Pharmacokinetics of high-titer anti–SARS-CoV-2 human convalescent plasma in high-risk children

Gordon, Oren; Brosnan, Mary Katherine; Yoon, Steve; Jung, Dawoon; Littlefield, Kirsten; Ganesan, Abhinaya; Caputo, Christopher; Li, Maggie; Morgenlander, William R.; Henson, Stephanie N.; Ordoñez, Alvaro A.; Jesus, Patricia De; Tucker, Elizabeth W.; Akindele, Nadine Peart; Ma, Zexu; Wilson, Jo Ann; Ruiz-Bedoya, Camilo A.; Younger, M. Elizabeth; Bloch, Evan M.; Shoham, Shmuel; Sullivan, David J.; Tobian, Aaron A.R.; Cooke, Kenneth R.; Larman, Ben; Gobburu, Jogarao; Casadevall, Arturo; Pekosz, Andrew; Lederman, Howard M.; Klein, Sabra L.; Jain, Sanjay

doi:10.1172/jci.insight.151518

Cited by 14 publications

(15 citation statements)

References 36 publications

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“…For these exploratory analyses, 13 uncontrolled large case series without individual patient data enrolling 358 participants were included in descriptive analysis . In this study, 125 case reports or case series enrolling 265 participants were included for patient-level exploratory analyses. One study was included in both the descriptive analysis and the individual patient data analysis because individual patient data were available only for a subgroup of patients.…”

Section: Resultsmentioning

confidence: 99%

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

et al. 2023

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ImportancePatients who are immunocompromised have increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19) because they less frequently mount antibody responses to vaccines. Although neutralizing anti-spike monoclonal-antibody treatment has been widely used to treat COVID-19, evolutions of SARS-CoV-2 have been associated with monoclonal antibody-resistant SARS-CoV-2 variants and greater virulence and transmissibility of SARS-CoV-2. Thus, the therapeutic use of COVID-19 convalescent plasma has increased on the presumption that such plasma contains potentially therapeutic antibodies to SARS-CoV-2 that can be passively transferred to the plasma recipient.ObjectiveTo assess the growing number of reports of clinical experiences of patients with COVID-19 who are immunocompromised and treated with specific neutralizing antibodies via COVID-19 convalescent plasma transfusion.Data SourcesOn August 12, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma use in patients who are immunocompromised.Study SelectionRandomized clinical trials, matched cohort studies, and case report or series on COVID-19 convalescent plasma use in patients who are immunocompromised were included. The electronic search yielded 462 unique records, of which 199 were considered for full-text screening.Data Extraction and SynthesisThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 3 independent reviewers in duplicate and pooled.Main Outcomes and MeauresThe prespecified end point was all-cause mortality after COVID-19 convalescent plasma transfusion; exploratory subgroup analyses were performed based on putative factors associated with the potential mortality benefit of convalescent plasma.ResultsThis systematic review and meta-analysis included 3 randomized clinical trials enrolling 1487 participants and 5 controlled studies. Additionally, 125 case series or reports enrolling 265 participants and 13 uncontrolled large case series enrolling 358 participants were included. Separate meta-analyses, using models both stratified and pooled by study type (ie, randomized clinical trials and matched cohort studies), demonstrated that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for the amalgam of both randomized clinical trials and matched cohort studies (risk ratio [RR], 0.63 [95% CI, 0.50-0.79]).Conclusions and RelevanceThese findings suggest that transfusion of COVID-19 convalescent plasma is associated with mortality benefit for patients who are immunocompromised and have COVID-19.

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Section: Resultsmentioning

confidence: 99%

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

et al. 2023

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“…In addition, we consider only the ‘administered dose’, as the studies did not directly measure plasma neutralisation titres in recipients after administration. Gordon et al 33 studied the pharmacokinetics of convalescent plasma after administration of a volume of 5 ml/kg to infants (leading to an estimated dilution of approximately 10-fold 34 ). Direct measurement of recipient titres 30 minutes after infusion found a mean of 6.2% of donor titres, suggesting a decrease in titre of around 40% compared to what would be predicted by dilution alone.…”

Section: Discussionmentioning

confidence: 99%

Determinants of passive antibody efficacy in SARS-CoV-2 infection

Stadler

Chai

Schlub

et al. 2022

Preprint

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Neutralising antibodies are an important correlate of protection from SARS-CoV-2 infection. Multiple studies have investigated the effectiveness of passively administered antibodies (either monoclonal antibodies, convalescent plasma or hyperimmune immunoglobulin) in preventing acquisition of or improving the outcome of infection. Comparing the results between studies is challenging due to different study characteristics including disease stage, trial enrolment and outcome criteria, and different product factors, including administration of polyclonal or monoclonal antibody, and antibody targets and doses. Here we integrate data from 37 randomised controlled trials to investigate how the timing and dose of passive antibodies predicts protection from SARS-CoV-2 infection. We find that both prophylactic and early therapeutic administration (to symptomatic ambulant subjects) have significant efficacy in preventing infection or progression to hospitalisation respectively. However, we find that effectiveness of passive antibody therapy in preventing clinical progression is significantly reduced with administration at later clinical stages (p<0.0001). To compare the dose-response relationship between different treatments, we normalise the administered antibody dose to the predicted neutralisation titre (after dilution) compared to the mean titre observed in early convalescent subjects. We use a logistic model to analyse the dose-response curve of passive antibody administration in preventing progression from symptomatic infection to hospitalisation. We estimate a maximal protection from progression to hospitalisation of 70.2% (95% CI: 62.1 - 78.3%). The dose required to achieve 50% of the maximal effect (EC-50) for prevention of progression to hospitalisation was 0.19-fold (95% CI: 0.087 - 0.395) of the mean early convalescent titre. This suggests that for current monoclonal antibody regimes, doses between 7- and >1000-fold lower than currently used could still achieve around 90% of the current effectiveness (depending on the variant) and allow much more widespread use at lower cost. For convalescent plasma, most current doses are lower than required for high levels of protection. This work provides a framework for the rational design of future passive antibody prophylaxis and treatment strategies for COVID-19.

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“…14 Limited case series in pediatric patients with severe pulmonary disease demonstrated potential benefits without significant side effects. 15,16,17,18 The use of CCP among critically ill obstetric patients is limited to case reports. 19 Our patients were hospitalized with various comorbidities including pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Convalescent plasma in hospitalized pediatric and obstetric coronavirus disease 2019 (COVID‐19) patients

Ikeda

Benzi

Hensch

et al. 2022

Pediatrics International

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Background Published data on coronavirus disease 2019 (COVID‐19) convalescent plasma (CCP) use in children and obstetric patients are limited. We describe a single‐center experience of hospitalized patients who received CCP for acute COVID‐19. Methods A retrospective review of children 0–18‐years‐old and pregnant patients hospitalized with laboratory‐confirmed acute COVID‐19 who received CCP from March 1, 2020 to March 1, 2021 was performed. Clinical and laboratory data were collected to assess the safety of CCP administration. Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) were measured in the CCP products and in patients before transfusion and at various time points post‐transfusion. Correlation between the administered SARS‐CoV‐2 administered versus the SARS‐CoV‐2 anti‐spike immunoglobulin response in patient serum was assessed. Results Twenty‐two children and ten obstetric patients were eligible. Twelve pediatric and eight obstetric patients had moderate disease and ten pediatric and two obstetric patients had severe disease. Five pediatric patients died. Eighteen of 37 (48.6%) CCP titers that were measured met US Food and Drug Administration (FDA) criteria for high immunoglobulin G (IgG) antibody titer. There were no complications with transfusion. High‐titer CCP showed a positive correlation with rise in patient total immunoglobulin levels only in obstetric patients but not in pediatric patients. Among pediatric patients, the median serum antibody level increased over time after transfusion. Conclusions Coronavirus 2019 convalescent plasma was administered safely to our patients. Our study suggested that CCP did not interfere with endogenous antibody production. The antibody titer of CCP correlated with post‐transfusion response only in obstetric patients. Randomized trials in pediatric and obstetric patients are needed to further understand how to dose CCP and evaluate efficacy.

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Pharmacokinetics of high-titer anti–SARS-CoV-2 human convalescent plasma in high-risk children

Abstract: The funders had no role in the design and conduct of the study; collection, management, analysis or interpretation of data; decision to submit, preparation, review, or approval of the manuscript for publication.

Cited by 14 publications

References 36 publications

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

Determinants of passive antibody efficacy in SARS-CoV-2 infection

Convalescent plasma in hospitalized pediatric and obstetric coronavirus disease 2019 (COVID‐19) patients

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