Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy

Joyner, Michael J.; Klassen, Stephen A.; Senefeld, Jonathon W.; Johnson, Patrick W.; Carter, Rickey E.; Wiggins, Chad C.; Shoham, Shmuel; Grossman, Brenda J.; Henderson, Jeffrey P.; Musser, James M.; Salazar, Eric; Hartman, William R.; Bouvier, Nicole M.; Liu, Sean; Pirofski, Liise-anne; Baker, Sarah E.; Helmond, Noud van; Wright, R. Scott; Fairweather, De Lisa; Bruno, Katelyn A.; Paneth, Nigel; Casadevall, Arturo

doi:10.1101/2020.07.29.20162917

Cited by 72 publications

(68 citation statements)

References 59 publications

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“…Early reports of convalescent sera therapies show a tolerable safety profile and modest benefits from this therapeutic approach. 17,20,29,[31][32][33]109 However, many of these trials only consider ELISA neutralization titers and utilize extremely variable ELISA endpoint titers from not reported/available to ranging from 1:40 to >1:1350. Interestingly, one pre-peer reviewed study incorporated functional neutralization studies by utilizing trypsin-treated live virus to screen for sera with >1:80 microneutralization titers on Vero E6 cells.…”

Section: Discussionmentioning

confidence: 99%

Quantifying absolute neutralization titers against SARS-CoV-2 by a standardized virus neutralization assay allows for cross-cohort comparisons of COVID-19 sera

Oguntuyo

Stevens²,

Hung

et al. 2020

Preprint

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The on-going coronavirus disease 2019 (COVID-19) pandemic has mobilized a global effort to develop vaccines and therapeutics that inhibit viral entry by inducing or transferring antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (CoV2-S). Phase I/II vaccine clinical trials, monoclonal antibodies, and convalescent sera have all shown promise. However, these efforts often require extensive screening with the live virus under onerous high biocontainment conditions (BSL-3). Virus neutralization assays (VNAs) remain the gold standard for evaluating the anti-viral potency of antibodies and entry inhibitors. The proliferation of pseudotyped virus systems that can be used in BSL-2 compatible VNAs is a positive development. Yet, there is marked variability between VNAs and how the findings are presented, making inter-group comparisons difficult. To address these limitations, we developed a standardized VNA using VSVdeltaG based CoV-2-S pseudotyped particles (CoV2pp) that can be robustly produced at scale. We used our CoV2pp to interrogate the role of exogenous and endogenous proteases in CoV-2-S mediated entry and standardized our VNA based on that understanding. Our CoV2pp VNA showed a strong positive correlation with CoV2-S ELISA and live virus neutralizations in a validated set of patient sera. Our system was subsequently validated by three independent groups as an out-of-the-box VNA. More than 120 patient sera were screened, and we report descriptive statistics for absolute (abs) IC50, IC80, and IC90 values from all positive patient sera. Lastly, we used our CoV2pp in a screen to identify ultrapermissive 293T clones that stably express ACE2 or ACE2+TMPRSS2. When used in combination with our CoV2pp, we can now produce CoV2pp sufficient for 150,000 standardized VNA/week.

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Section: Discussionmentioning

confidence: 99%

Quantifying absolute neutralization titers against SARS-CoV-2 by a standardized virus neutralization assay allows for cross-cohort comparisons of COVID-19 sera

Oguntuyo

Stevens²,

Hung

et al. 2020

Preprint

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“…Currently, the only available passive antibody therapy for patients with COVID-19 is transfusion of convalescent plasma obtained from recovered patients. The therapy is safe, and multiple emerging lines of evidence, including historical precedent, preclinical animal studies, small case series, and matched observational studies, suggest that convalescent plasma is efficacious in the treatment of COVID-19 (4,5). Clinical trials assessing efficacy in specific patient populations are underway, and clinical trials assessing the use of hyperimmune IgG may begin soon (6).…”

Section: Introductionmentioning

confidence: 99%

Convalescent plasma anti–SARS-CoV-2 spike protein ectodomain and receptor-binding domain IgG correlate with virus neutralization

Salazar¹,

Kuchipudi²,

Christensen³

et al. 2020

Journal of Clinical Investigation

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188

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The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship among anti-spike ectodomain (anti-ECD), antireceptor-binding domain (anti-RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by 2 in vitro assays using convalescent plasma samples from 68 patients with COVID-19. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titers. The probability of a VN titer of ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was ≥80% when anti-RBD or anti-ECD titers were ≥1:1350. Of all donors, 37% lacked VN titers of ≥160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of ≥1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers of ≥1:160, and all of them had anti-RBD titers of ≥1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of ≥1:1350 may provide critical information about protection against COVID-19 disease.

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“…Serological testing facilitates surveillance and assists in the identification of individuals susceptible to COVID-19 infection [ 6 , 7 ]. The serological analysis of convalescent SARS-CoV-2 antibodies also allows for the identification of individuals that are potentially suited to serve as plasma donors of convalescence plasma, which has been proposed to aid in the therapy of severe cases of COVID-19 [ 8 , 9 , 10 ]. Further, many individuals have not had access to the molecular diagnosis of COVID-19 with RT-PCR [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Pan-Immunoglobulin Assay Quantifying Antibodies Directed against the Receptor Binding Domain of the SARS-CoV-2 S1-Subunit of the Spike Protein: A Population-Based Study

Schaffner

Risch

Aeschbacher

et al. 2020

JCM

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Pan-immunoglobulin assays can simultaneously detect IgG, IgM and IgA directed against the receptor binding domain (RBD) of the S1 subunit of the spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 S1-RBD Ig). In this work, we aim to evaluate a quantitative SARS-CoV-2 S1-RBD Ig electrochemiluminescence immunoassay (ECLIA) regarding analytical, diagnostic, operational and clinical characteristics. Our work takes the form of a population-based study in the principality of Liechtenstein, including 125 cases with clinically well-described and laboratory confirmed SARS-CoV-2 infection and 1159 individuals without evidence of coronavirus disease 2019 (COVID-19). SARS-CoV-2 cases were tested for antibodies in sera taken with a median of 48 days (interquartile range, IQR, 43–52) and 139 days (IQR, 129–144) after symptom onset. Sera were also tested with other assays targeting antibodies against non-RBD-S1 and -S1/S2 epitopes. Sensitivity was 97.6% (95% confidence interval, CI, 93.2–99.1), whereas specificity was 99.8% (95% CI, 99.4–99.9). Antibody levels linearly decreased from hospitalized patients to symptomatic outpatients and SARS-CoV-2 infection without symptoms (p < 0.001). Among cases with SARS-CoV-2 infection, smokers had lower antibody levels than non-smokers (p = 0.04), and patients with fever had higher antibody levels than patients without fever (p = 0.001). Pan-SARS-CoV-2 S1-RBD Ig in SARS-CoV-2 infection cases significantly increased from first to second follow-up (p < 0.001). A substantial proportion of individuals without evidence of past SARS-CoV-2 infection displayed non-S1-RBD antibody reactivities (248/1159, i.e., 21.4%, 95% CI, 19.1–23.4). In conclusion, a quantitative SARS-CoV-2 S1-RBD Ig assay offers favorable and sustained assay characteristics allowing the determination of quantitative associations between clinical characteristics (e.g., disease severity, smoking or fever) and antibody levels. The assay could also help to identify individuals with antibodies of non-S1-RBD specificity with potential clinical cross-reactivity to SARS-CoV-2.

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Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy

Cited by 72 publications

References 59 publications

Quantifying absolute neutralization titers against SARS-CoV-2 by a standardized virus neutralization assay allows for cross-cohort comparisons of COVID-19 sera

Quantifying absolute neutralization titers against SARS-CoV-2 by a standardized virus neutralization assay allows for cross-cohort comparisons of COVID-19 sera

Convalescent plasma anti–SARS-CoV-2 spike protein ectodomain and receptor-binding domain IgG correlate with virus neutralization

Characterization of a Pan-Immunoglobulin Assay Quantifying Antibodies Directed against the Receptor Binding Domain of the SARS-CoV-2 S1-Subunit of the Spike Protein: A Population-Based Study

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