Safety and immunogenicity of a recombinant receptor-binding domain-based protein subunit vaccine (Noora vaccine™) against COVID-19 in adults: A randomized, double-blind, placebo-controlled, Phase 1 trial.

The development of a safe and effective vaccine is essential to protect populations against coronavirus disease 2019 (COVID-19). There are several vaccine candidates under investigation with different mechanisms of action. In the present study, we have evaluated the safety and immunogenicity of a recombinant receptor-binding domain (RBD)-based protein subunit vaccine (Noora vaccine) against COVID-19 in adults. This Phase 1 trial is a randomized, double-blind, placebo-controlled study to evaluate the safety and immunogenicity of the recombinant RBD-based protein subunit vaccine (Noora vaccine) against COVID-19 in healthy adults volunteers. Eligible participants were included in this study after evaluating their health status and considering the exclusion criteria. They were then randomized into three groups and received three doses of vaccine (80 µg, 120 µg, and placebo) on Days 0, 21, and 35. Primary outcomes including solicited, unsolicited, and medically attended adverse events were recorded during this study. Secondary outcomes including the humoral and cellular immunity (including anti-RBD IgG antibody and neutralizing antibody) were measured on Days 0, 21, 28, 35, 42, and 49 by using the ELISA kit and the Virus Neutralization Test (VNT) was performed on day 49. Totally 70 cases were included in this Phase 1 trial and 60 of them completed the study. Safety assessments showed no severe adverse events. Local pain at the vaccine injection site occurred in 80% of the vaccinated volunteers. Induration and redness at the injection site were the other adverse reactions of this vaccine. There was no significant difference between the studied groups regarding adverse reactions. Anti-RBD IgG antibody and neutralizing antibody assessment showed significant seroconversion in comparison to the placebo group (80%, and 100% respectively, p < 0.001). The cellular immunity panel also showed mild to moderate induction of TH1 responses and the VNT showed 78% of seroprotection. The results of this Phase 1 trial showed acceptable safety without serious adverse events and significant seroconversions in the humoral and cellular immunity panel. The dose of 80 µg is an appropriate dose for injection in the next phases of the trial.

Melatonin as a complementary and prophylactic agent against COVID-19 in high-risk populations: A narrative review of recent findings from clinical and preclinical studies.

The coronavirus disease 2019 (COVID-19) pandemic has been going on around the world for more than a year and has cost a lot, as well as affected the quality of life of many. The psychological stress like delirium and sleep disturbances caused by the COVID-19 has affected many people in direct or indirect way by the disease. Insomnia and sleep deprivation have a negative effect on the immune system as well as disorders of the hormonal system, including the production and secretion of melatonin, known as the sleep hormone. Melatonin is a known anti-inflammatory and antioxidant agent in addition to its role in regulating circadian rhythms. In this review, we investigated the relationship between the effect of psychological stress caused by COVID-19 on patients, their families, health care workers, and occupations as well as how melatonin might act as a prophylactic agent with sedative effects and sleep enhancement potential. Search terms "melatonin" and "COVID-19" were manually searched on PubMed or other electronic database and relevant articles were included. Based on the review of scholarly articles, it can be inferred that melatonin, as an endogenous hormone controlling and regulating sleep and wakefulness in various researches, has a good potential due to its antioxidant and anti-inflammatory with minimal side effects. These beneficial effects highlight the impact of melatonin as an adjuvant and a potential alternative for the better management of SARS-CoV-2 infection in high-risk populations.

NLRP3 inflammasome activation and oxidative stress status in the mild and moderate SARS-CoV-2 infected patients: impact of melatonin as a medicinal supplement.

The inflammasome as a multiprotein complex has a role in activating ASC and caspase-1 resulting in activating IL-1ß in various infections and diseases like corona virus infection in various tissues. It was shown that these tissues are affected by COVID-19 patients. According to the current evidence, melatonin is not veridical while possessing a high safety profile, however, it possesses indirect anti-viral actions owing to its anti-oxidation, anti-inflammation, and immune improving properties. This study aims to assess the impacts of melatonin as the complementary treatments on oxidative stress agents and inflammasome activation in patients with COVID-19. Melatonin supplement (9 mg daily, orally) was provided for the patients hospitalized with a COVID-19 analysis for 14 days. For measuring IL-10, IL-1ß, and TNF-α cytokines and malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) level and the expression of CASP1 and ASC genes, blood samples were gathered from the individuals at the start and termination of the therapy. Our findings indicated that melatonin is used as a complementary treatment to reduce the levels of TNF-α and IL-1ß cytokines, MDA, and NO levels in COVID-19 patients and significantly increase SOD level, however, the levels of IL-10 cytokine possesses no considerable changes. The findings revealed that genes of CASP1 and ASC were dysregulated by melatonin regulating the inflammasome complex. Based on the findings of the current study, it is found that melatonin can be effective as a medicinal supplement in decreasing the inflammasome multiprotein complex and oxidative stress along with beneficial impacts on lung cytokine storm of COVID-19 patients.

Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial.

BACKGROUND: Melatonin has been known as an anti-inflammatory agent and immune modulator that may address progressive pathophysiology of coronavirus disease 2019 (COVID-19). AIM OF THE STUDY: To evaluate the clinical efficacy of adjuvant, use of melatonin in patients with COVID-19. METHODS: This single-center, double-blind, randomized clinical trial included 74 hospitalized patients with confirmed mild to moderate COVID-19 at Baqiyatallah Hospital in Tehran, Iran, from April 25, 2020-June 5, 2020. Patients were randomly assigned in a 1:1 ratio to receive standard of care and standard of care plus melatonin at a dose of 3 mg three times daily for 14 d. Clinical characteristics, laboratory, and radiological findings were assessed and compared between two study groups at baseline and post-intervention. Safety and clinical outcomes were followed up for four weeks. RESULTS: A total of 24 patients in the intervention group and 20 patients in the control group completed the treatment. Compared with the control group, the clinical symptoms such as cough, dyspnea, and fatigue, as well as the level of CRP and the pulmonary involvement in the intervention group had significantly improved (p <0.05). The mean time of hospital discharge of patients and return to baseline health was significantly shorter in the intervention group compared to the control group (p <0.05). No deaths and adverse events were observed in both groups. CONCLUSIONS: Adjuvant use of melatonin has a potential to improve clinical symptoms of COVID-19 patients and contribute to a faster return of patients to baseline health.

Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment.

Coronavirus (SARS-CoV-2) is spreading rapidly in the world and is still taking a heavy toll. Studies show that cytokine storms and imbalances in T-helper (Th)1/Th2 play a significant role in most acute cases of the disease. A number of medications have been suggested to treat or control the disease but have been discontinued due to their side effects. Melatonin, as an intrinsic molecule, possesses pharmacological anti-inflammatory and antioxidant properties that decreases in concentration with age; as a result, older people are more prone to various diseases. In this study, patients who were hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) were given a melatonin adjuvant (9 mg daily, orally) for fourteen days. In order to measure markers of Th1 and Th2 inflammatory cytokines (such as interleukin (IL)-2, IL-4, and interferon (IFN)-γ) as well as the expression of Th1 and Th2 regulatory genes (signal transducer and activator of transcription (STAT)4, STAT6, GATA binding protein 3 (GATA3), and T-box expressed in T cell (T-bet)), blood samples were taken from patients at the beginning and end of the treatment. Adjuvant therapy with melatonin controlled and reduced inflammatory cytokines in patients with COVID-19. Melatonin also controlled and modulated the dysregulated genes that regulate the humoral and cellular immune systems mediated by Th1 and Th2. In this study, it was shown for the first time that melatonin can be used as a medicinal adjuvant with anti-inflammatory mechanism to reduce and control inflammatory cytokines by regulating the expression of Th1 and Th2 regulatory genes in patients with COVID-19.

Ozone therapy for the treatment of COVID-19 pneumonia: A scoping review.

Severe forms of COVID-19 can evolve into pneumonia, featured by acute respiratory failure due to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In viral diseases, the replication of viruses is seemingly stimulated by an imbalance between pro-oxidant and antioxidant activity as well as by the deprivation of antioxidant mechanisms. In COVID-19 pneumonia, oxidative stress also appears to be highly detrimental to lung tissues. Although inhaling ozone (O3) gas has been shown to be toxic to the lungs, recent evidence suggests that its administration via appropriate routes and at small doses can paradoxically induce an adaptive reaction capable of decreasing the endogenous oxidative stress. Ozone therapy is recommended to counter the disruptive effects of severe COVID-19 on lung tissues, especially if administered in early stages of the disease, thereby preventing the progression to ARDS.

Epidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in IRAN: A single center study.

BACKGROUND: An outbreak of COVID-19 in Iran has spread throughout the country. Identifying the epidemiological characteristics of this disease will help to make appropriate decisions and thus control the epidemic. The aim of this study was characterization of the epidemiological features of COVID-19 in Iran. METHODS: In this retrospective study, data related to the epidemiological characteristics of COVID-19 patients admitted to Baqiyatallah Hospital in Tehran, Iran, from 19 February 2020 to 15 April 2020 have been analyzed and reported. Patient characteristics including age, gender and underlying diseases were investigated. Data were collected through patient records. Sex ratio, Case Fatality Rate (CFR) and daily trend of cases were also determined. A multiple logistic regression analysis was also performed to assess affecting factors on mortality. RESULTS: From February 19, 2020 to April 15, 2020, 12870 patients referred to the hospital emergency department, of which 2968 were hospitalized with COVID-19 diagnosis. The majority of cases were in the age group of 50 to 60 years of old. The male-to-female ratio was 1.93:1. A total of 239 deaths occurred among all cases for an overall CFR of 1.85% based on the total number of patients (both outpatient and inpatient) and 8.06% among hospitalized patients. Out of all patients 10.89% had comorbidity. Diabetes, chronic respiratory diseases, hypertension, cardiovascular diseases, chronic Kidney diseases and cancer were the most common comorbidities with 3.81, 2.02 , 1.99 , 1.25, 0.60 and 0.57 %, respectively. Male gender (OR=1.45, 95% CI: 1.08-1.96), older age (OR=1.05, 95% CI: 1.04-1.06) and having underlying diseases (OR=1.53, 95% CI: 1.04-2.24) were significantly associated with mortality. CONCLUSIONS: The results of this study showed that Male gender, older age and having comorbidities were significantly associated with the risk of death among COVID-19 patients. It is important to pay special attention to male elderly patients with underlying diseases.