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BackgroundCOVID-19 Convalescent Plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe SARS-CoV-2 infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAb) between different CCP donors. The present study was designed to evaluate nAb titer threshold for clinically effective CCP. MethodsWe conducted a double-blind, phase 2 study to evaluate the safety and effectiveness of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive on a SARS-CoV-2 nucleic acid amplification test and with symptoms for < 10 days were eligible. Participants received either CCP with nAb titers [≥]1:160-1:640 (standard titer group) or >1:640 (high titer group) in addition to standard of care treatments. Adverse events were contrasted by CCP titer. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. FindingsBetween August 28 and December 4, 2020, 316 participants were screened, 55 received CCP, with 41 and 14 receiving standard versus high titer CCP, respectively. Participants were a median of 61 years of age (IQR 52-67), 36% women, 25% Black and 33% Hispanic. Severe adverse events (SAE) ([≥] grade 3) occurred in 4 (29%) and 23 (56%) of participants in the high versus standard titer groups, respectively by day 28 (Risk Difference -0.28 [95% CI -0.56, 0.01]). There were no observed treatment-related AEs. By day 55, time to hospital discharge was shorter among participants receiving high versus standard titer, accounting for death as a competing event (hazard ratio 1.94 [95% CI 1.05, 3.58], Grays p=0.02). InterpretationIn this phase 2 trial in a high-risk population of patients admitted for Covid-19, we found earlier time to hospital discharge and lower occurrences of life-threatening SAEs among participants receiving CCP with nAb titers >1:640 compared with participants receiving CCP with lower nAb titer CCP. Though limited by a small study size these findings support further study of high-nAb titer CCP defined as >1:640 in the treatment of COVID-19. FundingThis clinical study was supported by the UNC Health Foundation and the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund established and appropriated by the North Carolina General Assembly. The laboratory assays for neutralizing antibody titers and SARS-CoV-2 specific antibody-binding assays were partially supported by The NIH NCI/NIAID SeroNet Serocenter of Excellence Award U54 CA260543. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCOVID-19 Convalescent Plasma (CCP) has emergency use authorization from the FDA for early treatment of COVID-19 in either outpatient or inpatient settings. Evidence supporting the use of CCP for severe COVID-19 is mixed and still emerging. One major limitation in interpreting published clinical trials and the clinical role of CCP is incomplete understanding of necessary neutralizing antibody (nAb) titer for clinically effective CCP. Observational studies suggest that higher antibody-content CCP is more effective than lower antibody-content CCP, or that very low antibody-content CCP is harmful. We searched PubMed articles published between February 1, 2020, and April 15, 2022, using the terms "COVID-19", "convalescent plasma", "SARS-CoV-2", and "CCP" alone and in combination. Our search yielded 6,468 results which we filtered to 280 and 162 by selecting Clinical Trial and Randomized Controlled Trial article types, respectively. Among these, we identified 25 open-label or blinded efficacy or effectiveness studies in hospitalized patients that were relevant to our study. Preliminary reports show wide variability in the antibody content of CCP used in clinical trials, the assays used to define CCP antibody content, and the estimates of clinical outcomes following CCP therapy for hospitalized patients. Only one study deliberately infused CCP with nAb > 1:640. Post-hoc analyses of potent monoclonal antibody therapy in hospitalized patients in the UK showed survival benefit when monoclonal antibody was infused to patients who had not yet seroconverted by spike antibody ELISA, suggesting that if dosed appropriately, antibody-based therapies may have a role in improving outcomes of severe COVID-19. Added value of this studyThis phase 2 study showed that CCP with high nAb titer (>1:640) provided more rapid recovery to hospital discharge and fewer COVID-19 attributable AEs than CCP with nAb titer between the FDA-recommended minimum standard and 4-fold higher ([≥]1:160-1:640). The hazard ratio of time to hospital discharge from baseline through day 55, accounting for death as a competing event, contrasting patients receiving high versus standard CCP titer was 1.94 (95% CI 1.05-3.58). Adjusted hazard ratios of high versus standard titer CCP receipt for time to hospital discharge were consistent with the primary unadjusted findings. Mortality through 55 days was lower in the high titer group, but with a wide confidence interval that did not reach statistical significance. Implications of all available evidenceOur data that CCP with nAb >1:640 expedites recovery of patients admitted with COVID-19 compared with CCP with nAb [≥]1:160-1:640 suggests that a threshhold of nAb [≥]1:160 may be too low to define CCP as high titer. Analyses in larger CCP trials should consider full reporting of nAb in CCP units administered at individual study participant level, and specifically whether CCP contained nAb >1:640. Further investigation of CCP with nAb >1:640 is warranted given that raising the threshhold of nAb, or a correlative specific anti-spike antibody assay, used to qualify high titer CCP in clinical trials could inform policy guidance and clinical use of CCP.
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The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities. SignificanceIn this study we found that neutralizing antibody responses in COVID-19 convalescent individuals vary in magnitude but are durable and correlate well with RBD Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time, that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardio-metabolic co-morbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2.
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A new Severe Acute Respiratory Syndrome Coronavirus variant (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus present with clinically inapparent, mild or severe disease. Currently, the presence of the virus in individual patients and at the population level is being monitored by testing symptomatic cases by PCR for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the viral spike (S) protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV specific antibodies in people. Here we use a large panel of human sera (70 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate the performance of the RBD as an antigen for accurate detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) to antibodies induced by SARS-CoVs. We observed a robust correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, strongly support the use of RBD-based antibody assays for population-level surveillance and as a correlate of neutralizing antibody levels in people who have recovered from SARS-CoV-2 infections.
