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1.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-329166

ABSTRACT

SARS-CoV-2 infection has caused a lasting global pandemic costing millions of lives and untold additional costs. Understanding the immune response to SARS-CoV-2 has been one of the main challenges in the past year in order to decipher mechanisms of host responses and interpret disease pathogenesis. Comparatively little is known in regard to how the immune response against SARS-CoV-2 differs from other respiratory infections. In our study, we compare the peripheral blood immune signature from SARS-CoV-2 infected patients to patients hospitalized pre-pandemic with Influenza Virus or Respiratory Syncytial Virus (RSV). Our in-depth profiling indicates that the immune landscape in patients infected by SARS-CoV-2 is largely similar to patients hospitalized with Flu or RSV. Similarly, serum cytokine and chemokine expression patterns were largely overlapping. Unique to patients infected with SARS-CoV-2 who had the most critical clinical disease state were changes in the regulatory T cell (Treg) compartment. A Treg signature including increased frequency, activation status, and migration markers was correlated with the severity of COVID-19 disease. These findings are particularly relevant as Tregs are being discussed as a therapy to combat the severe inflammation seen in COVID-19 patients. Likewise, having defined the overlapping immune landscapes in SARS-CoV-2, existing knowledge of Flu and RSV infections could be leveraged to identify common treatment strategies. Highlights: The immune landscapes of hospitalized pre-pandemic RSV and influenza patients are similar to SARS-CoV-2 patientsSerum cytokine and chemokine expression patterns are largely similar between patients hospitalized with respiratory virus infections, including SARS-CoV-2, versus healthy donorsSARS-CoV-2 patients with the most critical disease displayed unique changes in the Treg compartmentadvances in understanding and treating SARS-CoV-2 could be leveraged for other common respiratory infections.

2.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326896

ABSTRACT

Numerous safe and effective COVID-19 vaccines have been developed that utilize various delivery technologies and engineering strategies. The influence of the SARS-CoV2 spike (S) glycoprotein conformation on antibody responses induced by vaccination or infection in humans remains unknown. To address this question, we compared plasma antibodies elicited by six globally-distributed vaccines or infection and observed markedly higher binding titers for vaccines encoding a prefusion-stabilized S relative to other groups. Prefusion S binding titers positively correlated with plasma neutralizing activity, indicating that physical stabilization of the prefusion conformation enhances protection against SARS-CoV-2. We show that almost all plasma neutralizing activity is directed to prefusion S, in particular the S1 subunit, and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants and longer durability than current technologies.

3.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326698

ABSTRACT

Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.

4.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326696

ABSTRACT

Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants;an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal. Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions we determined potential escape mutations by comparing antibody binding of peptides containing wildtype residues versus peptides containing a mutant residue. Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination. Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge, they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level. Funding: This work was supported by NIH grants AI138709 (PI Overbaugh) and AI146028 (PI Matsen). Julie Overbaugh received support as the Endowed Chair for Graduate Education (FHCRC). The research of Frederick Matsen was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.

5.
PUBMED; 2020.
Preprint in English | PUBMED | ID: ppcovidwho-293289

ABSTRACT

Defining long-term protective immunity to SARS-CoV-2 is one of the most pressing questions of our time and will require a detailed understanding of potential ways this virus can evolve to escape immune protection. Immune protection will most likely be mediated by antibodies that bind to the viral entry protein, Spike (S). Here we used Phage-DMS, an approach that comprehensively interrogates the effect of all possible mutations on binding to a protein of interest, to define the profile of antibody escape to the SARS-CoV-2 S protein using COVID-19 convalescent plasma. Antibody binding was common in two regions: the fusion peptide and linker region upstream of the heptad repeat region 2. However, escape mutations were variable within these immunodominant regions. There was also individual variation in less commonly targeted epitopes. This study provides a granular view of potential antibody escape pathways and suggests there will be individual variation in antibody-mediated virus evolution.

6.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-293155

ABSTRACT

SARS-CoV-2 infection has caused a lasting global pandemic costing millions of lives and untold additional costs. Understanding the immune response to SARS-CoV-2 has been one of the main challenges in the past year in order to decipher mechanisms of host responses and interpret disease pathogenesis. Comparatively little is known in regard to how the immune response against SARS-CoV-2 differs from other respiratory infections. In our study, we compare the peripheral blood immune signature from SARS-CoV-2 infected patients to patients hospitalized pre-pandemic with Influenza Virus or Respiratory Syncytial Virus (RSV). Our in-depth profiling indicates that the immune landscape in patients infected by SARS-CoV-2 is largely similar to patients hospitalized with Flu or RSV. Similarly, serum cytokine and chemokine expression patterns were largely overlapping. Unique to patients infected with SARS-CoV-2 who had the most critical clinical disease state were changes in the regulatory T cell (Treg) compartment. A Treg signature including increased frequency, activation status, and migration markers was correlated with the severity of COVID-19 disease. These findings are particularly relevant as Tregs are being discussed as a therapy to combat the severe inflammation seen in COVID-19 patients. Likewise, having defined the overlapping immune landscapes in SARS-CoV-2, existing knowledge of Flu and RSV infections could be leveraged to identify common treatment strategies. Highlights: The immune landscapes of hospitalized pre-pandemic RSV and influenza patients are similar to SARS-CoV-2 patientsSerum cytokine and chemokine expression patterns are largely similar between patients hospitalized with respiratory virus infections, including SARS-CoV-2, versus healthy donorsSARS-CoV-2 patients with the most critical disease displayed unique changes in the Treg compartmentadvances in understanding and treating SARS-CoV-2 could be leveraged for other common respiratory infections.

7.
Topics in Antiviral Medicine ; 29(1):89, 2021.
Article in English | EMBASE | ID: covidwho-1250744

ABSTRACT

Background: Mounting evidence indicates that antibodies generated during SARS-CoV-2 infection are correlates of protection. Antibodies targeting Spike (S) on the viral surface have been shown to neutralize the virus. However, the full repertoire of neutralizing and non-neutralizing antibodies against SARSCoV-2, as well as cross-reactivity between SARS-CoV-2 and other circulating (CoVs), remains unclear. We sought to profile the complete repertoire of linear CoV epitopes targeted by the humoral immune response in patients with and without COVID-19 from Seattle, WA. Methods: To map the linear epitope profiles in patients, we developed a comprehensive pan-CoV phage display library composed of 39 amino acid peptides covering the complete genomes of SARS-CoV-2 and the six other CoVs known to infect humans. Using samples from patients with confirmed COVID-19 and with no known SARS-CoV-2 exposure, we immunoprecipitated antibodies against CoV peptides, deep sequenced the co-immunoprecipitated phage, and applied a customized computational pipeline to define SARS-CoV-2 and crossreactive epitopes. Results: The dominant immune responses to SARS-CoV-2 were targeted to regions spanning S, Nucleocapsid (N), and ORF1ab. We identified 17 epitopes within S that were present in two or more individuals, spanning both the S1 and S2 subunits, with some detected in > 75% of individuals. The most commonly mapped S epitope (S- residues 1121-1159) was a region just upstream of the second heptad repeat. We identified nine epitopes within N that were reactive in at least two individuals, four of which were present in at least 35% of patients. The two most prominent N epitopes were derived from the RNA binding domain (N residues 141-179 and 161-199). Epitopes isolated from ORF1ab were the most variable across patients. Of the 46 unique ORF1ab epitopes we identified, only five were present in two or more individuals, suggesting that ORF1ab responses are individual-specific. We also found a high degree of variation in the total number of epitopes targeted by individuals (ranging from 2 to 25). Finally, we identified four unique cross-reactive sequences that were bound by antibodies in SARS-CoV-2 unexposed individuals. Conclusion: Our study comprehensively defined the linear epitope profiles of a population of COVID-19 and SARS-CoV-2 unexposed patients. Epitope maps and functional characterization of SARS-CoV-2 antibodies will be critical for the development of a broad repertoire of COVID-19 treatments and vaccine strategies.

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