Omicron SARS-CoV-2 Spike-1 Protein's Decreased Binding Affinity to α7nAChr: Implications for Autonomic Dysregulation of the Parasympathetic Nervous System and the Cholinergic Anti-Inflammatory Pathway—An In Silico Analysis

Omicron is the dominant strain of COVID-19 in the United States and worldwide. Although this variant is highly transmissible and may evade natural immunity, vaccines, and therapeutic antibodies, preclinical results in animal models and clinical data in humans suggest omicron causes a less severe form of infection. The molecular basis for the attenuation of virulence when compared to previous variants is currently not well understood. Using protein–ligand docking simulations to evaluate and compare the capacity of SARS-CoV-2 spike-1 proteins with the different COVID-19 variants to bind to the human α7nAChr (i.e., the core receptor under the control of the vagus nerve regulating the parasympathetic nervous system and the cholinergic anti-inflammatory pathway), we found that 10 out of the 14 mutated residues on the RBD of the B.1.1.529 (Omicron) spike, compared to between 0 and 2 in all previous variants, were present at the interaction interface of the α7nAChr. We also demonstrated, through protein–protein docking simulations, that these genetic alterations cause a dramatic decrease in the ability of the Omicron SARS-CoV-2 spike-1 protein to bind to the α7nAChr. These results suggest, for the first time, that the attenuated nature of Omicron infection in humans and animals compared to previous variants may be attributable to a particular set of genetic alterations, specifically affecting the binding site of the SARS-CoV-2 spike-1 protein to the α7nAChr. [ FROM AUTHOR]

In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds

Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of ivermectin and 14 related compounds, by which the infectivity and morbidity of the SARS-CoV-2 virus may be limited. Binding affinity computations were performed for these agents on several docking sites each for models of (1) the spike glycoprotein of the virus, (2) the CD147 receptor, which has been identified as a secondary attachment point for the virus, and (3) the alpha-7 nicotinic acetylcholine receptor (α7nAChr), an indicated point of viral penetration of neuronal tissue as well as an activation site for the cholinergic anti-inflammatory pathway controlled by the vagus nerve. Binding affinities were calculated for these multiple docking sites and binding modes of each compound. Our results indicate the high affinity of ivermectin, and even higher affinities for some of the other compounds evaluated, for all three of these molecular targets. These results suggest biological mechanisms by which ivermectin may limit the infectivity and morbidity of the SARS-CoV-2 virus and stimulate an α7nAChr-mediated anti-inflammatory pathway that could limit cytokine production by immune cells.

Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial.

Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. Design, Setting, and Participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). Main Outcomes and Measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). Conclusions and Relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. Trial Registration: ClinicalTrials.gov Identifier: NCT04364737.

Hyperimmune plasma infusion in an immunocompromised Covid-19 patient previously treated for follicular lymphoma.

Covid-19 in immunocompromised patients shows a prolonged course and may lead to a poor prognosis. Although data on hyperimmune plasma for treatment of Covid-19 suggest an improved outcome in immunocompetent patients, limited data are currently available in immunocompromised patients. We present the case of a 62-year-old Caucasian woman, who was previously treated with obinutuzumab and bendamustine for follicular lymphoma and showed a prolonged positive test for Covid-19. Since no improvement was observed with standard of care (including remdesivir), the possibility of hyperimmune plasma infusion was discussed. A first dose of hyperimmune plasma was administered, with subsequent onset of fever, increasing inflammatory indexes and worsening radiological findings. Three days later a second dose of plasma was administered. Within twelve hours cough and fever disappeared, and oxygen at rest was discontinued. The patient was discharged 5 days later, and nasopharyngeal swabs resulted negative 16 days after discharge.