Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen.
Animals
Antibodies, Monoclonal, Humanized
/ chemistry
Antibodies, Neutralizing
/ biosynthesis
Antibodies, Viral
/ biosynthesis
Cloning, Molecular
Computer-Aided Design
Epitopes
/ chemistry
Escherichia coli
/ genetics
Female
Gene Expression
Genetic Vectors
/ chemistry
Immunization
/ methods
Immunogenicity, Vaccine
Mice
Mice, Inbred BALB C
Nanoparticles
/ administration & dosage
Palivizumab
/ chemistry
Receptors, Antigen, B-Cell
/ chemistry
Recombinant Fusion Proteins
/ administration & dosage
Respiratory Syncytial Virus Vaccines
/ administration & dosage
Respiratory Syncytial Viruses
/ immunology
Structural Homology, Protein
Viral Fusion Proteins
/ administration & dosage
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
16
11
2018
accepted:
08
02
2019
revised:
05
03
2019
pubmed:
23
2
2019
medline:
26
11
2019
entrez:
22
2
2019
Statut:
epublish
Résumé
Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.
Identifiants
pubmed: 30789898
doi: 10.1371/journal.pbio.3000164
pii: PBIOLOGY-D-18-01249
pmc: PMC6400402
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antibodies, Neutralizing
0
Antibodies, Viral
0
Epitopes
0
Receptors, Antigen, B-Cell
0
Recombinant Fusion Proteins
0
Respiratory Syncytial Virus Vaccines
0
Viral Fusion Proteins
0
motavizumab
50Y163LK8Q
Palivizumab
DQ448MW7KS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000164Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Nat Commun. 2017 Nov 21;8(1):1655
pubmed: 29162799
Cell. 2016 Sep 8;166(6):1459-1470.e11
pubmed: 27610570
Nat Rev Immunol. 2002 Sep;2(9):706-13
pubmed: 12209139
Curr Opin Struct Biol. 2018 Aug;51:163-169
pubmed: 29980105
J Gen Virol. 2004 Jun;85(Pt 6):1643-1653
pubmed: 15166449
Philos Trans R Soc Lond B Biol Sci. 2015 Sep 5;370(1676):
pubmed: 26194761
Science. 2015 Sep 18;349(6254):1301-6
pubmed: 26303961
Nat Rev Immunol. 2011 Nov 04;11(12):865-72
pubmed: 22051890
Nature. 2016 Aug 4;536(7614):48-53
pubmed: 27338953
Structure. 2010 Sep 8;18(9):1116-26
pubmed: 20826338
J Virol. 2015 Nov 11;90(2):1116-28
pubmed: 26559834
Mol Syst Biol. 2011 Oct 11;7:539
pubmed: 21988835
J Mol Biol. 2011 Jun 24;409(5):853-66
pubmed: 21549714
Front Immunol. 2018 Jun 20;9:1401
pubmed: 29973938
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
Trends Biotechnol. 2017 Mar;35(3):203-214
pubmed: 28341036
PLoS One. 2008 Mar 12;3(3):e1766
pubmed: 18335041
Cell. 2016 Jul 28;166(3):596-608
pubmed: 27453466
Nanomedicine. 2017 Feb;13(2):411-420
pubmed: 27553073
Nature. 2014 Mar 13;507(7491):201-6
pubmed: 24499818
Science. 2009 Nov 27;326(5957):1279-83
pubmed: 19965480
Cell. 2006 Feb 24;124(4):767-82
pubmed: 16497587
Science. 2011 Aug 12;333(6044):843-50
pubmed: 21737702
J Mol Biol. 2011 Jan 7;405(1):284-97
pubmed: 20969873
Cell. 2017 May 04;169(4):597-609.e11
pubmed: 28475892
J Mol Biol. 2007 May 4;368(3):652-65
pubmed: 17362988
Nat Immunol. 2016 Sep;17(9):1102-8
pubmed: 27339099
Bioinformatics. 2014 Oct;30(19):2811-2
pubmed: 24930139
Annu Rev Immunol. 2016 May 20;34:635-59
pubmed: 27168247
Sci Adv. 2016 Mar 11;2(3):e1501371
pubmed: 26998518
Nat Immunol. 2017 Apr;18(4):456-463
pubmed: 28192417
Annu Rev Immunol. 2012;30:429-57
pubmed: 22224772
Science. 2016 Mar 4;351(6277):1078-83
pubmed: 26912366
Immunity. 2018 Feb 20;48(2):339-349.e5
pubmed: 29396163
Sci Immunol. 2017 Jun 30;2(12):
pubmed: 28783665
Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):17880-7
pubmed: 20876137
Sci Rep. 2017 Sep 11;7(1):11130
pubmed: 28894111
Nat Commun. 2014 Oct 03;5:5104
pubmed: 25277263
J Struct Biol. 2016 Jul;195(1):93-9
pubmed: 27108186
NPJ Vaccines. 2017;2:
pubmed: 29250437
Science. 2011 Aug 12;333(6044):850-6
pubmed: 21798894
Science. 2010 Aug 27;329(5995):1060-4
pubmed: 20647428
Science. 2011 Sep 16;333(6049):1633-7
pubmed: 21764753
Science. 2013 May 31;340(6136):1113-7
pubmed: 23618766
Curr Top Microbiol Immunol. 2015;386:323-41
pubmed: 25037260
Science. 2017 Jun 2;356(6341):923-928
pubmed: 28572385
Science. 2017 Nov 17;358(6365):929-932
pubmed: 29097492
Nat Med. 2015 Sep;21(9):1065-70
pubmed: 26301691
NPJ Vaccines. 2017 Jan 23;2:2
pubmed: 29263863
PLoS One. 2016 Jul 27;11(7):e0159709
pubmed: 27463224
Proc Natl Acad Sci U S A. 2018 Jan 2;115(1):168-173
pubmed: 29255041
Cell. 2015 Oct 22;163(3):545-8
pubmed: 26496601
Immunity. 2018 Jan 16;48(1):133-146.e6
pubmed: 29287996
Sci Immunol. 2016 Dec 16;1(6):
pubmed: 28111638
Clin Vaccine Immunol. 2010 Jul;17(7):1055-65
pubmed: 20463105
Sci Transl Med. 2015 Dec 2;7(316):316ra192
pubmed: 26631631
Nat Struct Mol Biol. 2010 Feb;17(2):248-50
pubmed: 20098425
J Virol. 2015 Mar;89(6):3308-17
pubmed: 25589639
Science. 2015 Jul 10;349(6244):156-61
pubmed: 26089355
Nat Methods. 2018 Jan 3;15(1):8-9
pubmed: 29298290
J Virol. 2016 Jun 10;90(13):5965-5977
pubmed: 27099320
Virology. 2015 May;479-480:498-507
pubmed: 25866377
Immunity. 2000 Jul;13(1):37-45
pubmed: 10933393
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10383-8
pubmed: 10984534
PLoS Pathog. 2016 Jun 23;12(6):e1005692
pubmed: 27336297
Nat Med. 2018 Jun;24(6):857-867
pubmed: 29867235
J Exp Med. 2013 Jul 29;210(8):1493-500
pubmed: 23857983
Nat Struct Mol Biol. 2016 Sep;23(9):811-820
pubmed: 27478931
J Exp Med. 2016 Apr 4;213(4):469-81
pubmed: 27022144
Cell Rep. 2017 Dec 26;21(13):3672-3680
pubmed: 29281817
Cold Spring Harb Perspect Biol. 2017 Nov 1;9(11):
pubmed: 28159875
PLoS Comput Biol. 2018 Nov 19;14(11):e1006623
pubmed: 30452434
Science. 2013 Nov 1;342(6158):592-8
pubmed: 24179220
J Immunol. 1996 Jul 15;157(2):772-80
pubmed: 8752928
Curr Opin Virol. 2015 Apr;11:70-5
pubmed: 25819327
J Struct Biol. 2012 Dec;180(3):519-30
pubmed: 23000701