Convalescent Plasma

COVID-19 convalescent plasma is plasma from recovered COVID-19 patients. The plasma contains neutralizing antibodies produced by the patient to fight a COVID-19 infection. Plasma samples are screened to identify patients with high titers of neutralizing antibodies. Unlike hyperimmune globulins and monoclonal antibodies, convalescent plasma can be created locally from recovered COVID-19 patients. A review of convalescent plasma with a graphic explanation of how it is attained is available in the Journal of Clinical Investigation. 
  • NIH recommends against the use of convalescent plasma that was collected prior to the emergence of the Omicron (B.1.1.529) variant. Convalescent plasma should not be used for treatment of COVID-19 in hospitalized, immunocompetent patients. NIH did not find sufficient evidence to recommend either for or against the use of high-titer convalescent plasma, collected after the emergence of Omicron for the treatment of immunocompromised patients and nonhospitalized, immunocompetent patients with COVID-19. 
  • ​Researchers tested antibodies from recovered COVID-19 patients, fully mRNA (Pfizer-BioNTech and Moderna) vaccinated subjects and who received the Regeneron monoclonal antibody combination in neutralizing the B.1.526 (New York) variant. The B.1.526 variant, decreased titers, but was still neutralized by all four types of antibodies.
  • Clinical Experience with Convalescent Plasma
    • In a convenience sample of 20,000 patients hospitalized with COVID-19, treatment with convalescent plasma was found to be safe. Rare adverse effects (< 1%) may include transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), allergic reactions, and death.
    • In a five patient Chinese case series, infusion of convalescent plasma, 10 to 22 days after hospital admission, improved clinical status with four of the five patients no longer needing respiratory support after nine days. After 12 days, patients had cleared the virus and 4 of 5 patients had their ARDS resolved. All patients had high viral loads and were receiving mechanical ventilation, antiviral drugs and methylprednisolone. 
    • In a ten patient Chinese case series, one 200 ml infusion of convalescent plasma infused 16.5 days after hospital admission improved or resolved symptoms within three days. All patients had severe pneumonia and were confirmed to have a COVID-19 infection. All patients received antivirals and eight out of ten were receiving antibiotics and six out of ten were receiving methylprednisolone. 
    • In an unreviewed, unedited 195 patient case control study, 39 patients that received a single transfusion of convalescent plasma were compared to a historical group of 156 patients that did not receive convalescent plasma. Convalescent plasma patients required the same or less supplemental oxygen and had lower mortality (13% vs 24%). In a sub-group analysis, non-intubated patients had a mortality benefit compared to controls, but there was no benefit for patients requiring mechanical ventilation. 
    • In a 28-day, 103 patient Chinese trial, treatment with convalescent plasma did not lead to a statistical difference in clinical improvement (discharge or reduction in severity) compared to placebo (51.9% vs 43.1%) in patients with severe or critical COVID-19 infection. Limitations of the trial include not being blinded and a delay in administering convalescent plasma for almost a month. An editorial in JAMA pointed out that patients with severe COVID-19 demonstrated clinical improvement (91.3% vs 68.2%) but not patients with critical infection (20.7% vs 24.1%).
    • In an unpublished, 35,322 patient, open-label trial, the seven-day mortality was 8.7% in patients treated with convalescent plasma within 3 days of diagnosis, and 11.9% if transfused four or more days later in patients hospitalized with COVID-19. Lower mortality was also seen with convalescent plasma that had higher antibody levels. Data from the trial was collected from patients treated through a convalescent plasma expanded access program for COVID-19 (NCT04338360).
    • In the 28-day, 464 patient, open-label, PLACID trial, treatment with convalescent plasma did not reduce progression to severe disease or all-cause mortality (19% vs 18%), despite an almost 20% greater conversion to a negative SARS-CoV-2 test on day seven in hospitalized Indian patients with moderate COVID-19. Patients in the trial were treated with antivirals (hydroxychloroquine, remdesivir, lopinavir/ritonavir, oseltamivir), broad spectrum antibiotics and immunomodulators (steroids, tocilizumab).
    • In a 30-day, 333 patient trial (NCT04383535), there was no difference in 30-day clinical status between treatment with convalescent plasma and placebo in Argentinian hospitalized patients with COVID-19. Most patients in the trial also received a glucocorticoid.
    • In a 15-day, 160 patient trial (NCT04479163), 16% of mild COVID-19 patients treated with high-antibody-titer convalescent plasma (IgG above 1:1000 against SARS-CoV-2 spike protein) progressed to severe COVID-19 compared to 31% with placebo. Argentinian patients with mild COVID-19 were enrolled if they were 75 or older with or without risk factors for severe COVID-19 or between 65-74 with at least one risk factor. Convalescent plasma was administered within 72 hours after the onset of mild COVID-19 symptoms. Enrollment in the trial was stopped early due to a reduction in available patients. The trial was originally designed to enroll 210 patients.
    • A retrospective review (NCT04338360) examined outcomes from 3,082 hospitalized COVID-19 patients who received convalescent plasma. At 30 days, mortality was 22.3% in patients that received convalescent plasma with high antibody titers, 27.4% with medium titers and 29.6% with low titers. An improvement in mortality was only significant in patients who didn't receive mechanical ventilation. Patients that received convalescent plasma within three days of a positive test had lower mortality than those who received it later.
    • A meta-analysis of four published and six unpublished convalescent plasma trials involving 11,782 patients with COVID-19 did not find a reduction in mortality or a positive benefit on other clinical measures compared to placebo.
    • NIH discontinued the 15-day, 900 patient, Phase III, C3PO trial (NCT04355767) after 511 patients were enrolled, when an interim analysis by the independent data and safety monitoring board did not find that treatment with convalescent plasma reduced emergency treatment, hospitalization or death in patients with mild-to-moderate COVID-19.
    • In the 11,558 patient, open-label, convalescent plasma arm of the British RECOVERY trial (NCT04381936), treatment with convalescent plasma did not decrease 28-day mortality compared to usual care (24% in both groups) in patients hospitalized with COVID-19.
    • In a 30-day, 940 patient, Phase III, CONCOR-1 trial (NCT04348656), treatment with convalescent plasma did not decrease intubation or death compared to standard of care (32.4% vs 28%) in patients with COVID-19 receiving oxygen within 12 days of respiratory symptom onset. Patients that received convalescent plasma experienced more adverse events than standard of care (33.4% versus 26.4%).
    • In the 21-day, 2,011 patient, Phase III, REMAP-CAP trial (NCT02735707), treatment with convalescent plasma did not improve organ support–free days or mortality compared to no convalescent plasma in critically ill adults with confirmed COVID-19.
    • In the 15-day, 511 patient, Phase III, C3PO trial (NCT04355767) treatment with convalescent plasma did not reduce emergency treatment, hospitalization or death in high-risk outpatients with COVID-19.
    • In a 14-day, 941 patient, Phase III, CONTAIN COVID-19 trial (NCT04364737), treatment with convalescent plasma did not increase the number of patients that achieved clinical improvement compared to placebo in hospitalized COVID-19 patients.
    • In a 28-day, 1,181 patient, Phase II trial (NCT04373460), 2.9% of patients treated with high titer convalescent plasma, within nine day of symptom onset, were hospitalized for COVID-19 compared to 6.3% with placebo in outpatients with recent onset of COVID-19. Over 80% of patents were unvaccinated.
    • A meta-analysis (COMPILE study) of eight COVID-19 convalescent plasma studies enrolling 2,341 patients did not find any clinical improvement with convalescent plasma, but data did support use of real-time individual patient data pooling and meta-analysis during a pandemic. Using data from the COMPILE meta-analysis, researchers identified the characteristics of COVID-19 patients most likely to benefit from treatment with convalescent plasma. This data, called the treatment benefit index (TBI), was used to create a prediction tool, called the Convalescent Plasma Benefit Index Calculator. The TBI divides patients into three groups: substantial benefit from convalescent plasma, moderate benefit, and no expected benefit. The TBI was validated with four external data sets.
Hyperimmune Immunoglobulin or Anti-COVID-19 polyclonal hyperimmune globulin (HIG)
 
Hyperimmune globulins are made from donated plasma from patients that have recovered from COVID-19 or have been vaccinated (when a vaccine is available). The antibodies are purified and used to create a standardized mixture with a defined neutralization activity. Because HIGs have been shown to be effective in the treatment of severe acute viral respiratory infections, they are being tested as a treatment option for COVID-19 and could potentially reduce illness severity or prevent it. The head of Research and Development for Takeda’s Plasma-Derived Therapies unit wrote an overview of HIGs for the journal CTS: Clinical Translational Science that provides more detail on the creation and use of the therapy. 
  • NIH feels there is insufficient evidence to recommend either for or against the use of SARS-CoV-2 immunoglobulins for the treatment of COVID-19.
  • The CoVIg-19 Plasma Alliance, a group that includes Takeda, CSL Behring, Biotest, Bio Products Laboratory, Octapharma, LFB, ADMA Biologics, BioPharma Plasma, GC Pharma, and Sanquin, have joined together to develop and manufacture a non-branded hyperimmune immunoglobulin. The group formed in order to accelerate collection, development, clinical trials and manufacturing.
  • The CoVIg-19 Plasma Alliance (CSL Behring, Takeda, BioPharma Plasma, Biotest, GC Pharma, LFB, National Bioproducts Institute, Octapharma and Sanquin) announced that in the 7-day, 600 patient, Phase III, ITAC trial (NCT04546581), adding anti-coronavirus hyperimmune intravenous immunoglobulin (H-Ig) to remdesivir did not reduce disease progression compared to remdesivir alone in hospitalized patients with COVID-19 who had symptoms for 12 days or fewer without life-threatening organ dysfunction or end-organ failure. NIH sponsored the trial.
  • Following the failure of ITAC, the CoVIg-19 Plasma Alliance disbanded and discontinued work on an H-Ig product for COVID-19.
  • Emergent BioSolutions – is developing two anti-COVID-19 polyclonal hyperimmune globulins (HIG). COVID-HIG will be made from human plasma with antibodies to SARS-CoV-2 and COVID-EIG will be made from plasma of immunized horses with antibodies to SARS-CoV-2.
Immune Globulin (IVIG)
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Intravenous immunoglobulin (IVIG) is non-specific, sterile, purified immunoglobulin G (IgG) immunoglobulins from a pool of plasma donors.