B lymphocytes in COVID-19: a tale of harmony and discordance.

B lymphocytes play a vital role in the human defense against viral infections by producing specific antibodies. They are also critical for the prevention of infectious diseases by vaccination, and their activation influences the efficacy of the vaccination. Since the beginning of coronavirus disease 2019 (COVID-19), which became the main concern of the world health system, many efforts have been made to treat and prevent the disease. However, for the development of successful therapeutics and vaccines, it is necessary to understand the interplay between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, and the immune system. The innate immune system provides primary and nonspecific defense against the virus, but within several days after infection, a virus-specific immune response is provided first by antibody-producing B cells, which are converted after the resolution of disease to memory B cells, which provide long-term immunity. Although a failure in B cell activation or B cell dysfunction can cause a severe form of the disease and also lead to vaccination inefficiency, some individuals with B cell immunodeficiency have shown less production of the cytokine IL-6, resulting in a better disease outcome. In this review, we present the latest findings on the interaction between SARS-CoV-2 and B lymphocytes during COVID-19 infection.

Paying Attention to Circadian Rhythms in the Treatment of COVID-19

The bidirectional association between the circadian system and innate-adaptive immune functions has been highlighted in many investigations. Viruses are a submicroscopic infectious agent that activate the immune system after entering the human host cell. A novel virus, so-called Coronavirus Disease 2019 (COVID-19), which has recently emerged, is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Previous investigations show that the factors that are strongly controlled by circadian rhythms, such as clock genes and melatonin, modulate the immune response and may, therefore, influence the healing processes of COVID-19. Moreover, the mechanism of COVID-19 shows that some host cell factors, such as an angiotensin-converting enzyme, exhibit daily rhythms. In this review, we explore key findings that show a link between circadian rhythms and viral infection. The results of these findings could be helpful for clinical and preclinical studies to discover a useful and highly effective treatment for eradicating the COVID-19 disease.

Reactogenicity within the first week after Sinopharm, Sputnik V, AZD1222, and COVIran Barekat vaccines: findings from the Iranian active vaccine surveillance system.

BACKGROUND: This study aimed to evaluate the reactogenicity effects of COVID-19 vaccines, used in Iran. METHODS: At least 1000 people were followed up with phone calls or self-report in a mobile application within 7 days after vaccination. Local and systemic reactogenicities were reported overall and by subgroups. RESULTS: The presence of one or more local and systemic adverse effects after the first dose of vaccines was 58.9% [(95% Confidence Intervals): 57.5-60.3)] and 60.5% (59.1-61.9), respectively. These rates were reduced to 53.8% (51.2-55.0) and 50.8% (48.8-52.7) for the second dose. The most common local adverse effect reported for all vaccines was pain in the injection site. During the first week after the first dose of vaccines, the frequency of the pain for Sinopharm, AZD1222, Sputnik V, and Barekat was 35.5%, 86.0%, 77.6%, and 30.9%, respectively. The same rates after the second dose were 27.3%, 66.5%, 63.9%, and 49.0%. The most common systemic adverse effect was fatigue. In the first dose, it was 30.3% for Sinopharm, 67.4% for AZD1222, 47.6% for Sputnik V, and 17.1% for Barekat. These rates were reduced to 24.6%, 37.1%, 36.5%, and 19.5%, in the second dose of vaccines. AZD1222 had the highest local and systemic adverse effects rates. The odds ratio of local adverse effects of the AZD1222 vaccine compared to the Sinopharm vaccine were 8.73 (95% CI 6.93-10.99) in the first dose and 4.14 (95% CI 3.32-5.17) in the second dose. Barekat and Sinopharm had the lowest frequency of local and systemic adverse effects. Compared to Sinopharm, systemic adverse effects were lower after the first dose of Barekat (OR = 0.56; 95% CI 0.46-0.67). Reactogenicity events were higher in women and younger people. Prior COVID-19 infection increased the odds of adverse effects only after the first dose of vaccines. CONCLUSIONS: Pain and fatigue were the most common reactogenicities of COVID-19 vaccination. Reactogenicities were less common after the second dose of the vaccines. The adverse effects of AZD1222 were greater than those of other vaccines.

COVID-19 cases, hospitalizations and deaths after vaccination: a cohort event monitoring study, Islamic Republic of Iran.

Objective: To investigate the incidence of coronavirus disease 2019 (COVID-19) cases, hospitalizations and deaths in Iranians vaccinated with either AZD1222 Vaxzevria, CovIran® vaccine, SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) or Sputnik V. Methods: We enrolled individuals 18 years or older receiving their first COVID-19 vaccine dose between April 2021 and January 2022 in seven Iranian cities. Participants completed weekly follow-up surveys for 17 weeks (25 weeks for AZD1222) to report their COVID-19 status and hospitalization. We used Cox regression models to assess risk factors for contracting COVID-19, hospitalization and death. Findings: Of 89 783 participants enrolled, incidence rates per 1 000 000 person-days were: 528.2 (95% confidence interval, CI: 514.0-542.7) for contracting COVID-19; 55.8 (95% CI: 51.4-60.5) for hospitalization; and 4.1 (95% CI: 3.0-5.5) for death. Compared with SARS-CoV-2 Vaccine (Vero Cell), hazard ratios (HR) for contracting COVID-19 were: 0.70 (95% CI: 0.61-0.80) with AZD1222; 0.73 (95% CI: 0.62-0.86) with Sputnik V; and 0.73 (95% CI: 0.63-0.86) with CovIran®. For hospitalization and death, all vaccines provided similar protection 14 days after the second dose. History of COVID-19 protected against contracting COVID-19 again (HR: 0.76; 95% CI: 0.69-0.84). Diabetes and respiratory, cardiac and renal disease were associated with higher risks of contracting COVID-19 after vaccination. Conclusion: The rates of contracting COVID-19 after vaccination were relatively high. SARS-CoV-2 Vaccine (Vero Cell) provided lower protection against COVID-19 than other vaccines. People with comorbidities had higher risks of contracting COVID-19 and hospitalization and should be prioritized for preventive interventions.

COVID-19 cases, hospitalizations and deaths after vaccination: a cohort event monitoring study, Islamic Republic of Iran Cas, hospitalisations et décès liés à la COVID-19 après la vaccination: étude de cohorte portant sur la surveillance des événements en République islamique d'Iran Casos, hospitalizaciones y muertes por la COVID-19 tras la vacunación: un estudio de cohortes sobre el seguimiento de eventos en la República Islámica de Irán حالات كوفيد 19، حالات الاستشفاء والوفيات بعد التطعيم: دراسة رصد إترابي للأحداث، جمهورية إيران الإسلامية 接种疫苗后的新冠肺炎病例、住院率以及死亡率：伊朗伊斯兰共和国的一项事件监测队列研究 Случаи заражения COVID-19, госпитализации и смерти после вакцинации: когортное исследование мониторинга событий, Исламская Республика Иран

Objective To investigate the incidence of coronavirus disease 2019 (COVID-19) cases, hospitalizations and deaths in Iranians vaccinated with either AZD1222 Vaxzevria, CovIran® vaccine, SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) or Sputnik V. Methods We enrolled individuals 18 years or older receiving their first COVID-19 vaccine dose between April 2021 and January 2022 in seven Iranian cities. Participants completed weekly follow-up surveys for 17 weeks (25 weeks for AZD1222) to report their COVID-19 status and hospitalization. We used Cox regression models to assess risk factors for contracting COVID-19, hospitalization and death. Findings Of 89 783 participants enrolled, incidence rates per 1 000 000 person-days were: 528.2 (95% confidence interval, CI: 514.0–542.7) for contracting COVID-19;55.8 (95% CI: 51.4–60.5) for hospitalization;and 4.1 (95% CI: 3.0–5.5) for death. Compared with SARS-CoV-2 Vaccine (Vero Cell), hazard ratios (HR) for contracting COVID-19 were: 0.70 (95% CI: 0.61−0.80) with AZD1222;0.73 (95% CI: 0.62–0.86) with Sputnik V;and 0.73 (95% CI: 0.63–0.86) with CovIran®. For hospitalization and death, all vaccines provided similar protection 14 days after the second dose. History of COVID-19 protected against contracting COVID-19 again (HR: 0.76;95% CI: 0.69–0.84). Diabetes and respiratory, cardiac and renal disease were associated with higher risks of contracting COVID-19 after vaccination. Conclusion The rates of contracting COVID-19 after vaccination were relatively high. SARS-CoV-2 Vaccine (Vero Cell) provided lower protection against COVID-19 than other vaccines. People with comorbidities had higher risks of contracting COVID-19 and hospitalization and should be prioritized for preventive interventions.

Recent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects.

In the last decade, the development of messenger RNA (mRNA) therapeutics by lipid nanoparticles (LNP) leads to facilitate clinical trial recruitment, which improves the efficacy of treatment modality to a large extent. Although mRNA-LNP vaccine platforms for the COVID-19 pandemic demonstrated high efficiency, safety and adverse effects challenges due to the uncontrolled immune responses and inappropriate pharmacological interventions could limit this tremendous efficacy. The current study reveals the interplay of immune responses with LNP compositions and characterization and clarifies the interaction of mRNA-LNP therapeutics with dendritic, macrophages, neutrophile cells, and complement. Then, pharmacological profiles for mRNA-LNP delivery, including pharmacokinetics and cellular trafficking, were discussed in detail in cancer types and infectious diseases. This review study opens a new and vital landscape to improve multidisciplinary therapeutics on mRNA-LNP through modulation of immunopharmacological responses in clinical trials.

Type-I interferons in the immunopathogenesis and treatment of Coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is currently the major global health problem. Still, it continues to infect people globally and up to the end of February 2022, over 436 million confirmed cases of COVID-19, including 5.95 million deaths, were reported to the world health organization (WHO). No specific treatment is currently available for COVID-19, and the discovery of effective therapeutics requires understanding the effective immunologic and immunopathologic mechanisms behind this infection. Type-I interferons (IFN-Is), as the critical elements of the immediate immune response against viral infections, can inhibit the replication and spread of the viruses. However, the available evidence shows that the antiviral IFN-I response is impaired in patients with the severe form of COVID-19. Moreover, the administration of exogenous IFN-I in different phases of the disease can lead to various outcomes. Therefore, understanding the role of IFN-I molecules in COVID-19 development and its severity can provide valuable information for better management of this disease. This review summarizes the role of IFN-Is in the pathogenesis of COIVD-19 and discusses the importance of autoantibodies against this cytokine in the spreading of SARS-CoV-2 and control of the subsequent excessive inflammation.

Molecular variants of SARS-CoV-2: antigenic properties and current vaccine efficacy.

An ongoing pandemic of newly emerged SARS-CoV-2 has puzzled many scientists and health care policymakers around the globe. The appearance of the virus was accompanied by several distinct antigenic changes, specifically spike protein which is a key element for host cell entry of virus and major target of currently developing vaccines. Some of these mutations enable the virus to attach to receptors more firmly and easily. Moreover, a growing number of trials are demonstrating higher transmissibility and, in some of them, potentially more serious forms of illness related to novel variants. Some of these lineages, especially the Beta variant of concern, were reported to diminish the neutralizing activity of monoclonal and polyclonal antibodies present in both convalescent and vaccine sera. This could imply that these independently emerged variants could make antiviral strategies prone to serious threats. The rapid changes in the mutational profile of new clades, especially escape mutations, suggest the convergent evolution of the virus due to immune pressure. Nevertheless, great international efforts have been dedicated to producing efficacious vaccines with cutting-edge technologies. Despite the partial decrease in vaccines efficacy against worrisome clades, most current vaccines are still effective at preventing mild to severe forms of disease and hospital admission or death due to coronavirus disease 2019 (COVID-19). Here, we summarize existing evidence about newly emerged variants of SARS-CoV-2 and, notably, how well vaccines work against targeting new variants and modifications of highly flexible mRNA vaccines that might be required in the future.

Design strategies for antiviral coatings and surfaces: A review

The routine disinfection and sanitization of surfaces, objects, and textiles has become a time-consuming but necessary task for managing the COVID-19 pandemic. Nonetheless, the excessive use of sanitizers and disinfectants promotes the development of antibiotic-resistant microbes. Moreover, that improper disinfection could lead to more virus transfer, which leads to more viral mutations. Recently developed antiviral surface coatings can reduce the reliance on traditional disinfectants. These surfaces remain actively antimicrobial between periods of active cleaning of the surfaces, allowing a much more limited and optimized use of disinfectants. The novel nature of these surfaces has led, however, to many inconsistencies within the rapidly growing literature. Here we provide tools to guide the design and development of antimicrobial and antiviral surfaces and coatings. We describe how engineers can best choose testing options and propose new avenues for antiviral testing. After defining testing protocols, we summarize potential inorganic and organic materials able to serve as antiviral surfaces and present their antiviral mechanisms. We discuss the main limitations to their application, including issues related to toxicity, antimicrobial resistance, and environmental concerns. We propose solutions to counter these limitations and highlight how the context of specific use of an antiviral surface must guide material selection. Finally, we discuss how the use of coatings that combine multiple antimicrobial mechanisms can avoid the development of antibiotic resistance and improve the antiviral properties of these surfaces.

Long-Term Persistence of Anti-SARS-COV-2 IgG Antibodies.

Antibodies against severe acute respiratory syndrome coronavirus-2 (Anti-SARS-COV-2) can be detected in patients with COVID-19 in 7 to 10 days post onset of symptoms (POS). However, there is no firm evidence of the long-term persistence of these antibodies in recovered COVID-19 patients. Therefore, this study aimed to evaluate the stability of anti-SARS-COV-2 IgG in recovered COVID-19 patients in a 15-month follow-up testing. Thirty hospitalized patients with real-time PCR-confirmed SARS-COV-2 infections were included in the study and five serum samples (1st, 2nd, 3rd, 4th, and 5th) were collected from each participant. The serum levels of N and S specific anti-SARS-COV-2 IgG and IgM antibodies were evaluated by the immunoassay technique at the same time. To determine the correlation between levels of anti-SARS-CoV-2 IgG/IgM with severity of disease, neutrophil-to-lymphocyte ratio (NLR %), and the serum levels of C-reactive protein were evaluated using an automated analyzer and turbidimetry assays, respectively. The mean serum level of anti-SARS-CoV-2 IgG antibody was at the highest level up to 90 days and then decreased significantly 1 year POS (P < 0.0001). However, it was still detectable in a 15-month follow-up testing. There were no significant differences in the mean levels of IgG antibody in patients with mild, moderate, and severe diseases. The results from this study suggest that the titer of anti-SARS-COV-2 IgG antibody is detectable at high levels up to 3 months and then decreases over time. However, these antibodies can be reliably detected in up to 15 months, and they may persist for a long time.

Investigation of the Molecular Mechanism of Coagulopathy in Severe and Critical Patients With COVID-19.

Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PTCRT (15.014) and PTSVR (13.846) (PTCRL = 13.383, p < 0.001), PTTCRT (42.923) and PTTSVR (37.8) (PTTCRL = 36.494, p < 0.001), LACCRT (49.414) and LACSVR (47.046) (LACCRL = 40.763, p < 0.001), FIBCRT (537.66) and FIBSVR (480.29) (FIBCRL = 283.57, p < 0.001), ProCCRT (85.57%) and ProCSVR (99.34%) (ProCCRL = 94.31%, p = 0.04), ProSCRT (62.91%) and ProSSVR (65.06%) (ProSCRL = 75.03%, p < 0.001), D-dimer (p < 0.0001, χ2 = 34.812), and FDP (p < 0.002, χ2 = 15.205). No significant association was found in the ATIII results in groups (ATIIICRT = 95.71% and ATIIISVR = 99.63%; ATIIICRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p-values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.

Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective.

The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people worldwide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the crucial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1ß levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utilization of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection.

Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management.

COVID-19 pandemic is a serious concern in the new era. Acute respiratory distress syndrome (ARDS), and lung failure are the main lung diseases in COVID-19 patients. Even though COVID-19 vaccinations are available now, there is still an urgent need to find potential treatments to ease the effects of COVID-19 on already sick patients. Multiple experimental drugs have been approved by the FDA with unknown efficacy and possible adverse effects. Probably the increasing number of studies worldwide examining the potential COVID-19 related therapies will help to identification of effective ARDS treatment. In this review article, we first provide a summary on immunopathology of ARDS next we will give an overview of management of patients with COVID-19 requiring intensive care unit (ICU), while focusing on the current treatment strategies being evaluated in the clinical trials in COVID-19-induced ARDS patients.

Azithromycin: Immunomodulatory and antiviral properties for SARS-CoV-2 infection.

Azithromycin, a member of the macrolide family of antibiotics, is commonly used to treat respiratory bacterial infections. Nevertheless, multiple pharmacological effects of the drug have been revealed in several investigations. Conceivably, the immunomodulatory properties of azithromycin are among its critical features, leading to its application in treating inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Additionally, azithromycin may directly inhibit viral load as well as its replication, or it could demonstrate indirect inhibitory impacts that might be associated with the expression of antiviral genes. Currently, coronavirus disease 2019 (COVID-19) is an extra urgent issue affecting the entire world, and it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute respiratory distress syndrome (ARDS), which is associated with hyper inflammation due to cytokine release, is among the leading causes of death in COVID-19 patients with critical conditions. The present paper aims to review the immunomodulatory and antiviral properties of azithromycin as well as its potential clinical applications in the management of COVID-19 patients.

Immunopharmacological perspective on zinc in SARS-CoV-2 infection.

The novel SARS-CoV-2 which was first reported in China is the cause of infection known as COVID-19. In comparison with other coronaviruses such as SARS-CoV and MERS, the mortality rate of SARS-CoV-2 is lower but the transmissibility is higher. Immune dysregulation is the most common feature of the immunopathogenesis of COVID-19 that leads to hyperinflammation. Micronutrients such as zinc are essential for normal immune function. According to the assessment of WHO, approximately one-third of the world's society suffer from zinc deficiency. Low plasma levels of zinc are associated with abnormal immune system functions such as impaired chemotaxis of polymorphonuclear cells (PMNs) and phagocytosis, dysregulated intracellular killing, overexpression of the inflammatory cytokines, lymphopenia, decreased antibody production, and sensitivity to microbes especially viral respiratory infections. Zinc exerts numerous direct and indirect effects against a wide variety of viral species particularly RNA viruses. The use of zinc and a combination of zinc-pyrithione at low concentrations impede SARS-CoV replication in vitro. Accordingly, zinc can inhibit the elongation step of RNA transcription. Furthermore, zinc might improve antiviral immunity by up-regulation of IFNα through JAK/STAT1 signaling pathway in leukocytes. On the other hand, zinc supplementation might ameliorate tissue damage caused by mechanical ventilation in critical COVID-19 patients. Finally, zinc might be used in combination with antiviral medications for the management of COVID-19 patients. In the current review article, we review and discuss the immunobiological roles and antiviral properties as well as the therapeutic application of zinc in SARS-CoV-2 and related coronaviruses infections.

Neurological manifestations of COVID-19: with emphasis on Iranian patients.

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has instigated a global pandemic as a formidable and highly contagious infectious disease. Although the respiratory system remains the most frequently affected organ, several case reports have revealed that the complications are not merely limited to the respiratory system, and neurotropic and neuroinvasive properties have also been observed, leading to neurological diseases. In the present paper, it was intended to review the possible neuroinvasive routes of SARS-CoV-2 and its mechanisms that may cause neurological damage. Additionally, the neurological manifestations of COVID-19 across the globe were discussed with emphasis on Iran, while highlighting the impact of SARS-CoV-2 on the central and peripheral nervous systems.

Advances in immunotherapy for COVID-19: A comprehensive review.

COVID-19 is an acute respiratory syndrome caused by SARS-COV-2 which has now become a huge pandemic worldwide. The immunopathogenesis of COVID-19 has been established that increased serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and reduction of the CD4+ and the CD8+ T lymphocyte populations, are the most reported immunological findings in these patients. High levels of other inflammatory cytokines and chemokines such as IL-2 and IL-8 with an increased number of neutrophils and eosinophils may induce immune abnormalities in patients with COVID-19. There is growing evidence to obtain a deeper understanding of the immunopathogenesis of COVID-19 which will lay the foundation for the development of new potential therapies. However, specific and non-specific immunotherapies such as convalescent plasma (CP) are widely performed to treat patients with severe COVID-19, there is no definitive evidence to suggest the effectiveness of these treatments. Hence, this review aimed to highlight the current and most recent studies to identify the new immunotherapeutics for COVID-19 disease.

Monocytes and macrophages in COVID-19: Friends and foes.

The COVID-19 is a novel infectious disease caused by SARS-CoV-2 and is known as a pandemic emergency that has led to a high rate of mortality throughout the world. Evidence has indicated that hyperinflammatory responses triggered by SARS-CoV-2 are the main cause of pathogenicity in the severe cases of patients who have died during the current viral disease. Monocytes and macrophages as the most important cells of the innate arm of the immune system play a substantial part in the body's defense against viral infections. They mainly respond to the microbial antigens by producing inflammatory mediators to remove pathogens and repair tissue injury. Nevertheless, aberrant alterations in their function such as cytokine storm can be so harmful to the host in the acute respiratory distress syndrome cases caused by SARS-CoV-2. Moreover, inflammatory responses stimulated by SARS-CoV-2 have affected the other vital organs of the body including the heart. As cardiovascular complications in COVID-19 patients have been reported in several studies. During the infection, monocytes and macrophages may be involved in the hypersensitive and exacerbated reactions that contribute to the tissue damage, especially lung injury resulted in its dysfunction and respiratory disorder. In this review, we discuss both advantageous and disadvantageous about the pathological potential of monocytes and macrophages during the infection of SARS-CoV-2 to clarify their mutual effects on immune processing as a fist line defender in the current disease.