Epitope-resolved antibody fine-specificities — not bulk titer — predict which convalescent plasma donations actually neutralize SARS-CoV-2.
The Journal of Clinical Investigation · April 2021 · DOI: 10.1172/JCI146927
Morgenlander WR, Henson SN, Monaco DR, et al. Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality. J Clin Invest. 2021;131(7):e146927. doi:10.1172/JCI146927
Morgenlander, W. R., Henson, S. N., Monaco, D. R., Chen, A., Littlefield, K., Bloch, E. M., Fujimura, E., Ruczinski, I., Crowley, A. R., Natarajan, H., Butler, S. E., Weiner, J. A., Li, M. Z., Bonny, T. S., Benner, S. E., Balagopal, A., Sullivan, D., Shoham, S., Quinn, T. C., ... Larman, H. B. (2021). Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality. The Journal of Clinical Investigation, 131(7), e146927. https://doi.org/10.1172/JCI146927
@article{morgenlander2021endemic,
title = {Antibody responses to endemic coronaviruses modulate {COVID-19} convalescent plasma functionality},
author = {Morgenlander, William R. and Henson, Stephanie N. and Monaco, Daniel R. and Chen, Athena and Littlefield, Kirsten and Bloch, Evan M. and Fujimura, Emily and Ruczinski, Ingo and Crowley, Andrew R. and Natarajan, Harini and Butler, Savannah E. and Weiner, Joshua A. and Li, Mamie Z. and Bonny, Tania S. and Benner, Sarah E. and Balagopal, Ashwin and Sullivan, David and Shoham, Shmuel and Quinn, Thomas C. and Eshleman, Susan H. and Casadevall, Arturo and Redd, Andrew D. and Laeyendecker, Oliver and Ackerman, Margaret E. and Pekosz, Andrew and Elledge, Stephen J. and Robinson, Matthew and Tobian, Aaron A.R. and Larman, H. Benjamin},
journal = {Journal of Clinical Investigation},
volume = {131},
number = {7},
pages = {e146927},
year = {2021},
doi = {10.1172/JCI146927}
}
This study profiled antibodies in 126 COVID-19 convalescent plasma (CCP) donations against peptide tiles spanning the SARS-CoV-2 proteome and the proteomes of the four endemic seasonal human coronaviruses (NL63, 229E, HKU1, OC43), then asked which epitope-level reactivities tracked with neutralizing function. The team derived a two-peptide serosignature that flags donations with high anti-spike titer but low neutralizing activity — the kind of donor that conventional titer screens fail to filter out. The findings reframe pre-existing endemic-coronavirus immunity from a confounder of serology to a functional modulator of the SARS-CoV-2 response.
In this publication:
COVID-19 convalescent plasma — blood plasma from people who have recovered from SARS-CoV-2 infection — was deployed early in the pandemic as one of the first available antibody therapies for newly infected patients. But its clinical performance varied dramatically from donor to donor, and it was not clear what biological feature explained the difference.
The authors profiled antibodies in 126 convalescent plasma donations against peptide tiles spanning the entire SARS-CoV-2 proteome and the proteomes of the four endemic human coronaviruses that circulate seasonally and cause common-cold-like illness: alphacoronaviruses NL63 and 229E, and betacoronaviruses HKU1 and OC43. They then asked which of these epitope-level reactivities tracked with functional measures of plasma performance, including neutralizing activity.
Three results stand out. First, antibody binding to many endemic-coronavirus spike peptides — not just SARS-CoV-2 spike — correlated with plasma functionality, including pan-coronavirus cross-reactive epitopes in a conserved region of the spike fusion peptide. Second, after statistically accounting for cross-reactivity, donors with stronger pre-existing alphacoronavirus NL63 responses were more likely to develop highly neutralizing antibodies against SARS-CoV-2, and donors whose plasma preferentially recognized SARS-CoV-2 spike receptor-binding domain over the betacoronavirus HKU1 receptor-binding domain showed higher neutralizing titer. Third, the team derived a two-peptide serosignature that flags donations with high anti-spike titer but low neutralizing activity — the kind of donor that conventional titer screens fail to filter out.
Together, the findings reframe pre-existing endemic-coronavirus immunity from a confounder of serology to a functional modulator of the SARS-CoV-2 response, and they make the case that epitope-resolved antibody fine-specificities — not bulk titer alone — are the right unit of measurement for selecting therapeutic plasma, designing pan-coronavirus vaccines, and interpreting cross-reactive immunity to emerging coronaviruses.
A peer-reviewed methodology white paper for VirSIGHT, Infinity Bio's unbiased antibody reactome assay covering 500+ huma…
Read more
VirSIGHT at a glance: antibody reactome profiling across the known human virome (500+ species).
Read more
Where the antibody reactome fits in the multi-omic stack, how MIPSA deciphers it, and what the HuSIGHT, VirSIGHT, and En…
Read more
Lindahl et al., 2026: viral immunity in IgG products and global immunity debt.
Read moreAntibody reactome profiling of bat reservoirs identifies emerging zoonotic potential for biosurveillance.
Read moreFrontiers Immunol 2023: pre-infection antibody reactome predicts post-infection HIV viral control.
Read moreAntibody reactome profiling of the human anellome: small DNA viruses persisting in healthy hosts.
Read moreFemales develop broader vaccine-induced antibody repertoires, driven by germinal-center B-cell diversity.
Read moreBjornevik et al., Science 2022: 10M serial serum samples link EBV to multiple sclerosis.
Read moreAntibody epitope selection is partially heritable, shown across twin and SNP-genotyped cohorts.
Read moreBioinformatic deconvolution of cross-reactive signals in virome-wide antibody reactome data.
Read moreSARS-CoV-2 antibody signatures predict convalescent plasma antiviral function.
Read more