Outcomes of convalescent plasma with defined high- versus lower-neutralizing antibody titers against SARS-CoV-2 among hospitalized patients: CoronaVirus Inactivating Plasma (CoVIP), double-blind phase 2 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 SARS-CoV-2 infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAb) between different CCP donors. The present study was designed to evaluate nAb titer threshold for clinically effective CCP.

Methods

We conducted a double-blind, phase 2 study to evaluate the safety and effectiveness of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive on a SARS-CoV-2 nucleic acid amplification test and with symptoms for < 10 days were eligible. Participants received either CCP with nAb titers ≥1:160-1:640 (standard titer group) or >1:640 (high titer group) in addition to standard of care treatments. Adverse events were contrasted by CCP titer. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes.

Findings

Between August 28 and December 4, 2020, 316 participants were screened, 55 received CCP, with 41 and 14 receiving standard versus high titer CCP, respectively. Participants were a median of 61 years of age (IQR 52-67), 36% women, 25% Black and 33% Hispanic. Severe adverse events (SAE) (≥ grade 3) occurred in 4 (29%) and 23 (56%) of participants in the high versus standard titer groups, respectively by day 28 (Risk Difference -0.28 [95% CI -0.56, 0.01]). There were no observed treatment-related AEs. By day 55, time to hospital discharge was shorter among participants receiving high versus standard titer, accounting for death as a competing event (hazard ratio 1.94 [95% CI 1.05, 3.58], Gray’s p=0.02).

Interpretation

In this phase 2 trial in a high-risk population of patients admitted for Covid-19, we found earlier time to hospital discharge and lower occurrences of life-threatening SAEs among participants receiving CCP with nAb titers >1:640 compared with participants receiving CCP with lower nAb titer CCP. Though limited by a small study size these findings support further study of high-nAb titer CCP defined as >1:640 in the treatment of COVID-19.

Funding

This clinical study was supported by the UNC Health Foundation and the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund established and appropriated by the North Carolina General Assembly. The laboratory assays for neutralizing antibody titers and SARS-CoV-2 specific antibody-binding assays were partially supported by The NIH NCI/NIAID SeroNet Serocenter of Excellence Award U54 CA260543.

Research in Context

Evidence before this study

COVID-19 Convalescent Plasma (CCP) has emergency use authorization from the FDA for early treatment of COVID-19 in either outpatient or inpatient settings. Evidence supporting the use of CCP for severe COVID-19 is mixed and still emerging. One major limitation in interpreting published clinical trials and the clinical role of CCP is incomplete understanding of necessary neutralizing antibody (nAb) titer for clinically effective CCP. Observational studies suggest that higher antibody-content CCP is more effective than lower antibody-content CCP, or that very low antibody-content CCP is harmful. We searched PubMed articles published between February 1, 2020, and April 15, 2022, using the terms “COVID-19”, “convalescent plasma”, “SARS-CoV-2”, and “CCP” alone and in combination. Our search yielded 6,468 results which we filtered to 280 and 162 by selecting ‘Clinical Trial’ and ‘Randomized Controlled Trial’ article types, respectively. Among these, we identified 25 open-label or blinded efficacy or effectiveness studies in hospitalized patients that were relevant to our study. Preliminary reports show wide variability in the antibody content of CCP used in clinical trials, the assays used to define CCP antibody content, and the estimates of clinical outcomes following CCP therapy for hospitalized patients. Only one study deliberately infused CCP with nAb > 1:640. Post-hoc analyses of potent monoclonal antibody therapy in hospitalized patients in the UK showed survival benefit when monoclonal antibody was infused to patients who had not yet seroconverted by spike antibody ELISA, suggesting that if dosed appropriately, antibody-based therapies may have a role in improving outcomes of severe COVID-19.

Added value of this study

This phase 2 study showed that CCP with high nAb titer (>1:640) provided more rapid recovery to hospital discharge and fewer COVID-19 attributable AEs than CCP with nAb titer between the FDA-recommended minimum standard and 4-fold higher (≥1:160-1:640). The hazard ratio of time to hospital discharge from baseline through day 55, accounting for death as a competing event, contrasting patients receiving high versus standard CCP titer was 1.94 (95% CI 1.05-3.58). Adjusted hazard ratios of high versus standard titer CCP receipt for time to hospital discharge were consistent with the primary unadjusted findings. Mortality through 55 days was lower in the high titer group, but with a wide confidence interval that did not reach statistical significance.

Implications of all available evidence

Our data that CCP with nAb >1:640 expedites recovery of patients admitted with COVID-19 compared with CCP with nAb ≥1:160-1:640 suggests that a threshhold of nAb ≥1:160 may be too low to define CCP as ‘high titer’. Analyses in larger CCP trials should consider full reporting of nAb in CCP units administered at individual study participant level, and specifically whether CCP contained nAb >1:640. Further investigation of CCP with nAb >1:640 is warranted given that raising the threshhold of nAb, or a correlative specific anti-spike antibody assay, used to qualify ‘high titer’ CCP in clinical trials could inform policy guidance and clinical use of CCP.

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  1. SciScore for 10.1101/2022.04.29.22274387: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Separate consent for blood transfusion was also obtained according to institutional standard operating procedures.
    IRB: The clinical trial protocol and informed consent (both in English and Spanish Language) were approved by the Institutional Review Board at UNC-CH (IRB 20-1544).
    Sex as a biological variablenot detected.
    RandomizationStudy design and participants: The CoronaVirus Inactivating Plasma (CoVIP) study was designed as a double-blind, randomized phase 2 trial of COVID-19 Convalescent Plasma with defined neutralizing antibody titers at minimum recommended titers (≥1:160) compared with COVID-19 Convalescent Plasma with a 4-fold higher neutralizing antibody titers (>1:640).
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Key exclusion criteria were ongoing or prior receipt of immune-based therapies including pooled immunoglobulin within the past 30 days, antibody or T-cell based therapies specific to SARS-CoV-2, contraindication to blood transfusion, absence of ABO-compatible plasma, and inability to infuse the first unit of CCP within 48 hours of enrollment.
    SARS-CoV-2
    suggested: None
    16 Binding antibody assays to SARS-CoV-2 spike protein receptor binding domain (RBD) and nucleocapsid (N) IgG (Abbott Laboratories) were done as previously described.
    SARS-CoV-2 spike protein receptor binding domain ( RBD ) and nucleocapsid ( N ) IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    16 Binding antibody assays to SARS-CoV-2 spike protein receptor binding domain (RBD) and nucleocapsid (N) IgG (Abbott Laboratories) were done as previously described.
    Abbott Laboratories
    suggested: None
    6 Briefly, RBD IgG, IgA and IgM end-point titers were obtained on heat-inactivated serum samples in an in-house developed enzyme-linked immunosorbent assay format starting with a titer of 1:20. 11 Nuceocapsid IgG levels were measured in the EUA approved Abbott SARS-CoV-2 IgG assay in a CLIA certified laboratory using the Abbott Architect i2000SR immunoassay analyzer, further described here.
    Abbott Architect
    suggested: (Abbott ARCHITECT i1000sr System, RRID:SCR_019328)
    Statistical analyses were performed using SAS software, version 9.4 (SAS Institute) and R software, version 4.0.
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).


    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has several limitations. First, like several prior CCP RCTs, we had difficulty reaching target enrollment for each of our titer-defined groups. Our inability to identify enough donors with high titer CCP resulted in 50% of the patients randomized to the high nAb titer group instead receiving standard nAb titer CCP. We therefore used a standard observational study analytic approach (ie. adjusted as-treated) considering a conventional intention-to-treat analysis uninterpretable. 17 Since treatment assignment deviation was based solely on CCP availability and investigators and treating providers remained blinded to treatment received, we did not observe any confounding and our adjusted analyses were consistent to our crude results. Second, since we could not adequately power a three-arm study, we were unable to include a CCP-free group. Third, we are underpowered in this single-center study to reach a statistical conclusion for outcomes like in-patient mortality. Fourth, since D614G was the most common variant in circulation during out study, we cannot extrapolate our findings to other variants like Omicron BA.1 and BA.2. As SARS-CoV-2 variants continue to emerge and spread, it is possible that CCP will remain an alternative therapeutic should others be unavailable or ineffective against an emergent variant. We suggest that a definition of high titer CCP exceeding >1:640 gives the greatest confidence in benefit potential, and that future CCP trials deliberately use dir...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04524507CompletedCoronavirus Disease 2019 (COVID-19) Antibody Plasma Research…


    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.


    About SciScore

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