Outcomes of convalescent plasma with defined high- versus lower-neutralizing antibody titers against SARS-CoV-2 among hospitalized patients: CoronaVirus Inactivating Plasma (CoVIP), double-blind phase 2 study. (preprint)

Background COVID-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. Methods We 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. Findings Between 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], Gray's p=0.02). Interpretation In 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.

The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies (preprint)

Introduction: The effect of SARS-CoV-2 infection on pregnant mothers, the placenta, and infants is not fully understood and sufficiently characterized. Methods: We performed a retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021. We performed a chart review to document the infant weight, length, head circumference, survival, congenital abnormalities, and hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria. Results: The average infant weight, length, and head circumference were all within the normal range for gestational age, the infants had no identifiable congenital abnormalities, and all infants and mothers survived. Only one infant (0.870%) became infected with SARS-CoV-2. Moderate and severe maternal COVID-19 were associated with increased caesarean section, premature delivery, infant NICU admission, and maternal respiratory failure, and were more likely in Type 1 (p=0.0055) and Type 2 (p=0.0285) diabetic mothers. Most placentas (n=63, 54.8%) showed normal or non-specific findings, while a subset had mild maternal vascular malperfusion (n=26, 22.6%) and/or mild microscopic ascending intrauterine infection (n=28, 24.3%). Discussion: Most mothers with SARS-CoV-2 and their infants had a routine clinical course. Maternal SARS-CoV-2 infection was not associated with intrauterine fetal demise, infant death, congenital abnormalities, or hearing loss. Infant infection with SARS-CoV-2 was rare and not via the placenta. Most placentas had non-specific findings and a subset showed mild maternal vascular malperfusion and/or mild microscopic ascending intrauterine infection, which were not associated with maternal COVID-19 severity.

Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals (preprint)

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.

The RBD Of The Spike Protein Of SARS-Group Coronaviruses Is A Highly Specific Target Of SARS-CoV-2 Antibodies But Not Other Pathogenic Human and Animal Coronavirus Antibodies (preprint)

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.