Since many patients improve on their own, large numbers of subjects will be required to show a benefit for CCP. To date, accrual to these RCTs has been a major challenge, particularly in regions of the world with high rates of vaccine administration.
CCP is procured from recovered patients e. These prospective donors can donate at blood collection organizations. CCP is collected through plasmapheresis and then the plasma is tested for SARS-CoV-2 antibody levels and undergoes standard donor and infectious disease screening before releasing the plasma for clinical use.
Plasmapheresis is desirable as a means to collect larger volumes of plasma. Donations can occur as frequently as weekly for several months before antibody titers begin decreasing. Allowed donation frequency varies between blood centers. Clinical assays that measure the level of antibodies reacting against various SARS-CoV-2 proteins are widely available and may correlate, albeit imperfectly, with neutralizing antibody titers, and thus might be used to predict the potency of CCP units.
It is important to consider the assay platform as well as the specificity e. A variety of passive antibody therapies are available for COVID, including hyperimmune globulin concentrating neutralizing antibody activity up to tenfold and engineered monoclonal antibodies.
Interim analyses of early-phase clinical trials 8 reporting decreased viral shedding, symptoms and hospitalizations with passive antibody treatment.
One preparation, bamlanivimab, consists of a single antibody, and the second preparation is a combination of two antibodies, casirivimab and imdevimab, all directed against the SARS-CoV2 spike protein.
However, NIH guidelines currently recommend against the use of bamlanivimab and etesevimab due to their lack of efficacy against emerging SARS-CoV-2 viral variants now prevalent worldwide, 9 and instead recommend use of casirivimab and imdevimab or sotrovimab, also available under an EUA in the United States.
There is also concern that variants are arising and being selected for in immunocompromised patients being treated with CCP or antibody therapies. In what settings should treatment with monoclonal antibody therapies be considered? Initial clinical trials focusing on hospitalized patients were stopped due to futility or lack of benefit, and this is not surprising given that accelerating viral clearance via antibodies is unlikely to improve clinical status in patients already making their own antibodies a week or more after infection.
The U. EUA for monoclonal antibodies restricts administration to those nonhospitalized patients at risk for severe disease, or those hospitalized for other reasons who become infected. Logistical challenges in administering intravenous antibodies to SARS-CoV-2 infectious outpatients has limited widespread use. The panel recommended against use in patients hospitalized for COVID, except as part of a clinical trial.
Agenda for Nematology Research. About Us. Precision Medicine. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer.
In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes.
We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID receiving oxygen within 12 d of respiratory symptom onset NCT The composite primary outcome was intubation or death by 30 d.
Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. In total, patients were randomized, and patients were included in the intention-to-treat analysis. Patients in the convalescent plasma arm had more serious adverse events The antibody content significantly modulated the therapeutic effect of convalescent plasma.
Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care. Based on previous experience in other viral infections 2 , the use of convalescent plasma has been proposed as a therapeutic form of passive immunization for patients with acute COVID refs.
Early in the pandemic, several small randomized trials found no difference in clinical outcomes 5 , 6 , 7 , 8. In the United States, an Extended Access Program outside of a controlled trial led to the use of convalescent plasma in over half a million patients. Data from these patients showed that the transfusion of plasma with high anti-SARS-CoV-2 antibody levels was associated with a lower risk of death in non-intubated patients compared to lower antibody levels; however, this study lacked a control group 9.
The RECOVERY trial was a large randomized trial in 11, hospitalized patients that found that the risk of death after the administration of high-titer plasma was not different from standard of care The variability in antibody titers allowed for a characterization of the effect-modifying role of functional and quantitative antibodies on the primary outcome intubation or death at 30 d.
This trial was stopped at the planned interim analysis because the conditional power estimate was 1. Between 14 May and 29 January , patients were randomized to convalescent plasma or standard of care in 72 hospital sites in Canada, the United States and Brazil Fig. Two patients randomized to plasma withdrew consent before treatment. Seventeen patients were lost to follow-up between discharge and day 30, precluding assessment of the primary outcome. Patient flow in the CONCOR-1 study detailing the intention-to-treat population, per-protocol analysis population and excluded patients.
The time to intubation or death was not significantly different between groups Fig. Secondary outcomes for the intention-to-treat population are shown in Fig. There were no differences in mortality or intubation or other secondary efficacy outcomes. Similarly, in the per-protocol analysis, there were no differences in the secondary efficacy outcomes Supplementary Table 4 and Extended Data Figs.
The subgroup of patients served by blood supplier 3 Fig. Forest plots are presented for the subgroup analyses for the intention-to-treat population. P values for RR and homogeneity are two sided without adjustment for multiple comparisons.
BMI, body mass index. Serious adverse events occurred in Most of these events were worsening hypoxemia and respiratory failure. Transfusion-related complications were recorded in 35 5. Of the 35 reactions, four were life-threatening two transfusion-associated circulatory overload, one possible transfusion-related acute lung injury and one transfusion-associated dyspnea , and none was fatal. Thirteen of the 35 reactions were classified as transfusion-associated dyspnea.
Two patients underwent serological investigation for transfusion-related acute lung injury both negative. The distributions of antibodies in convalescent plasma units varied by blood supplier Fig. Transfusion of convalescent plasma with average log-transformed levels of antibody-dependent cellular cytotoxicity ADCC yielded an OR of 1. Center line: median; box limits: 25th and 75th percentiles; whiskers: 1. Marker values are expressed as standard deviations of log values centered around the mean standardized log.
The P values two-sided test for trend without adjustment for multiple comparisons refer to the effect modification observed with each marker Supplementary Table The histograms present the frequency distribution by marker. Overlaid data points indicate the value of the two markers for each CCP transfusion. There was no evidence of significant interaction among the four serologic measures in the general additive model Fig.
Of the 15 other reported randomized trials, 11 used only high-titer plasma 5 , 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , and four applied less stringent plasma selection criteria, allowing for variable plasma titers 6 , 19 , 20 , Including the results from CONCOR-1, a total of 15, patients participated in trials using high-titer plasma, and participated in trials applying less stringent criteria. The summary estimates for the RR of mortality in high-titer plasma trials was 0.
Patients in the convalescent plasma arm experienced more serious adverse events. Convalescent plasma was not associated with an improvement in any of the secondary efficacy outcomes or in any of the subgroup analyses. A major additional contribution of our study comes from the study of immunologic markers, which suggest that the antibody profile significantly modified the effect of convalescent plasma compared to standard of care. The U. Our assessment of the role of antibody profile on the clinical effect relative to standard of care is aligned with both of these conclusions.
In contrast, the U. National Registry 9 could be explained by increased mortality with low antibody plasma rather than improved mortality with high antibody plasma.
This conclusion is corroborated by the meta-analysis of previous trials based on plasma selection strategy. Although the vast majority of patients included in convalescent plasma trials received high-titer plasma, most patients treated outside of clinical trials did not, including many of those who received plasma according to the current U.
National Registry was considered high-titer 9. The antibody content is critical in determining the potency and potential harm of passive antibody therapy. Convalescent plasma demonstrating high levels of viral neutralization and high levels of Fc-mediated function were independently associated with a reduced risk for intubation or death.
In animal models of COVID, mutation of monoclonal antibodies leading to loss of Fc-mediated function, but sparing the neutralizing function, abrogated the protective effect of the antibody 22 , 23 , 24 , In cohort studies of severe COVID, low Fc-mediated function, but not neutralization, was associated with mortality 26 , In contrast, high levels of IgG antibodies against the full transmembrane spike protein measured by flow cytometry which is distinct from commercial assays for IgG against spike subunit 1 were associated with an increased risk of intubation or death after controlling for other antibody markers, suggesting that the transfusion of convalescent plasma containing non-functional anti-SARS-CoV-2 antibodies might be harmful.
Antibody Fc-mediated function is dependent on the ability to aggregate and crosslink Fc receptors on target cells. This process can be disrupted by competition from other antibodies with low or absent Fc function Similar observations were made during HIV vaccine trials, where the development of IgA antibodies against the virus envelope paradoxically increased the risk of infection due to competition with IgG 29 , 30 , and in animal models of passive immunization where transfer of antibodies could be deleterious to the host The C3PO trial, which also assessed early treatment with high-titer plasma in high-risk patients, was stopped prematurely for futility after enrolling of planned participants NCT In our trial, the median time from the onset of symptoms was 8 d; however, we did not observe a difference in the primary outcome in the subgroup of patients who were randomized within 3 d of diagnosis.
The frequency of serious adverse events was higher in the convalescent plasma group compared to the standard of care group Most of these events were caused by worsening hypoxemia and respiratory failure occurring throughout the d follow-up period. This frequency is consistent with the recent Cochrane review that reported an OR of 1.
The frequency of transfusion-associated dyspnea and transfusion-associated circulatory overload was 2. CONCOR-1 site investigators included many transfusion medicine specialists, and the open-label design might have encouraged reporting.
CONCOR-1 was a randomized trial designed to examine the effect of convalescent plasma versus standard of care for the primary composite outcome of intubation or death, with a capacity to explore the immunological profile of convalescent plasma and its impact on the effect of convalescent plasma.
The trial involved four blood suppliers that provided local convalescent plasma units based on different antibody criteria. As a result, plasma units with a wide distribution of antibody content were included, and comprehensive antibody testing using both quantitative and functional assays provided a detailed description of the plasma product. The open-label design represents a limitation of this study, as knowledge of the treatment group could influence the decision to intubate, report adverse events or administer other treatments.
The antibody profile of recipients was unavailable at the time of this analysis. In future work, we will investigate the value of convalescent plasma in patients without a detectable humoral immune response.
In addition, other antibody isotypes IgM and IgA and IgG subclasses should be evaluated in future studies to determine their effect on clinical outcomes. Additional randomized trials are warranted to assess the early use of high-titer convalescent plasma units in immunocompromised patients with COVID who are unable to mount an efficient anti-SARS-CoV-2 antibody response.
In summary, the CONCOR-1 trial did not demonstrate a difference in the frequency of intubation or death at 30 d with convalescent plasma or standard of care in hospitalized patients with COVID respiratory illness.
The antibody content had a significant effect-modifying role for the effect of convalescent plasma on the primary outcome. The lack of benefit and the potential concern of harm caution against the unrestricted use of convalescent plasma for hospitalized patients with COVID CONCOR-1 was an investigator-initiated, multi-center, open-label, randomized controlled trial conducted at 72 hospital sites in Canada, the United States and Brazil Eligible patients were randomly assigned to receive either convalescent plasma or standard of care.
Regulatory authorization was obtained from Health Canada control no. The trial was registered at ClinicalTrials. An independent data safety monitoring committee performed trial oversight and made recommendations after review of safety reports planned at every patients and at the planned interim analysis based on the first patients.
External monitoring was performed at all sites to assess protocol adherence, reporting of adverse events and accuracy of data entry. Full details of the study design, conduct, oversight and analyses are provided in the protocol and statistical analysis plan, which are available online. Exclusion criteria were 1 more than 12 d from the onset of respiratory symptoms; 2 imminent or current intubation; 3 a contraindication to plasma transfusion; or 4 a plan for no active treatment.
Consent was obtained from all donors and participants or their legally authorized representative. Patients were randomized in a ratio to receive convalescent plasma or standard of care using a secure, concealed, computer-generated, web-accessed randomization sequence REDCap v Patients were monitored by clinical staff for transfusion-related adverse events as per local procedures.
Individuals assigned to standard of care received usual medical care as per routine practices at each site. Female donors with previous pregnancies were excluded from donation, unless they tested negative for HLA antibodies. NKr cells see supplement for complete description 42 , For each plasma unit, the absolute antibody content was defined as the product of the unit volume and the concentration of the antibody or functional capacity in the plasma.
In most cases, O RhD negative blood O- can safely be given to anyone. It's often used in medical emergencies when the blood type is not immediately known.
It's safe for most recipients because it does not have any A, B or RhD antigens on the surface of the cells, and is compatible with every other ABO and RhD blood group. To work out your blood group, your red cells are mixed with different antibody solutions. If, for example, the solution contains anti-B antibodies and you have B antigens on your cells you're blood group B , it will clump together.
If the blood does not react to any of the anti-A or anti-B antibodies, it's blood group O. A series of tests with different types of antibody can be used to identify your blood group. If you have a blood transfusion — where blood is taken from one person and given to another — your blood will be tested against a sample of donor cells that contain ABO and RhD antigens. Pregnant women are always given a blood group test.
This is because if the mother is RhD negative but the child has inherited RhD-positive blood from the father, it could cause complications if left untreated.
RhD-negative women of child-bearing age should always only receive RhD-negative blood. Most people are able to give blood, but only 1 in 25 people actually do. You can donate blood if you:. Read more about who can give blood.
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