Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection
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Abstract
Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses recapitulate, and thus appropriately model, the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage- DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in humans and macaques following either vaccination or infection. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix- heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques.
Author summary
Non-human primates, including macaques, are considered the best animal model for studying infectious diseases that infect humans. Vaccine candidates for SARS-CoV-2 are first tested in macaques to assess immune responses prior to advancing to human trials, and macaques are also used to model the human immune response to SARS-CoV-2 infection. However, there may be differences in how macaque and human antibodies recognize the SARS-CoV-2 entry protein, Spike. Here we characterized the locations on Spike that are recognized by antibodies from vaccinated or infected macaques and humans. We also made mutations to the viral sequence and assessed how these affected antibody binding, enabling a comparison of antibody binding requirements between macaques and humans at a very precise level. We found that macaques and humans share some responses, but also recognize distinct regions of Spike. We also found that in general, antibodies from different individuals had unique responses to viral mutations, regardless of species. These results will yield a better understanding of how macaque data can be used to inform human immunity to SARS-CoV-2.
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SciScore for 10.1101/2021.12.01.470697: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: All procedures were approved by the University of Washington’s Institutional Animal Care and Use Committee (IACUC) (IACUC #4266-14).
IRB: Because samples were de-identified, this study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board as nonhuman subjects research.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Code, software, and data availability: All analyses were performed in RStudio version 1.3.1093 RStudiosuggested: (RStudio, RRID:SCR_000432), GraphPad Prism version 9.0.1, and the phip-flow and phippery software suite … SciScore for 10.1101/2021.12.01.470697: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: All procedures were approved by the University of Washington’s Institutional Animal Care and Use Committee (IACUC) (IACUC #4266-14).
IRB: Because samples were de-identified, this study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board as nonhuman subjects research.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Code, software, and data availability: All analyses were performed in RStudio version 1.3.1093 RStudiosuggested: (RStudio, RRID:SCR_000432), GraphPad Prism version 9.0.1, and the phip-flow and phippery software suite (https://matsengrp.github.io/phippery/). GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)The phip-flow tools perform read alignment using Bowtie2 [97] in a Nextflow [98] pipeline script. Bowtie2suggested: (Bowtie 2, RRID:SCR_016368)The escape profile comparisons are done with phippery in Python 3.6.12 and depend on the NumPy [99], pandas [100, 101], xarray [102], POT [103], and biopython [104] packages. Pythonsuggested: (IPython, RRID:SCR_001658)NumPysuggested: (NumPy, RRID:SCR_008633)biopythonsuggested: (Biopython, RRID:SCR_007173)Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study had several limitations. Because the Phage-DMS library displays peptides 31AA in length, discontinuous or conformational epitopes are not readily detected using this method. Additionally, epitopes that may normally be glycosylated are exposed for antibody binding in Phage-DMS. There also are known germline-encoded differences in the properties of immunoglobulin subclasses and Fc receptors between macaques and humans, leading to differences in antibody function that cannot be assayed using Phage-DMS [90]. Additionally, our sample set includes variables that limit our ability to draw conclusions about species- specific (macaque vs. human) differences in antibody response. The vaccinated macaques and humans both received RNA vaccines encoding full-length Spike protein, but there were differences in vaccine technology, including: 1) the use of mRNA in the human vaccine vs. repRNA in the macaque vaccine, 2) the stabilization of Spike in its pre-fusion state in the human vaccine, 3) the dosage and number of doses delivered, and 4) the formulation used to deliver the RNA. Despite these differences, we found commonalities in some of the epitopes targeted by antibodies from both groups. Additionally, the convalescent rhesus macaques were experimentally infected twice with high titers of virus, compared to the convalescent humans who were naturally infected once. This important discrepancy could be the reason why the response in re-infected macaques aligned more closely with...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04283461 Active, not recruiting Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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