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

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with mutations in key antibody epitopes has raised concerns that antigenic evolution could erode adaptive immunity elicited by prior infection or vaccination. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted by antibodies elicited by vaccination or natural infection. To investigate how human antibody responses to vaccines are influenced by viral mutations, we used deep mutational scanning to compare the specificity of polyclonal antibodies elicited by either two doses of the mRNA-1273 COVID-19 vaccine or natural infection with SARS-CoV-2. The neutralizing activity of vaccine-elicited antibodies was more targeted to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein compared to antibodies elicited by natural infection. However, within the RBD, binding of vaccine-elicited antibodies was more broadly distributed across epitopes compared to infection-elicited antibodies. This greater binding breadth means that single RBD mutations have less impact on neutralization by vaccine sera compared to convalescent sera. Therefore, antibody immunity acquired by natural infection or different modes of vaccination may have a differing susceptibility to erosion by SARS-CoV-2 evolution.

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The SARS-CoV-2 mRNA-1273 vaccine elicits more RBD-focused neutralization, but with broader antibody binding within the RBD

10.1101/2021.04.14.439844 ◽

2021 ◽

Author(s):

Allison J Greaney ◽

Andrea N Loes ◽

Lauren E Gentles ◽

Katharine HD Crawford ◽

Tyler N Starr ◽

...

Keyword(s):

Receptor Binding ◽

Natural Infection ◽

Viral Evolution ◽

Antibody Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Neutralizing Activity ◽

Antigenic Evolution ◽

Antibody Epitopes

The emergence of SARS-CoV-2 variants with mutations in key antibody epitopes has raised concerns that antigenic evolution will erode immunity. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted. Here we compare the specificity of antibodies elicited by the mRNA-1273 vaccine versus natural infection. The neutralizing activity of vaccine-elicited antibodies is even more focused on the spike receptor-binding domain (RBD) than for infection-elicited antibodies. However, within the RBD, binding of vaccine-elicited antibodies is more broadly distributed across epitopes than for infection-elicited antibodies. This greater binding breadth means single RBD mutations have less impact on neutralization by vaccine sera than convalescent sera. Therefore, antibody immunity acquired by different means may have differing susceptibility to erosion by viral evolution.

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Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients

Science Immunology ◽

10.1126/sciimmunol.abe0367 ◽

2020 ◽

Vol 5 (52) ◽

pp. eabe0367 ◽

Cited By ~ 37

Author(s):

Anita S. Iyer ◽

Forrest K. Jones ◽

Ariana Nodoushani ◽

Meagan Kelly ◽

Margaret Becker ◽

...

Keyword(s):

Receptor Binding ◽

Symptom Onset ◽

Neutralizing Antibodies ◽

Serum Antibody ◽

Cross Reactivity ◽

Binding Domain ◽

Antibody Responses ◽

Human Antibody ◽

Receptor Binding Domain ◽

Recent Infection

We measured plasma and/or serum antibody responses to the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 in 343 North American patients infected with SARS-CoV-2 (of which 93% required hospitalization) up to 122 days after symptom onset and compared them to responses in 1548 individuals whose blood samples were obtained prior to the pandemic. After setting seropositivity thresholds for perfect specificity (100%), we estimated sensitivities of 95% for IgG, 90% for IgA, and 81% for IgM for detecting infected individuals between 15 and 28 days after symptom onset. While the median time to seroconversion was nearly 12 days across all three isotypes tested, IgA and IgM antibodies against RBD were short-lived with median times to seroreversion of 71 and 49 days after symptom onset. In contrast, anti-RBD IgG responses decayed slowly through 90 days with only 3 seropositive individuals seroreverting within this time period. IgG antibodies to SARS-CoV-2 RBD were strongly correlated with anti-S neutralizing antibody titers, which demonstrated little to no decrease over 75 days since symptom onset. We observed no cross-reactivity of the SARS-CoV-2 RBD-targeted antibodies with other widely circulating coronaviruses (HKU1, 229 E, OC43, NL63). These data suggest that RBD-targeted antibodies are excellent markers of previous and recent infection, that differential isotype measurements can help distinguish between recent and older infections, and that IgG responses persist over the first few months after infection and are highly correlated with neutralizing antibodies.

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An antibody-escape calculator for mutations to the SARS-CoV-2 receptor-binding domain

10.1101/2021.12.04.471236 ◽

2021 ◽

Author(s):

Allison J Greaney ◽

Tyler N Starr ◽

Jesse D Bloom

Keyword(s):

Receptor Binding ◽

Polyclonal Antibody ◽

Polyclonal Antibodies ◽

Binding Domain ◽

Receptor Binding Domain ◽

Experimental Characterization ◽

Antibody Recognition ◽

Antigenic Properties ◽

Interactive Version

A key goal of SARS-CoV-2 surveillance is to rapidly identify viral variants with mutations that reduce neutralization by polyclonal antibodies elicited by vaccination or infection. Unfortunately, direct experimental characterization of new viral variants lags their sequence-based identification. Here we help address this challenge by aggregating deep mutational scanning data into an "escape calculator" that estimates the antigenic effects of arbitrary combinations of mutations to the virus's spike receptor-binding domain (RBD). The calculator can be used to intuitively visualize how mutations impact polyclonal antibody recognition, and score the expected antigenic effect of combinations of mutations. These scores correlate with neutralization assays performed on SARS-CoV-2 variants, and emphasize the ominous antigenic properties of the recently described Omicron variant. An interactive version of the calculator is at https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/escape-calc/, and we provide a Python module for batch processing.

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SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains

Nature Communications ◽

10.1038/s41467-021-26803-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Peter Radvak ◽

Hyung-Joon Kwon ◽

Martina Kosikova ◽

Uriel Ortega-Rodriguez ◽

Ruoxuan Xiang ◽

...

Keyword(s):

Transgenic Mice ◽

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Antibody Neutralization ◽

Tissue Specific ◽

Medical Interventions ◽

Prior Infection ◽

D Dimer ◽

Hypoxia Signaling

AbstractSARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351 infection from those induced by early SARS-CoV-2 strains, and help inform potential medical interventions for combating COVID-19.

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Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

10.1101/2020.12.31.425021 ◽

2021 ◽

Author(s):

Allison J. Greaney ◽

Andrea N. Loes ◽

Katharine H.D. Crawford ◽

Tyler N. Starr ◽

Keara D. Malone ◽

...

Keyword(s):

Receptor Binding ◽

Binding Domain ◽

Binding Motif ◽

Human Antibody ◽

Receptor Binding Domain ◽

Serum Antibodies ◽

Main Target ◽

The Impact ◽

Polyclonal Serum ◽

Comprehensive Mapping

AbstractThe evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.

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A human coronavirus evolves antigenically to escape antibody immunity

10.1101/2020.12.17.423313 ◽

2020 ◽

Author(s):

Rachel Eguia ◽

Katharine H. D. Crawford ◽

Terry Stevens-Ayers ◽

Laurel Kelnhofer-Millevolte ◽

Alexander L. Greninger ◽

...

Keyword(s):

Receptor Binding ◽

Binding Domain ◽

Historical Evolution ◽

Receptor Binding Domain ◽

Human Coronavirus ◽

Human Sera ◽

Antigenic Evolution ◽

Human Coronavirus 229E

AbstractThere is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these “future” viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8–17 years later. The decreased neutralization of “future” viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.

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Landscape of human antibody recognition of the SARS-CoV-2 Receptor Binding Domain

Cell Reports ◽

10.1016/j.celrep.2021.109822 ◽

2021 ◽

pp. 109822

Author(s):

Adam K. Wheatley ◽

Phillip Pymm ◽

Robyn Esterbauer ◽

Melanie H. Dietrich ◽

Wen Shi Lee ◽

...

Keyword(s):

Receptor Binding ◽

Binding Domain ◽

Human Antibody ◽

Receptor Binding Domain ◽

Antibody Recognition

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High resolution linear epitope mapping of the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 mRNA vaccine recipients.

10.1101/2021.07.03.21259953 ◽

2021 ◽

Author(s):

Yuko Nitahara ◽

Yu Nakagama ◽

Natsuko Kaku ◽

Katherine Candray ◽

Yu Michimuko ◽

...

Keyword(s):

High Resolution ◽

Receptor Binding ◽

Messenger Rna ◽

Natural Infection ◽

Neutralizing Antibody ◽

Binding Domain ◽

Spike Protein ◽

Linear Epitope ◽

Receptor Binding Domain ◽

Population Immunity

The prompt rollout of the coronavirus disease (COVID-19) messenger RNA (mRNA) vaccine facilitated population immunity, which shall become more dominant than natural infection-induced immunity. At the beginning of the vaccine era, the initial epitope profile in naive individuals will be the first step to build an optimal host defense system towards vaccine-based population immunity. In this study, the high-resolution linear epitope profiles between Pfizer-BioNTech COVID-19 mRNA vaccine recipients and COVID-19 patients were delineated by using microarrays mapped with overlapping peptides of the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The vaccine-induced antibodies targeting RBD had broader distribution across the RBD than that induced by the natural infection. The relatively lower neutralizing antibody titers observed in vaccine-induced sera could attribute to less efficient epitope selection and maturation of the vaccine-induced humoral immunity compared to the infection-induced. Furthermore, additional mutation panel assays showed that the vaccine-induced rich epitope variety targeting the RBD may aid antibodies to escape rapid viral evolution, which could grant an advantage to the vaccine immunity.

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Enhancement of SARS-CoV-2 Receptor Binding Domain -CR3022 Human Antibody Binding Affinity via in Silico Engineering Approach

10.21203/rs.3.rs-56411/v1 ◽

2020 ◽

Author(s):

Fateme Sefid ◽

Zahra Payandeh ◽

Ghasem Azamirad ◽

Behzad Mansoori ◽

Behzad Baradaran ◽

...

Keyword(s):

Amino Acids ◽

Binding Affinity ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Affinity Maturation ◽

Binding Domain ◽

Human Antibody ◽

Receptor Binding Domain ◽

Receptor Binding Site ◽

Specificity And Sensitivity

Abstract Background: The nCoV-2019 is a cause of COVID-19 disease. The surface spike glycoprotein (S), which is necessary for virus entry through the intervention of the host receptor and it mediates virus-host membrane fusion, is the primary coronavirus antigen (Ag). The angiotensin-converting enzyme 2 (ACE2) is reported to be the effective human receptor for SARS-CoVs 2. ACE2 receptor can be prevented by neutralizing antibodies (nAbs) such as CR3022 targeting the virus receptor-binding site. Considering the importance of computational docking, and affinity maturation we aimed to find the important amino acids of the CR3022 antibody (Ab). These amino acids were then replaced by other amino acids to improve Ab-binding affinity to a receptor-binding domain (RBD) of the 2019-nCoV spike protein. Finally, we measured the binding affinity of Ab variants to the Ag. Result: Our findings disclosed that several variant mutations could successfully improve the characteristics of the Ab binding compared to the normal antibodies. Conclusion: The modified antibodies may be possible candidates for stronger affinity binding to Ags which in turn can affect the specificity and sensitivity of antibodies.

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Neutralizing antibodies targeting the SARS-CoV-2 receptor binding domain isolated from a naïve human antibody library

10.1101/2021.01.07.425806 ◽

2021 ◽

Author(s):

Benjamin Nikola Bell ◽

Abigail E. Powell ◽

Carlos Rodriguez ◽

Jennifer R Cochran ◽

Peter S. Kim

Keyword(s):

Receptor Binding ◽

Neutralizing Antibodies ◽

In Vitro Selection ◽

Surface Display ◽

Binding Domain ◽

Yeast Surface Display ◽

Surface Glycoprotein ◽

Human Antibody ◽

Receptor Binding Domain

Infection with SARS-CoV-2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient-derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naive antibody libraries are a viable means for discovery of novel SARS-CoV-2 neutralizing antibodies. Here, we used a yeast surface-display library of human naive antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin-converting enzyme 2 (ACE2), the human receptor for SARS-CoV-2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS-CoV-2 spike-pseudotyped lentivirus with IC50 values as low as 60 ng/mL in vitro. Using a biolayer interferometry-based binding competition assay, we determined that these antibodies have distinct but overlapping epitopes with antibodies elicited during natural COVID-19 infection. Taken together, these analyses highlight how in vitro selection of naive antibodies can mimic the humoral response in vivo, yielding neutralizing antibodies and various epitopes that can be effectively targeted on the SARS-CoV-2 RBD.

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