Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study

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ABSTRACT

COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for <10 days were eligible. Participants received either CCP with nAb titers of >1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray’s P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher’s P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507).

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Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

Chenguang Shen, Zhaoqin Wang, Fang Zhao … (2020)

Could administration of convalescent plasma transfusion be beneficial in the treatment of critically ill patients with coronavirus disease 2019 (COVID-19)? In this uncontrolled case series of 5 critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS), administration of convalescent plasma containing neutralizing antibody was followed by an improvement in clinical status. These preliminary findings raise the possibility that convalescent plasma transfusion may be helpful in the treatment of critically ill patients with COVID-19 and ARDS, but this approach requires evaluation in randomized clinical trials. Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments. To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; P ao 2 /F io 2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion. Patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission. Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), P ao 2 /F io 2 , viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion. All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and P ao 2 /F io 2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion. In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials. This case series describes clinical outcomes in 5 Chinese patients with laboratory-confirmed COVID-19, ARDS, and high viral loads despite antiviral treatment who were given human plasma with SARS-CoV-2 antibodies obtained from previously infected and recovered patients.

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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Christopher Barnes, Claudia A. Jette, Morgan E. Abernathy … (2020)

The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein1-5 show promise therapeutically and are being evaluated clinically6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs9. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.

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SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

Yixuan Hou, Kenichi Okuda, Caitlin Edwards … (2020)

Summary The mode of acquisition and causes for the variable clinical spectrum of COVID-19 remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore SARS-CoV-2 pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest ACE2 expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) vs distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.

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Author and article information

Contributors

Luther A. Bartelt:

ORCID: https://orcid.org/0000-0002-7596-4272

David M. Margolis:

ORCID: https://orcid.org/0000-0001-5714-0002

Arturo Casadevall: Role: Editor

Journal

Journal ID (nlm-ta): mBio

Journal ID (iso-abbrev): mBio

Journal ID (publisher-id): mbio

Title: mBio

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2150-7511

Publication date (Electronic, pub): 22 September 2022

Publication date (Electronic, collection): Sep-Oct 2022

Publication date PMC-release: 22 September 2022

Volume: 13

Issue: 5

Electronic Location Identifier: e01751-22

Affiliations

[a ] Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

[b ] Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

[c ] The AIDS Center at Montefiore, Division of Infectious Diseases, Montefiore Medical Center, Bronx, New York, USA

[d ] UNC HIV Cure Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

[e ] Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, , Chapel Hill, North Carolina, USA

[f ] Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

[g ] Department of Pathology, Carolinas Pathology Group, Atrium Health Carolinas Medical Center, Charlotte, North Carolina, USA

Johns Hopkins Bloomberg School of Public Health

Author notes

The authors declare a conflict of interest. D.M.M. has provided consultancy to Merck outside of this work, and owns common stock in Gilead Sciences. All other authors have no conflicts of interest to declare.

Author information

Luther A. Bartelt https://orcid.org/0000-0002-7596-4272

Alena J. Markmann https://orcid.org/0000-0003-3656-9322

John L. Schmitz https://orcid.org/0000-0002-1425-236X

Ralph Baric https://orcid.org/0000-0001-6827-8701

David van Duin https://orcid.org/0000-0003-4784-3227

David M. Margolis https://orcid.org/0000-0001-5714-0002

Article

Publisher ID: 01751-22 Publisher ID: mbio.01751-22

DOI: 10.1128/mbio.01751-22

PMC ID: 9601237

PubMed ID: 36135380

SO-VID: 99d391ae-7deb-4a02-a10a-b9b6524cb9ce

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 24 June 2022

Date accepted : 6 September 2022

Page count

supplementary-material: 4, Figures: 3, Tables: 4, Equations: 0, References: 47, Pages: 14, Words: 11845

Funding

Funded by: UNC Health Foundation;

Award Recipient : Luther A. Bartelt

Funded by: North Carolina Policy Collaboratory and North Carolina Coronavirus Relief Fund;

Award Recipient : Luther A. Bartelt

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), FundRef https://doi.org/10.13039/100000060;

Award ID: U54 CA260543

Award Recipient : Ralph S. Baric

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cover-date September/October 2022

ScienceOpen disciplines: Life sciences

Keywords: antibodies,sars-cov-2,convalescent plasma,immunology,neutralizing antibodies,coronavirus

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ScienceOpen disciplines: Life sciences

Keywords: antibodies, sars-cov-2, convalescent plasma, immunology, neutralizing antibodies, coronavirus

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Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study

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Novel Coronavirus Disease COVID-19

Most cited references 45

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

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