Convalescent plasma for COVID‐19 — encouraging signals of efficacy (2021)

Convalescent plasma has emerged as a promising experimental therapy for COVID-19. The premise of COVID-19 convalescent plasma (CCP) is based on the notion that the administration of antibodies mediates a therapeutic effect by neutralizing virus and thus interrupting the pathogenic process. Consistent with this view, administration of CCP is associated with a reduction in SARS-CoV-2 viral burden in COVID-19.1 However, obtaining definitive evidence for its clinical utility from randomized clinical trials (RCT) has proven difficult because of unforeseen circumstances including their premature termination as a result of local control of the pandemic2 and the use of plasma with low titer.3 Nevertheless, the three RCTs published to date have each provided encouragement for CCP.2-4 In addition, several observational studies have associated CCP use with reduced mortality, especially when used early in the course of hospitalization in patients without mechanical ventilation.5-7 In this issue of the BJH, Shenoy et al.8 report that administration of CCP in COVID-19 was associated with reduced mortality in a large observational study that provides additional evidence for the efficacy of CCP. The major finding of Shenoy et al.8 was that CCP administration was associated with a statistically significant reduction in mortality at days 7 and 14 but not at day 28. At first glance this result appears incongruous since it is difficult to imagine how CCP reduced early mortality but had no effect later on the course of disease. However, they did find a 5·6% reduction in mortality at day 28, which barely missed statistical significance at P = 0·06. Hence, the absence of a statistically significant effect at day 28 is more likely to be a Type II error, or false negative finding, than a reflection of CCP efficacy or the progression of the COVID-19 pathogenic process in the cohorts studied. Furthermore, there is evidence that despite the attempts to construct a matched control group for comparison the CCP group was sicker than the controls, as suggested by statistically significant increased use of corticosteroids, remdesivir and tocilizumab in the CCP-treated group. Hence, it is conceivable that in this retrospective observational study the group receiving CCP included sicker patients where plasma was also used because of concern about deteriorating clinical status. A sicker cohort in the CCP-treated group would also explain why these patients had a longer average length of hospital stay relative to those in the control group. If this is the case, the efficacy of CCP is likely to be greater than simply reducing early mortality in COVID-19 hospitalized patients. Another important finding in the Shenoy et al.8 study comes from subgroup analysis showing reduced supplemental oxygen requirements in patients treated with CCP within three days of hospitalization. This finding is consistent with other reports that CCP improves oxygenation5 and reinforces recent reports that the efficacy of CCP is greatest when used early in the course of hospitalization. The mechanism by which CCP administration is associated with improved pulmonary function could reflect interruption of viral replication through antibody-mediated SARS-CoV-2 neutralization, with consequent reductions in inflammation and lung damage. The encouraging signals of efficacy from Shenoy et al.8 are noteworthy given that CCP was used without knowledge of its specific antibody content for SARS-Cov-2. In this regard, analysis of a large population of patients treated with CCP in the United States under the Expanded Access Program (EAP) of the Food and Drug Administration showed a correlation between the use of CCP with higher antibody titer to SARS-CoV-2 with reduced mortality.9 The mechanism of action of CCP is not fully understood. It is assumed the primary mechanism of efficacy is that neutralizing antibodies help to clear the virus, and consequently it is most important to provide convalescent plasma early.10 While most COVID-19 convalescent individuals develop a strong antibody response, the neutralizing antibody titers and binding avidity are highly heterogeneous in CCP with up to 20% of units not having detectable neutralizing antibody levels.11, 12 Data from the EAP suggest high neutralizing antibody CCP is most efficacious, but low titer CCP units may have also been efficacious suggesting additional functional aspects of the humoral immune response may contribute to this benefit.9 Compared to healthy blood donor control plasma, CCP has significantly higher plasma levels of IFN-γ, IL-10, IL-15, IL-21 and MCP-1.13 Using multiplexed Fc array binding assays, as well as a variety of validated functional antibody response assays, it has recently been reported that CCP provides additional antiviral activities in the form of antibody-dependent cellular cytotoxicity, complement activation and phagocytosis.14 Thus, CCP may provide benefits beyond just the neutralizing antibody, and it will be important to understand these differences when comparing efficacy to monoclonal antibodies. While Shenoy et al.8 help us understand the potential for CCP, it is important to continue the randomized trials and other mechanistic studies of CCP. One of the key questions is when is the best time to provide CCP. Historic use of CCP suggests earlier use is best.15 However, the Shenoy et al. study8 provided CCP to a wide range of patients during their illness. Most studies to date have primarily evaluated clinical end points (e.g. mortality, oxygen saturation, etc.). To fully understand the mechanism of CCP, it will be helpful to know the inflammatory state (e.g. cytokines, D-dimer, ferritin, etc.) of recipients pre and post transfusion. Finally, it is important to evaluate the neutralizing titer of the CCP units and also the recipients pre and post transfusion. In summary, Shenoy et al.8 provide encouraging evidence for the usefulness of CCP in treating COVID-19. The data come from the early days of the pandemic in the United States, a time when knowledge about the need for early use of plasma with high antibody titer to SARS-CoV02 was absent and serological assays for characterizing plasma were not widely available. CCP is currently under evaluation by numerous RCTs, which will hopefully clarify its efficacy for the treatment of COVID-19. The magnitude of the mortality effects measured by Shenoy et al.8 provide important information for the design of RCTs while their encouraging signals of efficacy should stimulate continued investigation into the effectiveness of CCP for COVID-19. AC was supported in part by NIH grants AI052733, AI15207 and HL059842. AART was supported in part by NIH grants AI120938, AI120938S1 and AI128779. Both AC and AART wrote this paper.