Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study (original) (raw)
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Immunomodulation in COVID-19: A Review of Literature
Scholars Journal of Medical Case Reports
The outbreak of novel corona virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 in Wuhan, China caused a worldwide pandemic. Both symptomatic and asymptomatic carriers were responsible for the transmission of the diseases. Many studies showed high infectivity of the virus. It is therefore urgent to control the transmission of the virus and treat patients infected with SARS-CoV-2 virus. Many evidences have suggested that involvement of human hyperactivation and severe acute respiratory syndrome plays an important role in pathogenesis of critically ill patients with COVID-19. Therefore, repurposing of approved drugs has been used to tackle COVID-19 as the pharmacokinetic and safety profile of these drugs are known. Several immunomodulatory drugs such as disease modifying anti-rheumatic drugs (DMARD) have been proposed as potential therapies for treatment of COVID-19. In this Review we discuss human immune response to virus, pathogenesis of COVID-...
Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review
BioNanoScience
Coronavirus infection can have various degrees of severity and outcomes. In some cases, it causes excessive production of pro-inflammatory cytokines, a so-called cytokine storm, leading to acute respiratory distress syndrome. Unfortunately, the exact pathophysiology and treatment, especially for severe cases of COVID-19, are still uncertain. Results of preliminary studies showed that immunosuppressive therapy, such as interleukin (IL)-6, IL-1, and TNF-α antagonists commonly used in rheumatology, can be considered as treatment options for COVID-19, especially in severe cases. The review focused on the most common and currently studied monoclonal antibody drugs, as well as up-to-date data on the pathogenesis of COVID-19, host immune response against SARS-CoV-2 and its association with cytokine storm. It also covered effects of interleukin (IL)-6, IL-1, and TNF-α blockers on the course of coronavirus infection and outcome in patients treated for the main autoimmune disease and subsequently infected with COVID-19.
The Lancet, 2022
Background Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of antispike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1•06 (95% CI 0•77-1•45; p=0•72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18•6% vs 9•5% for placebo; p=0•002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0•98, 95% CI 0•66-1•46; p=0•91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2•21, 95% CI 1•14-4•29); for patients who were antibody negative, the OR was 0•51 (0•29-0•90; p interaction =0•001). Interpretation When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry.
Immunomodulatory approaches in managing lung inflammation in COVID-19: A double-edge sword
Introduction: The novel coronavirus infectious disease 2019 (COVID-19) which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a gigantic problem. The lung is the major target organ of SARS-CoV-2 and some of its variants like Delta and Omicron variant adapted in such a way that these variants can significantly damage this vital organ of the body. These variants raised a few eyebrows as the outbreaks have been seen in the vaccinated population. Patients develop severe respiratory illnesses which eventually prove fatal unless treated early. Main Body: Studies have shown that SARS-CoV-2 causes the release of proinflammatory cytokines such as interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α which are mediators of lung inflammation, lung damage, fever, and fibrosis. Additionally, various chemokines have been found to play an important role in the disease progression. A plethora of pro-inflammatory cytokines "cytokine storm" has been observed in severe cases of SARS-CoV-2 infection leading to acute respiratory distress syndrome (ARDS) and pneumonia that may prove fatal. To counteract cytokine storm-inducing lung inflammation, several promising immunomodulatory approaches are being investigated in numerous clinical trials. However, the benefits of using these strategies should outweigh the risks involved as the use of certain immunosuppressive approaches might lead the host susceptible to secondary bacterial infections. Conclusion: The present review discusses promising immunomodulatory approaches to manage lung inflammation in COVID-19 cases which may serve as potential therapeutic options in the future and may prove lifesaving.
The American Journal of Medicine
BACKGROUND: We systematically assessed beneficial and harmful effects of monoclonal antibodies for coronavirus disease 2019 (COVID-19) treatment, and prophylaxis in individuals exposed to severe acute respiratory syndrome coronavirus 2. METHODS: We searched 5 engines and 3 registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19-related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to assess certainty of evidence. RESULTS: Twenty-seven randomized controlled trials were included: 20 in hospitalized patients (n = 8253), 5 in non-hospitalized patients (n = 2922), and 2 in prophylaxis (n = 2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74; 95% confidence interval [CI], 0.60-0.9; I 2 = 20%, low certainty of evidence) and bacteremia (RR 0.77; 95% CI, 0.64-0.92; I 2 = 7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31; 95% CI, 1.02-1.67; I 2 = 77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30; 95% CI, 0.17-0.53; I 2 = 0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47; 95% CI, 0.22-1.01; I 2 = 33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (mean difference À0.8 log 10 ; 95% CI, À1.21 to À0.39, moderate certainty of evidence). There were no effects on other outcomes. CONCLUSIONS: Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data are needed to determine their efficacy and safety.
Immunomodulation: a broad perspective for patients' survival of COVID-19 infection
2020
The pathogenesis of the SARS-CoV-2 virus is yet to be well understood. However, patients with the virus show clinical manifestations which are very similar to those of SARS-CoV and MERS-CoV. This and other scientific findings reveal that acute respiratory distress syndrome (ARDS) is the main cause of death in most COVID-19 patients. A vital mechanism for the development of the ARDS is cytokine storm which arises from an aggressive uncontrolled systemic inflammatory response that results from the release of large numbers of pro-inflammatory cytokines. This review seeks to draw the attention of the scientific community to the possibilities of improving the clinical outcome of COVID-19 patients based on the knowledge of altering the development of this hyper-inflammatory process by suggesting drugs that targets the implicated immune cells, receptors, cytokines and inflammatory pathways without having generalized effect on the entire immune system.
The Journal of Infectious Diseases, 2023
Background. Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. Methods. Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), antinucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. Results. Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma NAg compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. Conclusions. Our study suggests that nmAb has an antiviral effect assessed by plasma NAg among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. Clinical Trials Registration. NCT04501978.
Revista da Associação Médica Brasileira
Neutralizing monoclonal antibody (mAb) therapies targeting with high specificity to SARS-CoV-2 has been considered as one of the potential therapies for COVID-19 since the beginning of the pandemic. Preclinical studies demonstrated a marked reduction in viral loads in the upper and lower respiratory tract with the use of neutralizing mAbs 1. The mAbs have the ability to coordinate the immune defense to link to the virus and control the virus load. The mAbs are defined as an antibody derived from a single B-cell clone and recognize a single and unique epitope that can link to their specific epitope on target antigens and can mediate multiple effects such as disruption of the function and eliminate cells or pathogens 2. These mAbs for COVID-19 are fully human and were discovered from COVID-19 patient' donors, and one of their targets is to block the S protein of the SARS-CoV-2, preventing viral entry into host cells 3. The U.S. Food and Drug Administration (FDA) issued an emergency use authorization for mAbs to be used as pre-exposure prophylaxis and mild-moderate COVID-19. However, given to the Omicron variant, the FDA did not recommend using casirivimab+imdevimab. In Brazil, mAbs were approved by the Brazilian regulatory agency, i.e., The National Health Surveillance Agency (ANVISA), for use in patients with mild-to-moderate nonhospitalized COVID-19 patients and for the prevention of COVID-19 infection. This systematic review aimed to identify, describe, evaluate, and synthesize evidence of effectiveness of mAbs in clinical outcomes in COVID-19 patients. METHODS This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations 4. Eligibility criteria The study protocol followed the patients of interest, intervention to be studied, comparison of interventions, and outcome of interest (PICO) methodology. With the use of a mAb as the main study point, the PICO framework was as follows: patients, adult COVID-19 patients; intervention, use of an mAb (casiriv-imab+imdevimab, bamlanivimab, bamlanivimab+etesevimab, sotrovimab, regdanvimab, and tixagevimab+cilgavimab); comparison between the standard of care (SOC) and placebo; and outcome, symptomatic COVID-19 infection, symptom resolution, adverse event, severe adverse event, hospitalization, and the mortality rate due to any cause in 29 days. The protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews: CRD42022320972. All phase 3 randomized controlled trials (RCTs) on the topic were included. No restrictions were imposed with regard to the date of publication, language, or availability of the full text of the article. Information sources and search strategy Two authors developed a search strategy that was revised and approved by the team, selected information sources, and systematically searched MEDLINE, EMBASE, Central Cochrane, and ClinicalTrials.gov. Specific search strategies were used for each database:
The Possible Role of Immunoglobulin A Monoclonal Antibodies against COVID‑19 Infection
The coronavirus adheres to the nasal ciliated epithelium and replicates before transporting it to the nasopharynx. Immunopathogenesis and severity of coronavirus disease 2019 (COVID-19) are influenced by viral and immune system factors. COVID-19 infection is capable of producing an excessive immune reaction in the host that called a cytokine storm. The effect is extensive tissue destruction. Detection and monitoring of the immunopathological changes in patients with COVID-19 may provide potential targets for drug development and discovery, besides it is necessary for clinical management. Immunoglobulin A (IgA) is the most abundant antibody class present at mucosal surfaces, including the upper respiratory tract, providing the first line of defense in mucosal immunity at the primary site of virus infection. Secretory IgA neutralizes the virus without causing inflammation because of its inability to fix and activate the complement cascade. Hence, it is suggested that induction of the mucosal immune response is more desirable to prevent respiratory infection to avoid unregulated inflammatory innate responses and impaired adaptive immune responses that may lead to locally and systemically harmful tissue damage. The advantage of IgA for protecting mucosal surfaces, such as the respiratory tract, relates to the presence of a specialized mechanism for transporting oligomeric IgA across epithelial surfaces.