Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

PLoS Biology
Fabian SesterhennBruno E Correia

Abstract

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.

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Citations

Sep 2, 2020·Virologica Sinica·Ruikun DuLijun Rong
Sep 11, 2019·Vaccines·Ralph A Tripp, Ultan F Power
Jul 20, 2019·Human Antibodies·Manzoor A MirSyed Suhail Hamdani
Jan 6, 2021·Nature Chemical Biology·Che YangBruno E Correia
Feb 28, 2021·Current Opinion in Structural Biology·Robin Pearce, Yang Zhang
Sep 7, 2021·Molecular Systems Biology·Zhixin Cyrillus TanAaron S Meyer
Dec 19, 2021·NPJ Vaccines·Timothy M Caradonna, Aaron G Schmidt

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Datasets Mentioned

BETA
AY911262.1

Methods Mentioned

BETA
surface plasmon resonance
electron microscopy
dynamic
blood
ELISA
chip
affinity purification
size-exclusion chromatography
PCR
transfection

Software Mentioned

XMIPP
GraphPad Prism
PyMol
CTFFIND4
Biacore
Python script
EPU
BLAST omega
SCIPION
RELION

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