High-dose coenzyme Q10 therapy versus placebo in patients with post COVID-19 condition: A randomized, phase 2, crossover trial.

Background: Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms. Methods: In this placebo-controlled, double-blind, 2 × 2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for 6 weeks, with crossover treatment after a 4-week washout period. The ED-5Q and a PCC-symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the 6-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment. Findings: From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods - 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43.06 (95% CI: 40.18; 45.94), and the mean EQ-5D health index was 0.66 (95% CI: 0.64; 0.68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0.01; 95% CI: -0.02; 0.04; p = 0.45) or the change in PCC-related symptom score (with a mean difference of -1.18; 95% CI: -3.54; 1.17; p = 0.32). Interpretation: Based on self-reported data, CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. However, we observed a significant spontaneous improvement on both scores regardless of treatment during 20 weeks observation. Funding: Placebo and CoQ10 capsules were provided by Pharma Nord, and the trial was supported by grants from the Novo Nordisk Foundation (NNF21OC0066984). This trial is registered with EudraCT, 2020-005961-16 and ClinicalTrials.gov, NCT04960215. The trial is completed.

The Impact of IFNλ4 on the Adaptive Immune Response to SARS-CoV-2 Infection.

Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8+ T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8+ T cell responses of these patients.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Host Displaying Treatment Induced Viral Evolution.

We report a coronavirus disease 2019 case with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persisting beyond 333 days in an immunocompromised patient with chronic lymphocytic leukemia, asymptomatically carrying infectious SARS-CoV-2 at day 197 postdiagnosis. In addition, viral sequencing indicates major changes in the spike protein over time, temporally associated with convalescent plasma treatment.

SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity.

BACKGROUND: The SARS-CoV-2 pandemic currently prevails worldwide. To understand the immunological signature of SARS-CoV-2 infections and aid the search and evaluation of new treatment modalities and vaccines, comprehensive characterization of adaptive immune responses towards SARS-CoV-2 is needed. METHODS: We included 203 recovered SARS-CoV-2 infected patients in Denmark between April 3rd and July 9th 2020, at least 14 days after COVID-19 symptom recovery. The participants had experienced a range of disease severities from asymptomatic to severe. We collected plasma, serum and PBMC's for analysis of SARS-CoV-2 specific antibody response by Meso Scale analysis including other coronavirus strains, ACE2 competition, IgA ELISA, pseudovirus neutralization capacity, and dextramer flow cytometry analysis of CD8+ T cells. The immunological outcomes were compared amongst severity groups within the cohort, and 10 pre-pandemic SARS-CoV-2 negative controls. FINDINGS: We report broad serological profiles within the cohort, detecting antibody binding to other human coronaviruses. 202(>99%) participants had SARS-CoV-2 specific antibodies, with SARS-CoV-2 neutralization and spike-ACE2 receptor interaction blocking observed in 193(95%) individuals. A significant positive correlation (r=0.7804) between spike-ACE2 blocking antibody titers and neutralization potency was observed. Further, SARS-CoV-2 specific CD8+ T-cell responses were clear and quantifiable in 95 of 106(90%) HLA-A2+ individuals. INTERPRETATION: The viral surface spike protein was identified as the dominant target for both neutralizing antibodies and CD8+ T-cell responses. Overall, the majority of patients had robust adaptive immune responses, regardless of their disease severity. FUNDING: This study was supported by the Danish Ministry for Research and Education (grant# 0238-00001B) and The Danish Innovation Fund (grant# 0208-00018B).

SARS-CoV-2 persistence is associated with antigen-specific CD8 T-cell responses.

BACKGROUND: Upon SARS-CoV-2 infection, most individuals develop neutralizing antibodies and T-cell immunity. However, some individuals reportedly remain SARS-CoV-2 PCR positive by pharyngeal swabs weeks after recovery. Whether viral RNA in these persistent carriers is contagious and stimulates SARS-CoV-2-specific immune responses is unknown. METHODS: This cohort study was conducted between April 3rd-July 9th 2020, recruiting COVID-19 recovered individuals that were symptom-free for at least 14 days. We collected serum for SARS-CoV-2-specific total Ig, IgA and IgM detection by ELISA, pharyngeal swabs (two time points) for ddPCR and PBMCs for anti-SARS-CoV-2 CD8 T-cell dextramer analyses. FINDINGS: We enrolled 203 post-symptomatic participants with a previous RT-PCR-verified SARS-CoV-2 infection. At time point 1, a median of 23 days (range 15-44) after recovery, 26 individuals (12⋅8%) were PCR positive. At time point 2, 90 days (median, range 85-105) after recovery, 5 (5⋅3%) were positive. There was no difference in SARS-CoV-2 antibody levels between the PCR negative and positive group. The persistent PCR positive group however, had SARS-CoV-2-specific CD8 T-cell responses of significantly increased breadth and magnitude. Assisted contact tracing among persistent PCR positive individuals revealed zero new COVID-19 diagnoses among 757 close contacts. INTERPRETATION: Persistent pharyngeal SARS-CoV-2 PCR positivity in post-symptomatic individuals is associated with elevated cellular immune responses and thus, the viral RNA may represent replicating virus. However, transmission to close contacts was not observed indicating that persistent PCR positive individuals are not contagious at the post-symptomatic stage of the infection.