Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality
William R. Morgenlander, Stephanie N. Henson, Daniel R. Monaco, Athena Chen, Kirsten Littlefield, Evan M. Bloch, Eric Fujimura, Ingo Ruczinski, Andrew R. Crowley, Harini Natarajan, Savannah E. Butler, Joshua A. Weiner, Mamie Z. Li, Tania S. Bonny, Sarah E. Benner, Ashwin Balagopal, David Sullivan, Shmuel Shoham, Thomas C. Quinn, Susan H. Eshleman, Arturo Casadevall, Andrew D. Redd, Oliver Laeyendecker, Margaret E. Ackerman, Andrew Pekosz, Stephen J. Elledge, Matthew Robinson, Aaron A.R. Tobian, H. Benjamin Larman
William R. Morgenlander, Stephanie N. Henson, Daniel R. Monaco, Athena Chen, Kirsten Littlefield, Evan M. Bloch, Eric Fujimura, Ingo Ruczinski, Andrew R. Crowley, Harini Natarajan, Savannah E. Butler, Joshua A. Weiner, Mamie Z. Li, Tania S. Bonny, Sarah E. Benner, Ashwin Balagopal, David Sullivan, Shmuel Shoham, Thomas C. Quinn, Susan H. Eshleman, Arturo Casadevall, Andrew D. Redd, Oliver Laeyendecker, Margaret E. Ackerman, Andrew Pekosz, Stephen J. Elledge, Matthew Robinson, Aaron A.R. Tobian, H. Benjamin Larman
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Research Article Immunology Infectious disease

Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

Abstract

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.

Authors

William R. Morgenlander, Stephanie N. Henson, Daniel R. Monaco, Athena Chen, Kirsten Littlefield, Evan M. Bloch, Eric Fujimura, Ingo Ruczinski, Andrew R. Crowley, Harini Natarajan, Savannah E. Butler, Joshua A. Weiner, Mamie Z. Li, Tania S. Bonny, Sarah E. Benner, Ashwin Balagopal, David Sullivan, Shmuel Shoham, Thomas C. Quinn, Susan H. Eshleman, Arturo Casadevall, Andrew D. Redd, Oliver Laeyendecker, Margaret E. Ackerman, Andrew Pekosz, Stephen J. Elledge, Matthew Robinson, Aaron A.R. Tobian, H. Benjamin Larman

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Figure 3

Reactivities against some CoV2 peptides are highly correlated with reactivities against homologous HCoV peptides.

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Reactivities against some CoV2 peptides are highly correlated with react...
(A) Spearman’s correlation coefficient matrix between dominant CoV2 peptides and dominant HCoV peptides is shown in the form of a clustered heatmap. CoV2 peptides (y axis) are ordered by genomic location from top to bottom, while HCoV peptides (x axis) are clustered according to their correlations. The heatmap annotations depict peptides’ protein of origin and virus of origin. Highly correlated peptides map to fusion peptide (FP) or heptad repeat 2 (HR2). (B) Sequence similarity (defined by the negative log of the blastp E value) between dominant CoV2 peptides and dominant HCoV peptides is shown. The rows and columns of the heatmap match those of the correlation heatmap to facilitate comparison. The regions of highest correlation (boxes as in A) show strongest alignment. (C–E) Antibody reactivity (measured as fold changes) to 3 HKU1 S peptides are plotted against reactivity to homologous peptides of CoV2 S. The 2 CS peptides have no sequence homology and their reactivity is not correlated. The 2 RBD peptides have moderate homology and show frequent coreactivity but no strong correlation. The 2 FP peptides have high sequence homology and strong correlation among all sample groups. Asterisks indicate Pearson’s correlation with nonzero coefficient for a given plasma group (P < 0.05).