United Kingdom Erasmus Medical Centre, Rotterdam, Netherlands WHO Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge, United Kingdom.
Judith M
JM
Fonville
Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Chin-Hui
CH
Lin
Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan Department of Emergency Medicine, National Cheng Kung University, Tainan, Taiwanx.
Shih-Min
SM
Wang
Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan Department of Pediatrics, National Cheng Kung University, Tainan, Taiwan.
Ching-Chung
CC
Liu
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
Ih-Jen
IJ
Su
University of Cambridge, Cambridge, United Kingdom Erasmus Medical Centre, Rotterdam, Netherlands WHO Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge, United Kingdom National Institutes of Health, Bethesda, Maryland, USA dsmith@zoo.cam.ac.uk jrwang@mail.ncku.edu.tw.
Derek J
DJ
Smith
Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan dsmith@zoo.cam.ac.uk jrwang@mail.ncku.edu.tw.
Jen-Ren
JR
Wang
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood; D000940:Antigenic Variation / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D005075:Biological Evolution; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002675:Child, Preschool; D029821:Enterovirus A, Human / Q000145:classification / Q000235:genetics / Q000276:immunology*; D004769:Enterovirus Infections / Q000276:immunology / Q000517:prevention & control*; D018604:Epitope Mapping; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D014765:Viral Vaccines / Q000276:immunology*
D000914:Antibodies, Viral; D036022:Capsid Proteins; D000939:Epitopes; D014765:Viral Vaccines