Antibody Correlates of Protection for COVID-19 Convalescent Plasma Associated with Reduced Outpatient Hospitalizations (preprint)

SARS-CoV-2 antibody levels associated with reduced hospitalization risk remain undefined. Our outpatient COVID-19 convalescent plasma (CCP), placebo-controlled trial observed SARS-CoV-2 antibody levels decreasing 22-fold from matched donor units into post-transfusion seronegative recipients. Unvaccinated recipients were jointly stratified by a) early or late transfusion (< 5 or >5 days from symptom onset) and b) high or low post-transfusion SARS-CoV-2 antibody levels (< or > geometric mean). Early treatment with high post-transfusion antibody levels reduced hospitalization risk-0/102 (0%) compared to all other CCP recipients-17/370 (4.6%; Fisher exact-p-0.03) and to all control plasma recipients-35/461 (7.6%; Fisher exact p-0.001). A similar donor upper/lower half antibody level and early late transfusion stratified analyses indicated significant hospital risk reduction. Pre-transfusion nasal viral loads were similar in CCP and control recipients regardless of hospitalization outcome. Therapeutic CCP should comprise the upper 30% of donor antibody levels to provide effective outpatient use for immunocompromised and immunocompetent outpatients.

Early Treatment, Inflammation and Post-COVID Conditions (preprint)

ABSTRACT Background: Post-COVID conditions (PCC) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about early treatment, inflammation, and PCC. Methods: Among 883 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of CCP vs. control plasma with available biospecimens and symptom data, the association between early COVID treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay (Mesoscale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between COVID treatment, cytokine levels and PCC were examined using multivariate logistic regression models. Results: One-third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and loss of smell (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis including diabetes, body mass index, race, and vaccine status, female sex (adjusted odds ratio[AOR]=2.70[1.93-3.81]), older age (AOR=1.32[1.17-1.50]), and elevated baseline levels of IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC. There was a trend for decreased PCC in those with early CCP treatment (<5 days after symptom onset) compared to late CCP treatment. Conclusion: Increased IL-6 levels were associated with the development of PCC and there was a trend for decreased PCC with early CCP treatment in this predominately unvaccinated population. Future treatment studies should evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma (preprint)

BACKGROUND: The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain. METHODS: This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults >18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021. RESULTS: A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions. CONCLUSION: Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors (preprint)

Treatment and prevention of coronavirus disease 2019 (COVID-19) have attempted to harness the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including the development of successful COVID-19 vaccines and therapeutics (e.g., Remdesivir, convalescent plasma [CP]). Evidence that SARS-CoV-2 exists as quasispecies evolving locally suggests that immunological differences may exist that could impact the effectiveness of antibody-based treatments and vaccines. Regional variants of SARS-CoV-2 were reported in the USA beginning in November 2020 but were likely present earlier. There is available evidence that the effectiveness of CP obtained from donors infected with earlier strains in the pandemic may be reduced when tested for neutralization against newer SARS-Cov-2 variants. Using data from the Expanded Access Program to convalescent plasma, we used a gradient-boosting machine to identify predictors of 30-day morality and a series of regression models to estimate the relative risk of death at 30 days post-transfusion for those receiving near sourced plasma (defined as plasma transported [≤] 150 miles) vs. distantly sourced plasma (> 150 miles). Our results show a lower risk of death at 30 days post-transfusion for near sourced plasma. Additional analyses stratified by disease severity, time to treatment, and donor region further supported these findings. The results of this study suggest that near sourced plasma is superior to distantly sourced plasma, which has implications for interpreting the results of clinical studies and designing effective treatment of COVID-19 patients as additional local variant are likely to emerge.

Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience (preprint)

Importance: Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. Objective: To explore potential signals of efficacy of COVID-19 convalescent plasma. Design: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. Setting: Multicenter, including 2,807 acute care facilities in the US and territories. Participants: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. Intervention: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality. Results: The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. Conclusions and Relevance: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. Trial Registration: ClinicalTrials.gov Identifier: NCT04338360