Production of Hyperimmune Anti-SARS-CoV-2 Intravenous Immunoglobulin from Pooled COVID-19 Convalescent Plasma

Ali, Shaukat; Uddin, S. M. Sohrab; Ali, Ayesha; Anjum, Fatima; Ali, Rashid; Shalim, Elisha; Khan, Mujtaba; Ahmed, Iqra; Muhaymin, Sheikh Muhammad; Bukhari, Uzma; Luxmi, Shobha; Khan, Abdul Samad; Quraishy, Saeed

doi:10.2217/imt-2020-0263

Cited by 26 publications

(28 citation statements)

References 32 publications

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“…This study is the first report of usage of hyperimmune anti COVID-19 Intravenous Immunoglobulin (C-IVIG) prepared from convalescent plasma [7] to evaluate its safety and efficacy in severe and critical COVID-19 patients. The use of C-IVIG to treat COVID-19 was found safe as no immediate or serious drug related adverse event was reported in any patient of intervention arms.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma donors with variable titers contributed to the pool, however a lower limit of 10 cut-off index (COI) was established by measurement through electrochemiluminescence immunoassay analyzer (ECLIA). The variable titer of convalescent plasma donors led to the variable titer of pooled plasma, and subsequently variable anti-SARS-CoV-2 antibody level of up to 104 § 30 COI measured through ECLIA [7]. Patients infused with C-IVIG followed a pre-infusion protocol and were given methylprednisolone (40-mg) I.V.…”

Section: Interventionmentioning

confidence: 99%

“…Intravenous immunoglobulin (IVIG), has been used as a therapeutic agent against a variety of inflammatory, infectious, autoimmune, and viral diseases including SARS and Middle East respiratory syndrome (MERS) [5,6]. This study explores Hyperimmune anti-COVID- 19 Intravenous Immunoglobulin (C-IVIG), prepared using pooled high titer convalescent plasma (cut-off index >10) obtained from COVID-19 recovered individuals [7]. C-IVIG when infused in COVID-19 patients, is expected to regulate disease progression via multiple mechanisms including SARS-CoV-2 neutralization, immunomodulation to prevent cytokine storm, and prevention of superimposed bacterial infection (sepsis) due to presence of polyclonal antibodies against other endemic pathogens [8,9,10].…”

Section: Introductionmentioning

confidence: 99%

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Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial

Ali¹,

Uddin²,

Shalim³

et al. 2021

EClinicalMedicine

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Background: Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) is an unexplored therapy amidst the rapidly evolving spectrum of medical therapies for COVID-19 and is expected to counter the three most lifethreatening consequences of COVID-19 including lung injury by the virus, cytokine storm and sepsis. Methods: A single center, phase I/II, randomized controlled, single-blinded trial was conducted at Dow University of Health Sciences, Karachi, Pakistan. Participants were COVID-19 infected individuals, classified as either severely or critically ill with Acute Respiratory Distress Syndrome (ARDS). Participants were randomized through parallel-group design with sequential assignment in a 4:1 allocation to either intervention group with four C-IVIG dosage arms (0.15, 0.20, 0.25, 0.30 g/kg), or control group receiving standard of care only (n = 10). Primary outcomes were 28-day mortality, patient's clinical status on ordinal scale and Horowitz index (HI), and were analysed in all randomized participants that completed the follow-up period (intentionto-treat population). The trial was registered at clinicaltrials.gov (NCT04521309). Findings: Fifty participants were enrolled in the study from June 19, 2020 to February 3, 2021 with a mean age of 56.54 §13.2 years of which 22 patients (44%) had severe and 28 patients (56%) had critical COVID-19. Mortality occurred in ten of 40 participants (25%) in intervention group compared to six of ten (60%) in control group, with relative risk reduction in intervention arm I (RR, 0.333; 95% CI, 0.087À1.272), arm II (RR, 0.5; 95% CI, 0.171À1.463), arm III (RR, 0.167; 95% CI, 0.024À1.145), and arm IV (RR, 0.667; 95% CI, 0.268À1.660). In intervention group, median HI significantly improved to 359 mmHg [interquartile range (IQR) 127À400, P = 0.009)] by outcome day, while the clinical status of intervention group also improved as compared to control group, with around 15 patients (37.5%) being discharged by 7th day with complete recovery. Additionally, resolution of chest X-rays and restoration of biomarkers to normal levels were also seen in intervention groups. No drug-related adverse events were reported during the study. Interpretation: Administration of C-IVIG in severe and critical COVID-19 patients was safe, increased the chance of survival and reduced the risk of disease progression. Funding: Higher Education Commission (HEC), Pakistan (Ref no. 20-RRG-134/RGM/R&D/HEC/2020).

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Section: Discussionmentioning

confidence: 99%

Section: Interventionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial

Ali¹,

Uddin²,

Shalim³

et al. 2021

EClinicalMedicine

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“…There is currently an IVIG scarcity worldwide, and the COVID-19 pandemic would disrupt the collection of plasma from donors for IVIG processing. As a result, delivering IVIG to those patients who depend on it should take precedence over starting an IVIG trial in COVID-19 patients during this emergency phase ( 190 ). Numerous case-reports explaining the efficacy of IVIG against SARS-CoV-2 are available in the literature; nevertheless, it is very difficult to gather solid data from them on the basis of various IVIG formulations and doses, patient comorbidities and quality of treatment.…”

Section: Therapeutics Strategiesmentioning

confidence: 99%

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update

et al. 2021

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.

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“…It is thus of high interest -in the light of increasing seroconversion in the donor population -how currently manufactured IVIG/SCIG can serve these immunodeficient patient groups in terms of protection against a SARS-CoV-2 infection or impede disease severity of Covid-19. First reports of anti-SARS-CoV-2 reactivity and neutralization capacities in commercially produced immunoglobulins have already been published [31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Neutralization in Convalescent Plasma and Commercial Lots of Plasma-derived Immunoglobulin

Volk¹,

Covini-Souris

Kuehnel³

et al. 2021

Preprint

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Introduction: Patients suffering from primary or secondary immunodeficiency face times of increased insecurity and discomfort in the light of the raging Covid-19 pandemic, not knowing if and to what extend their comorbidities impact a potential Covid-19 course of disease. Furthermore, recently available vaccination options might not be amenable or effective for all patients of this heterogeneous population. Therefore, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG). Whether the ongoing Covid-19 pandemic and/or the progress in vaccination programs lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated e.g. for humoral immunodeficiency remains a pressing question for this patient population. Purpose: Here we investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/SCIG products from the end of 2020 until 06/2021 as well as in convalescent plasma (CP) from 05/2020 to 08/2020. Methods: Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for SARS-CoV-2 S1-RBD IgG as well as microneutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate. Neutralization capacities of 313 plasma single donations and 119 plasma-derived IVIG/SCIG lots were determined. Results obtained from both analytical methods were normalized against the international WHO standard. Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations. Results: CP donations presented with a high variability with regards to anti-SARS-reactivity in ELISA as well as in neutralization testing. While approximately 50% of convalescent donations were none/low neutralizing, approximately 10% were at or above 1000 IU/ml. IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities of SARS-CoV-2. Lots produced between 12/2020 and 06/2021, entailing plasma donations after emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time. Neutralization capacity increased from a mean of 20 IU/ml in 12/2020 to 505 IU/ml in 06/2021, while lot-to-lot variability was substantial. Pharmacokinetic (PK) extrapolations based on non-compartmental superposition principles using steady-state reference profiles from previously published PK investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/ml based on the average final container concentration from 05/2021 with 216 IU/ml. Maximum extrapolated trough levels could reach 64 IU/ml based on the latest maximal final container potency tested in 06/2021. Conclusions: SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from US plasma rapidly and in part exponentially increased in the first half of 2021. The observed increase of final container potencies is likely trailing the serological status of the US donor population in terms of Covid-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until fall 2021. In summary, the data support rapidly increasing levels of SARS-COV-2 antibodies in IVIG/SCIG products implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients. Nevertheless, more research to confirm, which plasma levels are needed for protection against SARS-CoV-2 infection of immune-compromised patients is still needed.

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Production of Hyperimmune Anti-SARS-CoV-2 Intravenous Immunoglobulin from Pooled COVID-19 Convalescent Plasma

Cited by 26 publications

References 32 publications

Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial

Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update

SARS-CoV-2 Neutralization in Convalescent Plasma and Commercial Lots of Plasma-derived Immunoglobulin

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