Exosomal microRNAs Drive Thrombosis in COVID-19

Thrombotic and thromboembolic complications have been shown to play a critical role in the clinical outcome of COVID-19. Emerging evidence has shown that exosomal miRNAs are functionally involved in a number of physiologic and pathologic processes. However, neither exosomes nor miRNAs have been hitherto investigated in COVID-19. To test the hypothesis that exosomal miRNAs are a key determinant of thrombosis in COVID-19, we enrolled patients positive for COVID-19. Circulating exosomes were isolated from equal amounts of serum and levels of exosomal miRNAs were quantified. We divided our population in two groups based on the serum level of D-dimer on admission. Strikingly, we found that exosomal miR-424 was significantly upregulated whereas exosomal miR-103a, miR-145, and miR-885 were significantly downregulated in patients in the high D-dimer group compared to patients in the low D-Dimer group (p<0.0001).

Negative impact of hyperglycemia on Tocilizumab therapy in COVID-19 patients

Tocilizumab is used for treating moderate-severe Covid-19 pneumonia by targeting IL-6 receptors (IL-6R) and reducing cytokine release, but the pooled rate ratio among diabetic patients with adverse vs those with the more favorable course was 2.26. To date, the hyperglycemia has been shown to increase IL-6 and IL-6R, which has been suggested as a severity predictor in lung diseases of Covid-19 patients. However, there are no data about the effects of tocilizumab therapy on outcomes of hyperglycemic Covid-19 patients with pneumonia. To investigate this unsolved need, 475 Covid-19 positive patients were retrospectively studied since March 1st, 2020. Among them, 78 patients with pneumonia disease and treated with tocilizumab were further evaluated for a severe outcome (encompassing both the use of mechanical ventilation and/or death). Thirty-one (39.7%) hyperglycemic and 47 (60.3%) normoglycemic Covid-19 positive patients (blood glucose levels >140 mg/dl, at admission and/or during hospital stay) were evaluated. Noteworthy, 20 (64%) of hyperglycemic and 11 (23.4%) of normoglycemic patients were also diabetics (P<0.01). At admission, more elevated IL-6 levels in hyperglycemic patients were found and persists even after Tocilizumab administration. In a risk adjusted Cox-regression analysis, Tocilizumab in hyperglycemic did not attenuate the risks of severe outcome as did in normoglycemic patients (p<0.009). Therefore, we could conclude that reduced effects of Tocilizumab in hyperglycemic patients may due to the higher plasma IL-6 levels. Interestingly, when we added IL-6 levels in a Cox regression model the significance for the tocilizumab effect was lost (p<0.07). In this context, our observations evidence that optimal Covid-19 infection management with tocilizumab is not achieved during hyperglycemia both in diabetic and non-diabetic patients.

GRAd-COV2 vaccine provides potent and durable immunity in a randomised placebo-controlled phase 2 trial (COVITAR)

BackgroundSARS-CoV-2 ongoing pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccines portfolio. We report safety and immunogenicity of GRAd-COV2, a novel gorilla adenovirus-based COVID-19 vaccine, in a phase 2 trial aimed at identifying the appropriate dose and schedule. Method917 eligible adults aged 18 years or older, including participants with co-morbidities, were randomised to receive, 21 days apart, a single vaccine administration at 2x1011 viral particles (vp) followed by placebo, or repeated vaccine administration at 1x1011 vp, or two doses of placebo. Primary endpoints were the incidence of local and systemic solicited AEs for 7 days post each dose and the post-treatment (35 days after the first dose), geometric mean titers (GMTs) and geometric mean fold rise (GMFRs) of ELISA antibody responses to Spike protein. Additional humoral and cellular immune response parameters were monitored for up to six months. ResultsThe safety profile of GRAd-COV2 was characterized by short-term, mild-to-moderate pain and tenderness at injection site, fatigue, headache, malaise, and myalgia. Neither related SAEs nor deaths were reported. Humoral (binding and neutralizing) Ab responses peaked at day 35 after a single administration, were boosted by a second vaccination, were sustained until day 57 to then decline at day 180. Potent, VOC cross-reactive T cell responses peaked already after first dose with high frequencies of long-lived CD8 T cells. ConclusionGRAd-COV2 was safe, and induced robust immune responses after a single immunization; the second administration increased humoral but not cellular immune responses. Trial RegistrationClinicalTrials.gov NCT04791423. FundingReiThera Srl