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2.
PLoS Pathog ; 18(4): e1010468, 2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1779781

ABSTRACT

An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of ß2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1ß cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330937

ABSTRACT

SARS-CoV-2 infection triggers adaptive immune responses from both T and B cells. However, most studies focus on peripheral blood, which may not fully reflect immune responses in lymphoid tissues at the site of infection. To evaluate both local and systemic adaptive immune responses to SARS-CoV-2, we collected peripheral blood, tonsils, and adenoids from 110 children undergoing tonsillectomy/adenoidectomy during the COVID-19 pandemic and found 24 with evidence of prior SARS-CoV-2 infection, including detectable neutralizing antibodies against multiple viral variants. We identified SARS-CoV-2-specific germinal center (GC) and memory B cells;single cell BCR sequencing showed that these virus-specific B cells were class-switched and somatically hypermutated, with overlapping clones in the adenoids and tonsils. Oropharyngeal tissues from COVID-19-convalescent children showed persistent expansion of GC and anti-viral lymphocyte populations associated with an IFN-γ-type response, with particularly prominent changes in the adenoids, as well as evidence of persistent viral RNA in both tonsil and adenoid tissues of many participants. Our results show robust, tissue-specific adaptive immune responses to SARS-CoV-2 in the upper respiratory tract of children weeks to months after acute infection, providing evidence of persistent localized immunity to this respiratory virus.

5.
EBioMedicine ; 77, 2022.
Article in English | EuropePMC | ID: covidwho-1743737

ABSTRACT

Summary Background Limited knowledge exists in post-partum women regarding durability of SARS-CoV-2 vaccine-induced antibody responses and their neutralising ability against SARS-CoV-2 variants of concern (VOC). Methods We elucidated longitudinal mRNA vaccination-induced antibody profiles of 13 post-partum and 13 non-post-partum women (control). Findings The antibody neutralisation titres against SARS-CoV-2 WA-1 strain were comparable between post-partum and non-post-partum women and these levels were sustained up to four months post-second vaccination in both groups. However, neutralisation titers declined against several VOCs, including Beta and Delta. Higher antibody binding was observed against SARS-CoV-2 receptor-binding domain (RBD) mutants with key VOC amino acids when tested with post-second vaccination plasma from post-partum women compared with controls. Importantly, post-vaccination plasma antibody affinity against VOCs RBDs was significantly higher in post-partum women compared with controls. Interpretation This study demonstrates that there is a differential vaccination-induced immune responses in post-partum women compared with non-post-partum women, which could help inform future vaccination strategies for these groups.

6.
Vaccines (Basel) ; 10(3)2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1742768

ABSTRACT

In healthy adults, hybrid immunity induced by prior SARS-CoV-2 infection followed by two doses of mRNA vaccination provide protection against symptomatic SARS-CoV-2 infection. However, the role of hybrid immunity in autoimmune patients against Omicron is not well documented. Here, we report a young autoimmune patient with prior infection and two doses of mRNA-1273 vaccination who was exposed to Omicron and developed a symptomatic disease. Prior to Omicron infection, the patient had strong neutralizing antibody titers against the vaccine strain, but no neutralization of Omicron. Post Omicron infection, high neutralizing titers against Omicron were observed. Furthermore, enhanced neutralizing antibody titers against other variants of concern-Alpha, Beta, Gamma, and Delta-were observed, suggesting an expansion of cross-reactive memory B-cell response by the SARS-CoV-2 Omicron infection. Autoimmune patients may require careful monitoring of immune function over time to optimize booster vaccine administration.

7.
J Infect Dis ; 2022 Feb 01.
Article in English | MEDLINE | ID: covidwho-1722493

ABSTRACT

Passive antibody immunotherapeutics directed against SARS-CoV-2 are promising countermeasures for protection and treatment of COVID-19. SARS-CoV-2 Variants of Concern (VOCs) and Variants of Interest (VOIs) can impact the clinical efficacy of immunotherapeutics. A fully human polyclonal antibody immunotherapeutic purified from plasma of transchromosomic (Tc) bovines hyperimmunized with SARS-CoV-2 WA-1 spike (SAB-185) is being assessed for efficacy in a phase 2/3 clinical trial when different circulating SARS-CoV-2 variants predominated. We evaluated antibody binding, avidity maturation, and SARS-CoV-2 VOCs/VOIs virus neutralizing capacity of convalescent plasma (CP) compared with different lots of SAB-185 and individual Tc bovine sera sequentially obtained after each vaccination against Alpha, Epsilon, Iota, Gamma, Beta, Kappa and Delta variants. In contrast to CP, sera and SAB-185 derived from hyperimmunized Tc bovines demonstrated higher antibody avidity and more potent cross-neutralizing activity of VOCs/VOIs. Thus, SAB-185 is a potential promising therapeutic candidate for the treatment of patients infected with SARS-CoV-2 variants.

8.
Clin Infect Dis ; 2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1700771

ABSTRACT

BACKGROUND: Following the failure of antibody therapies in treating COVID-19 hospitalized patients we investigated the impact of viral replication on the pharmacokinetics (PK) and efficacy of a hyperimmune SARS-CoV-2 Immune Globulin (CoVIG) product in treatment of SARS-CoV-2 infection using the adult Syrian hamster model. METHODS: The CoVIG was manufactured from plasma donors who had recovered from COVID-19. The dose used (400 mg/kg) was based on the dose given in clinical trials to hospitalized COVID-19 patients. Hamsters were given a single dose of CoVIG two days after challenge with the SARS-CoV-2 virus (isolate NY/PV08410/2020), followed by sampling of blood, nasal, tracheal and lung tissues at different time points. The blood samples were assayed for anti-SARS-CoV-2 spike binding and used to calculate PK parameters. Nasal washes, trachea, and lung samples were assayed for viral replication by PCR (sgRNA). RESULTS: CoVIG-treated hamsters showed a reduction in viral replication in the lower respiratory tract, but minimally in the upper respiratory tract, following challenge with SARS-CoV-2. Challenge with SARS-CoV-2 resulted in altered PK parameters proportionate to viral replication, resulting in decreased area under the curve (AUC), accelerated clearance and shorter half-life of CoVIG. CONCLUSIONS: These data indicate that in the presence of actively replicating SARS-CoV-2 virus, PK parameters are altered and should trigger an adjustment in dosing of CoVIG.

9.
Vaccines (Basel) ; 10(2)2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1700517

ABSTRACT

Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, especially in the lower respiratory tract of children coronavirus disease 2019 (COVID-19) and post-infectious multisystem inflammatory syndrome in children (MIS-C) against emerging SARS-CoV-2 variants. Therefore, we evaluated neutralizing antibody responses in paired plasma and endotracheal aspirates of pediatric severe, acute COVID-19 or MIS-C patients against SARS-CoV-2 WA1/2020, as well as against variants of concern (VOCs). Neutralizing antibody responses against the SARS-CoV-2 WA1/2020 strain in pediatric plasma were 2-fold or 35-fold higher compared with the matched endotracheal aspirate in COVID-19 or MIS-C patients, respectively. In contrast to plasma, neutralizing antibody responses against the VOCs and variants of interest (VOIs) in endotracheal aspirates were lower, with only one endotracheal aspirate demonstrating neutralizing titers against the Iota, Kappa, Beta, Gamma, and Omicron variants. In conclusion, our findings suggest that children and adolescents with severe COVID-19 or MIS-C have weak mucosal neutralizing antibodies in the trachea against circulating SARS-CoV-2 Omicron and other VOCs, which may have implications for recovery and for re-infection with emerging SARS-CoV-2 variants.

10.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327751

ABSTRACT

Viral infections can have profound and durable functional impacts on the immune system. There is an urgent need to characterize the long-term immune effects of SARS-CoV-2 infection given the persistence of symptoms in some individuals and the continued threat of novel variants including the recent rapid acceleration in infections. As the majority of COVID-19 patients experienced mild disease, here we use systems immunology approaches to comparatively assess the post-infection immune status (mean: 151 [5 th - 95 th percentile: 58 - 235] days after diagnosis) and subsequent innate and adaptive responses to seasonal influenza vaccination (as an "immune challenge") in 33 previously healthy individuals after recovery from mild, non-hospitalized COVID-19, as compared to 40 age- and sex-matched healthy controls with no history of COVID-19. Sex-specific, temporally stable shifts in signatures of metabolism, T-cell activation, and innate immune/inflammatory processes suggest that mild COVID-19 can establish new post-infection immunological set-points. COVID-19-recovered males had an increase in CD71 hi B-cells (including influenza-specific subsets) before vaccination and more robust innate, influenza-specific plasmablast, and antibody responses after vaccination compared to healthy males. Intriguingly, by day 1 post-vaccination in COVID-19-recovered subjects, the expression of numerous innate defense/immune receptor genes (e.g., Toll-like receptors) in monocytes increased and moved away from their post-COVID-19 repressed state toward the pre-vaccination baseline of healthy controls, and these changes tended to persist to day 28 in females, hinting that the acute inflammatory responses induced by vaccination could partly reset the immune states established by prior mild COVID-19. Our study reveals sex-dimorphic immune imprints and in vivo functional impacts of mild COVID-19 in humans, suggesting that prior COVID-19 could change future responses to vaccination and in turn, vaccines could help reset the immune system after COVID-19, both in an antigen-agnostic manner.

11.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327163

ABSTRACT

Coronavirus vaccines that are highly effective against SARS-CoV-2 variants are needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected monkeys from SARS-CoV-2 WA-1 infection. Here, we demonstrate SARS-CoV-2 RBD-scNP immunization induces potent neutralizing antibodies against all eight SARS-CoV-2 variants tested including the Beta, Delta, and Omicron variants in non-human primates (NHPs). The Omicron variant was neutralized by RBD-scNP-induced serum antibodies with a mean of 4.3-fold reduction of ID50 titers compared to SARS-CoV-2 D614G. Immunization with RBD-scNPs protected NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protected mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect NHPs and mice from multiple different SARS-related viruses. Such a vaccine could provide the needed immunity to slow the spread of and reduce disease caused by SARS-CoV-2 variants such as Delta and Omicron.

12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322505

ABSTRACT

Hyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in several clinical trials of hospitalized COVID-19 patients. Here we explored the antibody epitope repertoire, antibody binding and virus neutralizing capacity of six hCoV-2IG batches as well as nine convalescent plasma (CP) lots against SARS-CoV-2 and emerging variants of concern (VOC). The Gene-Fragment Phage display library spanning the SARS-CoV-2 spike-based epitope-mapping demonstrated broad recognition of multiple antigenic sites spanning the entire spike including NTD, RBD, S1/S2 cleavage site, S2-fusion peptide and S2-heptad repeat regions. Antibody binding to the immunodominant epitopes was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay (PsVNA) and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of SARS-CoV-2 VOCs from around the globe were reduced to a different extent by hCoV-2IG lots. The most significant loss of neutralizing activity was seen against the B.1.351 (9-fold) followed by P.1 (3.5-fold), with minimal loss of activity against the B.1.17 and B.1.429 ( < 2-fold). Again, the CP showed more pronounced loss of cross-neutralization against the VOCs compared with hCoV-2IG. Significant reduction of hCoV-2IG binding was observed to the RBD-E484K followed by RBD-N501Y and minimal loss of binding to RBD-K417N compared with unmutated RBD. This study suggests that post-exposure treatment with hCoV-2IG is preferable to CP. In countries with co-circulating SARS-CoV-2 variants, identifying the infecting virus strain could inform optimal treatments, but would likely require administration of higher doses achieved by larger volumes or repeated infusions of hCOV-2IG or CP, in patients infected with the emerging SARS-CoV-2 variants.Funding: The research work described in this manuscript was supported by FDA Medical Countermeasures Initiative (MCMi) grant # OCET 2021-1565 and NIH-NIAID IAA #AAI20040. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Declaration of Interest: The authors declare no competing interests.Ethical Approval: This study was approved by Food and Drug Administration’s Research Involving Human Subjects Committee (RIHSC #2020-04-02). This study complied with all relevant ethical regulations for work with human participants, and informed consent was obtained. Samples were collected from patients who provided informed consent to participate in the study.

14.
Clin Infect Dis ; 74(2): 327-334, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1662105

ABSTRACT

Convalescent plasma (CP) have been used for treatment of coronavirus disease 2019 (COVID-19), but their effectiveness varies significantly. Moreover, the impact of CP treatment on the composition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 patients and antibody markers that differentiate between those who survive and those who succumb to the COVID-19 disease are not well understood. Herein, we performed longitudinal analysis of antibody profile on 115 sequential plasma samples from 16 hospitalized COVID-19 patients treated with either CP or standard of care, only half of them survived. Differential antibody kinetics was observed for antibody binding, immunoglobulin M/immunoglobulin G/immunoglobulin A (IgM/IgG/IgA) distribution, and affinity maturation in "survived" versus "fatal" COVID-19 patients. Surprisingly, CP treatment did not predict survival. Strikingly, marked decline in neutralization titers was observed in the fatal patients prior to death, and convalescent plasma treatment did not reverse this trend. Furthermore, irrespective of CP treatment, higher antibody affinity to the SARS-CoV-2 prefusion spike was associated with survival outcome. Additionally, sustained elevated IgA response was associated with fatal outcome in these COVID-19 patients. These findings propose that treatment of COVID-19 patients with convalescent plasma should be carefully targeted, and effectiveness of treatment may depend on the clinical and immunological status of COVID-19 patients, as well as the quality of the antibodies in the convalescent plasma.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive
15.
EBioMedicine ; 74: 103748, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1568650

ABSTRACT

BACKGROUND: Limited knowledge exists regarding antibody affinity maturation following mRNA vaccination in naïve vs. COVID-19 recovered individuals and potential sex differences. METHODS: We elucidated post-vaccination antibody profiles of 69 naïve and 17 COVID-19 convalescent adults using pseudovirus neutralization assay (PsVNA) covering SARS-CoV-2 WA-1, variants of concern (VOCs) and variants of interest (VOIs). Surface Plasmon Resonance (SPR) was used to measure antibody affinity against prefusion spike and receptor binding domain (RBD) and RBD mutants. FINDINGS: Higher neutralizing antibodies were observed in convalescent vs. naïve adults against, WA-1, VOCs, and VOIs. Antibody binding to RBD and RBD mutants showed lower binding of post-vaccination sera from naïve compared with convalescent individuals. Moreover, we observed early antibody affinity maturation in convalescent individuals after one vaccine dose and higher antibody affinity after two doses compared with the naïve group. Among the naïve participants, antibody affinity against the SARS-CoV-2 prefusion spike was significantly higher for males than females even though there were no difference in neutralization titers between sexes. INTERPRETATION: This study demonstrates the impact of prior infection on vaccine-induced antibody affinity maturation and difference in antibody affinity between males and females. Further studies are needed to determine whether antibody affinity may contribute to correlates of protection against SARS-CoV-2 and its variants. FUNDING: The antibody characterization work described in this manuscript was supported by FDA's Medical Countermeasures Initiative (MCMi) grant #OCET 2021-1565 to S.K and intramural FDA-CBER COVID-19 supplemental funds. The SPARTA program was supported by the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Department of Health and Human Services contract 75N93019C00052, and the University of Georgia (US) grant UGA-001. T.M.R is also supported by the Georgia Research Alliance (US) grant GRA-001. The CTRU was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378.


Subject(s)
/immunology , Antibodies, Neutralizing/blood , Antibody Affinity/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Viral/blood , COVID-19/immunology , Cell Line , Female , Humans , Male , Neutralization Tests , Protein Domains/immunology , Surface Plasmon Resonance , Vaccination , /immunology
16.
Sci Adv ; 7(42): eabi6533, 2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1467653

ABSTRACT

Mucosal immunity plays a key role in prevention of SARS-CoV-2 virus spread to the lungs. In this study, we evaluated systemic and mucosal immune signatures in asymptomatic SARS-CoV-2­infected versus symptomatic COVID-19 adults compared with RSV-infected adults. Matched serum and nasal wash pairs were subjected to cytokine/chemokine analyses and comprehensive antibody profiling including epitope repertoire analyses, antibody kinetics to SARS-CoV-2 prefusion spike and spike RBD mutants, and neutralization of SARS-CoV-2 variants of concern. The data suggest independent evolution of antibody responses in the mucosal sites as reflected in differential IgM/IgG/IgA epitope repertoire compared with serum. Antibody affinity against SARS-CoV-2 prefusion spike for both serum and nasal washes was significantly higher in asymptomatic adults compared with symptomatic COVID-19 patients. Last, the cytokine/chemokine responses in the nasal washes were more robust than in serum. These data underscore the importance of evaluating mucosal immune responses for better therapeutics and vaccines against SARS-CoV-2.

17.
Nat Immunol ; 22(11): 1452-1464, 2021 11.
Article in English | MEDLINE | ID: covidwho-1454797

ABSTRACT

There is limited understanding of the viral antibody fingerprint following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Herein, SARS-CoV-2 proteome-wide immunoprofiling of children with mild/moderate or severe coronavirus disease 2019 (COVID-19) versus multisystem inflammatory syndrome in children versus hospitalized control patients revealed differential cytokine responses, IgM/IgG/IgA epitope diversity, antibody binding and avidity. Apart from spike and nucleocapsid, IgG/IgA recognized epitopes in nonstructural protein (NSP) 2, NSP3, NSP12-NSP14 and open reading frame (ORF) 3a-ORF9. Peptides representing epitopes in NSP12, ORF3a and ORF8 demonstrated SARS-CoV-2 serodiagnosis. Antibody-binding kinetics with 24 SARS-CoV-2 proteins revealed antibody parameters that distinguish children with mild/moderate versus severe COVID-19 or multisystem inflammatory syndrome in children. Antibody avidity to prefusion spike correlated with decreased illness severity and served as a clinical disease indicator. The fusion peptide and heptad repeat 2 region induced SARS-CoV-2-neutralizing antibodies in rabbits. Thus, we identified SARS-CoV-2 antibody signatures in children associated with disease severity and delineate promising serodiagnostic and virus neutralization targets. These findings might guide the design of serodiagnostic assays, prognostic algorithms, therapeutics and vaccines in this important but understudied population.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/complications , COVID-19/immunology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , COVID-19/diagnosis , Child , Child, Preschool , Disease Progression , Epitopes/metabolism , Female , Hospitalization , Humans , Immunity, Humoral , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Male , Prognosis , Proteome , Severity of Illness Index , Systemic Inflammatory Response Syndrome/diagnosis
18.
Clin Infect Dis ; 2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1434384

ABSTRACT

BACKGROUND: Following the failure of antibody therapies in treating COVID-19 hospitalized patients we investigated the impact of viral replication on the pharmacokinetics (PK) and efficacy of a hyperimmune SARS-CoV-2 Immune Globulin (CoVIG) product in treatment of SARS-CoV-2 infection using the adult Syrian hamster model. METHODS: The CoVIG was manufactured from plasma donors who had recovered from COVID-19. The dose used (400 mg/kg) was based on the dose given in clinical trials to hospitalized COVID-19 patients. Hamsters were given a single dose of CoVIG two days after challenge with the SARS-CoV-2 virus (isolate NY/PV08410/2020), followed by sampling of blood, nasal, tracheal and lung tissues at different time points. The blood samples were assayed for anti-SARS-CoV-2 spike binding and used to calculate PK parameters. Nasal washes, trachea, and lung samples were assayed for viral replication by PCR (sgRNA). RESULTS: CoVIG-treated hamsters showed a reduction in viral replication in the lower respiratory tract, but minimally in the upper respiratory tract, following challenge with SARS-CoV-2. Challenge with SARS-CoV-2 resulted in altered PK parameters proportionate to viral replication, resulting in decreased area under the curve (AUC), accelerated clearance and shorter half-life of CoVIG. CONCLUSIONS: These data indicate that in the presence of actively replicating SARS-CoV-2 virus, PK parameters are altered and should trigger an adjustment in dosing of CoVIG.

19.
iScience ; 24(9): 103006, 2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1364140

ABSTRACT

Hyperimmune immunoglobulin (hCoV-2IG) generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in clinical trials. Here we explored the antibody epitope repertoire, and virus neutralizing capacity of six hCoV-2IG batches as well as nine CP against SARS-CoV-2 and emerging variants of concern (VOCs). Epitope-mapping by gene-fragment phage display library spanning the SARS-CoV-2 spike demonstrated broad recognition of multiple antigenic sites spanning the entire spike that was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of VOCs were reduced to different extent by hCoV-2IG lots but were higher than CP. Significant reduction of hCoV-2IG binding was observed to RBD-E484K followed by RBD-N501Y (but not RBD-K417N). This study suggests that post-exposure treatment with hCoV-2IG could be preferable to CP.

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