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Cited by 248SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

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Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection

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Greaney, Allison J., Loes, Andrea N., Gentles, Lauren E., Crawford, Katharine H.D., Starr, Tyler N., Malone, Keara D., Chu, Helen Y., Bloom, Jesse D.·2021·Science Translational Medicine
DOI 10.1126/scitranslmed.abi9915PMC PMC8369496

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Abstract

Deep mutational scanning shows that the mRNA-1273 RBD-binding antibody response is less affected by single viral mutations than the infection response.

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Fig. 1 RBD-binding antibodies are responsible for most neutralizing activity of mRNA-1273 vaccine–elicited sera. (A) Binding of serum antibodies to SARS-CoV-2 RBD, as measured by ELISA area under the curve (AUC), for vaccine-elicited sera and convalescent plasma before and after depletion of RBD-binding antibodies. The dashed pink line indicates binding of prepandemic sera. (B) Binding of serum antibodies to the full spike ectodomain. The y-axis scale units in (A) and (B) are not comparable between samples from vaccinated and convalescent individuals owing to different dilution factors (beginning at 1:500 for vaccine sera and 1:100 for convalescent plasma samples). (C) Neutralization titer (NT50) of vaccine-elicited sera and convalescent plasma samples before and after depletion of RBD-binding antibodies. The limit of detection is shown as a dashed horizontal pink line. (D) Percentage of neutralizing activity of vaccine-elicited sera and convalescent plasma samples due to RBD-binding antibodies. P values are from a log-rank test accounting for censoring. n = 17 for each time point for convalescent plasma samples and n = 14 for each time point for vaccine sera. ns, not significant. All measurements of convalescent plasma binding and neutralization were previously reported in (15).
Fig. 1 RBD-binding antibodies are responsible for most neutralizing activity of mRNA-1273 vaccine–elicited sera. (A) Binding of serum antibodies to SARS-CoV-2 RBD, as measured by ELISA area under the curve (AUC), for vaccine-elicited sera and convalescent plasma before and after depletion of RBD-binding antibodies. The dashed pink line indicates binding of prepandemic sera. (B) Binding of serum antibodies to the full spike ectodomain. The y-axis scale units in (A) and (B) are not comparable between samples from vaccinated and convalescent individuals owing to different dilution factors (beginning at 1:500 for vaccine sera and 1:100 for convalescent plasma samples). (C) Neutralization titer (NT50) of vaccine-elicited sera and convalescent plasma samples before and after depletion of RBD-binding antibodies. The limit of detection is shown as a dashed horizontal pink line. (D) Percentage of neutralizing activity of vaccine-elicited sera and convalescent plasma samples due to RBD-binding antibodies. P values are from a log-rank test accounting for censoring. n = 17 for each time point for convalescent plasma samples and n = 14 for each time point for vaccine sera. ns, not significant. All measurements of convalescent plasma binding and neutralization were previously reported in (15).CC BY · PubMed Central
Fig. 2 Complete maps of RBD mutations that reduce binding by sera collected 119 days after vaccination with the 250-μg dose of the mRNA-1273 vaccine. (A) The epitopes of four major classes (24) of RBD-binding antibodies are colored on the RBD surface (PDB 6M0J). ACE2 is shown as a gray ribbon diagram. (B) Number of sera that fell into each of the four major categories of binding-escape maps as categorized by subjective visual inspection. (C) Escape maps for six representative sera are shown. The line plots on the left indicate the sum of effects of all mutations at each RBD site on serum antibody binding, with larger values indicating more escape. The logo plots on the right show key sites (highlighted in purple on the line plot x axes). The height of each letter is that mutation’s escape fraction; larger letters indicate a greater reduction in binding. Escape fractions are not strictly comparable between samples owing to the use of sample-specific FACS selection gates; therefore, for each sample, the y axis is scaled independently. RBD sites are colored by epitope as in (A). The escape fractions were correlated between independent libraries, and we report the average of duplicate measurements throughout. Interactive versions of logo plots and structural visualizations are at https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_Moderna/.
Fig. 2 Complete maps of RBD mutations that reduce binding by sera collected 119 days after vaccination with the 250-μg dose of the mRNA-1273 vaccine. (A) The epitopes of four major classes (24) of RBD-binding antibodies are colored on the RBD surface (PDB 6M0J). ACE2 is shown as a gray ribbon diagram. (B) Number of sera that fell into each of the four major categories of binding-escape maps as categorized by subjective visual inspection. (C) Escape maps for six representative sera are shown. The line plots on the left indicate the sum of effects of all mutations at each RBD site on serum antibody binding, with larger values indicating more escape. The logo plots on the right show key sites (highlighted in purple on the line plot x axes). The height of each letter is that mutation’s escape fraction; larger letters indicate a greater reduction in binding. Escape fractions are not strictly comparable between samples owing to the use of sample-specific FACS selection gates; therefore, for each sample, the y axis is scaled independently. RBD sites are colored by epitope as in (A). The escape fractions were correlated between independent libraries, and we report the average of duplicate measurements throughout. Interactive versions of logo plots and structural visualizations are at https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_Moderna/.CC BY · PubMed Central
Fig. 3 Comparison of escape maps for sera collected at days 36 and 119 after vaccination shows that the RBD-binding response becomes more focused over time. (A and B) Escape maps for sera at day 36 (A) and day 119 (B) from five individuals who received the 250-μg vaccine dose are shown. The day 36 maps are all relatively flat, indicating that no RBD mutation has a large effect on serum antibody binding. By day 119, the maps are often more focused on sites 456 and 484. The y axis is scaled separately for each serum sample. Interactive versions are at https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_Moderna/.
Fig. 3 Comparison of escape maps for sera collected at days 36 and 119 after vaccination shows that the RBD-binding response becomes more focused over time. (A and B) Escape maps for sera at day 36 (A) and day 119 (B) from five individuals who received the 250-μg vaccine dose are shown. The day 36 maps are all relatively flat, indicating that no RBD mutation has a large effect on serum antibody binding. By day 119, the maps are often more focused on sites 456 and 484. The y axis is scaled separately for each serum sample. Interactive versions are at https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_Moderna/.CC BY · PubMed Central
Fig. 4 The binding of vaccine-elicited polyclonal antibodies is more broadly distributed across the RBD than the binding of infection-elicited antibodies. (A) Escape from RBD-binding antibodies at each site in the RBD was mapped for vaccine sera or convalescent plasma samples collected at early or late time points. Thin gray lines show individual serum or plasma samples, and the thick black line shows the mean (number of samples is indicated in the plot titles). Key sites within the epitopes of each major RBD antibody class are highlighted with the colors defined in Fig. 2A and in (B). (B) Relationships among escape maps of vaccine sera, convalescent plasma samples, and monoclonal antibodies visualized with a multidimensional scaling projection. Vaccine sera include both doses and time points. Convalescent plasma samples include all time points. (C) Total binding escape at each site mapped onto the RBD surface after averaging across all serum or plasma in each group. The RBD surface coloring is scaled from white to red, with white indicating no escape, and red indicating the site with the greatest escape. The color scaling spans the full range of white to red for each serum or plasma group, so a quantitative scale is not comparable across groups. Escape maps for monoclonal antibodies are previously described in (16, 22, 27–29), and convalescent plasma samples are described in (15, 16). An interactive version of (B) where you can mouse over points for details is at https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_Moderna/mds.html.
Fig. 4 The binding of vaccine-elicited polyclonal antibodies is more broadly distributed across the RBD than the binding of infection-elicited antibodies. (A) Escape from RBD-binding antibodies at each site in the RBD was mapped for vaccine sera or convalescent plasma samples collected at early or late time points. Thin gray lines show individual serum or plasma samples, and the thick black line shows the mean (number of samples is indicated in the plot titles). Key sites within the epitopes of each major RBD antibody class are highlighted with the colors defined in Fig. 2A and in (B). (B) Relationships among escape maps of vaccine sera, convalescent plasma samples, and monoclonal antibodies visualized with a multidimensional scaling projection. Vaccine sera include both doses and time points. Convalescent plasma samples include all time points. (C) Total binding escape at each site mapped onto the RBD surface after averaging across all serum or plasma in each group. The RBD surface coloring is scaled from white to red, with white indicating no escape, and red indicating the site with the greatest escape. The color scaling spans the full range of white to red for each serum or plasma group, so a quantitative scale is not comparable across groups. Escape maps for monoclonal antibodies are previously described in (16, 22, 27–29), and convalescent plasma samples are described in (15, 16). An interactive version of (B) where you can mouse over points for details is at https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_Moderna/mds.html.CC BY · PubMed Central
Fig. 5 Effects of RBD mutations on neutralization by day 100 to 150 sera from vaccinated and convalescent individuals. (A) Total binding escape at each RBD site is shown for the samples from vaccinated (n = 6) or convalescent (n = 6) individuals tested in neutralization assays. The thin gray lines show individual samples, and the dark black line shows the mean. Key sites within each epitope are highlighted using the same color scheme as in Fig. 2A. (B) Neutralization of G614 spike-pseudotyped lentiviral particles with the indicated RBD mutations, shown as the fold decrease in NT50 compared to G614 spike with no additional mutations. Mutations that have been observed in human SARS-CoV-2 isolates are colored white, and nonnaturally occurring mutations are in gray. The orange dashed line represents the effect of depleting all RBD-binding antibodies. (C) The fold decrease in neutralization titer caused by individual mutations in each of the three major neutralizing epitopes of the RBD: K417 in the class 1 epitope, E484K in the class 2 epitope, and G446V in the class 3 epitope. The combination of all three mutations is also shown. Horizontal lines represent the median. In (B) and (C), the dashed gray line indicates no change in neutralization relative to unmutated spike. (D) Representative neutralization curves from two vaccine and two convalescent samples against the triple mutant and its composite single mutations.
Fig. 5 Effects of RBD mutations on neutralization by day 100 to 150 sera from vaccinated and convalescent individuals. (A) Total binding escape at each RBD site is shown for the samples from vaccinated (n = 6) or convalescent (n = 6) individuals tested in neutralization assays. The thin gray lines show individual samples, and the dark black line shows the mean. Key sites within each epitope are highlighted using the same color scheme as in Fig. 2A. (B) Neutralization of G614 spike-pseudotyped lentiviral particles with the indicated RBD mutations, shown as the fold decrease in NT50 compared to G614 spike with no additional mutations. Mutations that have been observed in human SARS-CoV-2 isolates are colored white, and nonnaturally occurring mutations are in gray. The orange dashed line represents the effect of depleting all RBD-binding antibodies. (C) The fold decrease in neutralization titer caused by individual mutations in each of the three major neutralizing epitopes of the RBD: K417 in the class 1 epitope, E484K in the class 2 epitope, and G446V in the class 3 epitope. The combination of all three mutations is also shown. Horizontal lines represent the median. In (B) and (C), the dashed gray line indicates no change in neutralization relative to unmutated spike. (D) Representative neutralization curves from two vaccine and two convalescent samples against the triple mutant and its composite single mutations.CC BY · PubMed Central

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Citations

Cites

Research works printed but not linked: 3

  1. Pfizer and BioNTech confirm high efficacy and no serious safety concerns through up to six months following second dose in updated topline analysis of landmark COVID-19 vaccine study; www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-confirm-high-efficacy-and-no-serious.
  2. A. J. Greaney, T. N. Starr, C. O. Barnes, Y. Weisblum, F. Schmidt, M. Caskey, C. Gaebler, M. Agudelo, S. Finkin, Z. Wang, D. Poston, F. Muecksch, T. Hatziioannou, P. D. Bieniasz, D. F. Robbiani, M. C. Nussenzweig, P. J. Bjorkman, J. D. Bloom, Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. bioRxiv 2021.03.17.435863 (2021).
  3. M. K. Annavajhala, H. Mohri, J. E. Zucker, Z. Sheng, P. Wang, A. Gomez-Simmonds, D. D. Ho, A.-C. Uhlemann, A novel SARS-CoV-2 variant of concern, B.1.526, identified in New York. medRxiv 2021.02.23.21252259 (2021).

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Authors
Greaney, A. J., Loes, A. N., Gentles, L. E., Crawford, K. H. D., Starr, T. N., Malone, K. D., Chu, H. Y., & Bloom, J. D.
Affiliations
  • University of Washington (US)
  • Howard Hughes Medical Institute (US)
  • Fred Hutch Cancer Center (US)
Corresponding author
Bloom, Jesse D.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-06-30
Volume
13
Issue
600
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abi9915
PMC
PMC8369496
OpenAlex
W3169651048
Cited by
244
References
53
Citations by year
2026: 11 · 2025: 23 · 2024: 29 · 2023: 52 · 2022: 79 · 2021: 49
FWCI
16.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Science Translational Medicine (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Institutes of Health (UM1AI148373, UM1AI148576, UM1AI148684, NIH P51 OD011132, AI149644, R01AI127893, S10OD028685, T32AI083203, F30AI149928)
  • National Institute of Allergy and Infectious Diseases (UM1AI148373, R01AI141707, R01AI127893, T32AI083203, F30AI149928, UM1AI148576, UM1AI148684, NIH AID AI149644)
  • Howard Hughes Medical Institute
  • ASCRS Research Foundation (R01AI141707, R01AI127893, T32AI083203, F30AI149928, INV-004949, INV-016575, S10OD028685, DRG-2381-19, RNA-1273, UM1AI148373, UM1AI148576, UM1AI148684, NIH P51 OD011132, NIH AID AI149644, HHSN272201500002C)
  • Bill and Melinda Gates Foundation (INV-004949, INV-016575)
  • Gates Foundation (INV-004949, INV-016575)
  • Damon Runyon Cancer Research Foundation (DRG-2381-19)
  • Department of Health and Human Services (HHSN272201500002C)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
SARS-CoV-2, mRNA-1273 vaccine, COVID-19 vaccination, natural infection, receptor binding domain, spike protein, neutralizing antibodies, epitope specificity, viral evolution, antigenic drift, deep mutational scanning, convalescent sera

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