Nat Med 27:1205C1211. Heterogeneity in CCP quality undoubtedly contributed to the variable therapeutic efficacy. Analysis of the COVID-19 serology data suggest that, for the next infectious disease emergency, the best approach after quick establishment of methods for robust antibody-level stratification would be to use CP units in the top quintile of antibody content and neutralizing capacity. KEYWORDS: COVID-19, SARS-CoV-2, convalescent plasma COMMENTARY When the coronavirus disease 2019 (COVID-19) pandemic struck the United States in the spring of 2020, the country responded by deploying convalescent plasma (CP) as an emergency interim therapy, first under Nystatin the Expanded Access Program (EAP) Nystatin Rabbit polyclonal to ALX4 (1) and later under emergency use authorization (EUA), resulting in treatment of >500,000 hospitalized patients (2). In those terrible early days of the COVID-19 pandemic, there were no specific therapies available, and COVID-19 CP (CCP) was deployed based on historical knowledge of efficacy against prior epidemics. At the time, a paucity of serological tests precluded determination of antibody presence or levels in real time, with qualifications based on documented severe acute respiratory syndrome coronavirus 2?(SARS-CoV-2) tests and COVID-19 symptoms. A variety of commercial serological tests were later allowed with little validation because of the emergency nature of the pandemic. Now, Zhang et al. (3) have analyzed >19,000 CCP donor samples from March and August 2020, providing a detailed look at CCP antibody quantity and quality in the early days of the pandemic. This information provides a retrospective analysis of the functional content of CCP used and informs best practices for the deployment of CP in future emergencies with other respiratory viruses. Before considering the results of Zhang et al. (3), it is worthwhile to review the anatomy of SARS-CoV-2 and its interactions with specific antibodies. The SARS-CoV-2 virion has about 100 spike protein molecules, 2,000 membrane proteins, and about 20 envelope proteins exposed on a 31,314-nm2 coronal viral surface (4). The 200-amino acid receptor binding domain (RBD) represents 15% of the spike protein content but accounts for the most potent virus-neutralizing antibodies; antibodies to RBD epitopes are better neutralizers than are antibodies to epitopes on the stalk of the spike. Antibodies raised solely to the spike protein, such as those elicited by infection vaccines or included in monoclonal antibody preparations, are sufficient to prevent infection and halt disease progression through virus neutralization. While non-spike viral antibodies can contribute to virus neutralization, these are not necessary or sufficient. In addition, nonantibody innate and acute-phase proteins also make minor contributions to early, variable viral clearance, including mannose-binding lectins, membrane C-type lectins, the inflammasome, and endosomal viral nucleic acid recognition proteins such as the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway, which also are insufficient for virus neutralization (5). Good news and bad news for CP therapeutic use are evident in the results. The good news is that there is a reasonably good correlation between antibody quantitative content and the neutralizing activity of CCP, a finding that was hinted at by earlier smaller studies (6). This is important because it implies that it should be possible to select high-quality CCP units using antibody titers alone with a good probability that they would contain neutralizing antibody. However, a caveat in this insight is that the correlation between antibody content and neutralization was strongest for units in the higher percentiles. After validation of assays with 420 plasma donors, Zhang et al. (3) found strong correlations of virus-neutralizing activities and serological levels for the upper one-half of the 19,000 plasma donors but weaker correlations for the lower 30%. Strikingly, nearly 10% of samples were not seropositive in the RBD enzyme-linked immunosorbent assay (ELISA), while 8% (1,570 samples) did not have detectable virus-neutralizing activity. Another 25% of Nystatin CCP units had low virus-neutralizing activity, with two-thirds possessing moderate to high virus-neutralizing activity. Interestingly, about 10% of the samples had indeterminate IgG RBD or nucleocapsid (N) antibodies. It is noteworthy that the antibody content assay measured only IgG, although IgA and IgM also neutralize SARS-CoV-2; this might have reduced the correspondence between antibody content and neutralization capacity for some samples. Indeed, neutralization by IgA, IgM, or S1-specific IgG antibodies was proved in a small subset of 25 samples without measurable antibodies to RBD or N. Hence, it is good news to know that, early in the pandemic, there have been a lot of people with high-titer replies who were exceptional donors for CCP and several COVID-19 patients had been treated with high-quality CCP. The poor news is normally that about one-third from the CCP examples had little if any neutralizing activity, which implies that such systems are insufficient for unaggressive therapy. Hence, collection of CCP for therapy without Nystatin calculating antibody titers, as was performed in the first times of the pandemic, would bring about about one-third.