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 transfusing convalescent plasma as post-exposure prophylaxis against SARS-CoV-2 infection (preprint)

BACKGROUND: The efficacy of SARS-CoV-2 convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. We hypothesized that CCP might prevent infection when administered before symptoms or laboratory evidence of infection. METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer ([≥]1:320) CCP with standard plasma. Asymptomatic participants aged [≥]18 years with close contact exposure to a person with confirmed COVID-19 in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was development of SARS-CoV-2 infection. RESULTS: 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for SARS-CoV-2 RT-PCR positivity at screening. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. There were 28 adverse events in CCP and 58 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs. 25.2 days; p=0.49) and COVID-19 (26.3 vs. 25.9 days; p=0.35) were similar for both groups. CONCLUSION: In this trial, which enrolled persons with recent exposure to a person with confirmed COVID-19, high titer CCP as post-exposure prophylaxis appeared safe, but did not prevent SARS-CoV-2 infection. Trial Registration: Clinicaltrial.gov number NCT04323800.

Vaccination of COVID-19 Convalescent Plasma Donors Increases Binding and Neutralizing Antibodies Against SARS-CoV-2 Variants (preprint)

BackgroundCOVID-19 convalescent plasma (CCP) was widely used as passive immunotherapy during the first waves of SARS-CoV-2 infection in the US. However, based on observational studies and randomized controlled trials, beneficial effects of CCP were limited, and its use was virtually discontinued early in 2021, in concurrence with increased vaccination rates and availability of monoclonal antibody (mAb) therapeutics. However, as new variants of the SARS-CoV-2 spread, interest in CCP derived from vaccine-boosted CCP donors is resurging. The effect of vaccination of previously infected CCP donors on antibodies against rapidly spreading variants of concern (VOC) is still under investigation. Study Design/MethodsIn this study, paired samples from 11 CCP donors collected before and after vaccination were tested to measure binding antibodies levels and neutralization activity against the ancestral and SARS-CoV-2 variants (Wuhan-Hu-1, B.1.1.7, B.1.351, P.1, D614G, B.1.617.2, B.1.427) on the Ortho Vitros Spike Total Ig and IgG assays, the MSD V-PLEX SARS-CoV-2 Panel 6 arrays for IgG binding and ACE2 inhibition, and variant-specific Spike Reporter Viral Particle Neutralization (RVPN) assays. Results/FindingsBinding and neutralizing antibodies were significantly boosted by vaccination, with several logs higher neutralization for all the variants tested post-vaccination compared to the pre-vaccination samples, with no difference found among the individual variants. DiscussionVaccination of previously infected individuals boosts antibodies including neutralizing activity against all SARS-CoV-2 VOC, including the current spreading delta (B.1.617.2) variant. Animal model and human studies to assess clinical efficacy of vaccine boosted CCP are warranted, especially since 15-20% of current donations in the US are from previously infected vaccine-boosted donors.