Repurposing of poly-gamma-glutamic acid, immunotherapeutic drug for cervical intraepithelial neoplasia 1, as covid-19 treatment

Covid-19 virus variants identified so far are due to viral genetic diversity, genetic evolution, and variable infectivity, suggesting that high infection rates and high mortality rates may be contributed by these mutations. And it has been reported that the targeting strategies for innate immunity should be less vulnerable to viral evolution, variant emergence and resistance. Therefore, the most effective solution to Covid-19 infection has been proposed to prevent and treat severe exacerbation of patients with moderate disease by enhancing human immune responses such as NK cell and T cell. In previous studies, we demonstrated for the first time that gamma-PGA induced significant antitumor activity and antiviral activity by modulating NK cell-mediated cytotoxicity. Especially intranasal administration of gamma-PGA was found to effectively induce protective innate and CTL immune responses against viruses and we found out that gamma-PGA can be an effective treatment for cervical intraepithelial neoplasia 1 through phase 2b clinical trial. In this study, the possibility of gamma-PGA as a Covid-19 immune modulating agent was confirmed by animal experiments infected with Covid-19 viruses. After oral administration of gamma-PGA 300mug/mouse once a day for 5 days in a K18-hACE2 TG mouse model infected with SARS-CoV-2 (NCCP 43326;original strain) and SARS-CoV-2 (NCCP 43390;Delta variant), virus titer and clinical symptom improvement were confirmed. In the RjHan:AURA Syrian hamster model infected with SARS-CoV-2 (NCCP 49930;Delta variant), 350 or 550 mug/head of gamma-PGA was administered orally for 10 days once a day. The virus for infection was administered at 5 x 104 TCID50, and the titer of virus and the improvement of pneumonia lesions were measured to confirm the effectiveness in terms of prevention or treatment. In the mouse model infected with original Covid-19 virus stain, the weight loss was significantly reduced and the survival rate was also improved by the administration of gamma-PGA. And gamma-PGA alleviated the pneumonic lesions and reduced the virus titer of lung tissue in mice infected with delta variant. In the deltavariant virus infected hamster model, gamma-PGA showed statistically significant improvement of weight loss and lung inflammation during administration after infection. This is a promising result for possibility of Covid-19 therapeutics along with the efficacy results of mouse model, suggesting gammaPGA can be therapeutic candidate to modulate an innate immune response for Covid-19.

Drug Repurposing for, ENT and Head and Neck, Infectious and Oncologic Diseases: Current Practices and Future Possibilities

The specialty of otolaryngology and head and neck surgery involves various subspecialties, encompassing clinical conditions ranging from medical to surgical issues in infections, noninfectious benign conditions and various benign and malignant tumors. Drug repurposing has proven to be significant in multiple fields and is still investigational in many promising possible solutions to different clinical challenges in this specialty. We discuss some classes of drugs that have been successfully repurposed for ENT pathologies. We also discuss the novel research goals that are being pursued in our department in the context of drug repurposing for airway infectious diseases including COVID-10 and mucormycosis. There has been a silent and underappreciated rise in drug-resistant invasive fungal infections (IFIs). Emerging Mucorales are difficult to diagnose and tolerant to many of the frontline antifungal therapies. There is an urgent need to combat these emerging pathogens and investigate the molecular mechanisms underlying their potentiated virulence traits to identify potential therapeutic targets susceptible to anti-fungal compounds. The drug development process for IFIs remains largely expensive, and is inherently risky. These challenges declare an urgent need for discovery of new antifungal drugs and encourage drug repurposing as alternative approach to fungal control. The understanding of molecular underpinnings behind fungi and human host continue to grow, however, further research endeavors are underway to fully explore the fungal pathogenesis, (including the role of iron) to gather new insights to achieve improved therapeutics. Above all, creative screening tools and out-of-the-box ideas aimed at increasing the possibility of identifying potential first-in-class antifungals are highly encouraged. The recently emerging fungal co-infections in the COVID-19 disease patients has revived the interest in the pathophysiology and clinical management of the IFIs, and identification of potential druggable nodes in olfactory niche to inhibit the spread of COVID-19 and associated co-infections by leveraging in vitro-disease models of host-pathogen interaction. We employed our recently established COVID-19 disease model to decipher potential anti-metabolic molecules that can be repurposed as novel bilateral drugs having anti-fungal and host-directed features with extended applicability in diabetes, COVID-19, and mucormycosis with and without COVID-19. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.

Immune Responses and Pathogenesis following Experimental SARS-CoV-2 Infection in Domestic Cats.

Several reports demonstrated the susceptibility of domestic cats to SARS-CoV-2 infection. Here, we describe a thorough investigation of the immune responses in cats after experimental SARS-CoV-2 inoculation, along with the characterization of infection kinetics and pathological lesions. Specific pathogen-free domestic cats (n = 12) were intranasally inoculated with SARS-CoV-2 and subsequently sacrificed on DPI (days post-inoculation) 2, 4, 7 and 14. None of the infected cats developed clinical signs. Only mild histopathologic lung changes associated with virus antigen expression were observed mainly on DPI 4 and 7. Viral RNA was present until DPI 7, predominantly in nasal and throat swabs. The infectious virus could be isolated from the nose, trachea and lungs until DPI 7. In the swab samples, no biologically relevant SARS-CoV-2 mutations were observed over time. From DPI 7 onwards, all cats developed a humoral immune response. The cellular immune responses were limited to DPI 7. Cats showed an increase in CD8+ cells, and the subsequent RNA sequence analysis of CD4+ and CD8+ subsets revealed a prominent upregulation of antiviral and inflammatory genes on DPI 2. In conclusion, infected domestic cats developed a strong antiviral response and cleared the virus within the first week after infection without overt clinical signs and relevant virus mutations.

Challenges in the Development and Application of Organ-on-Chips for Intranasal Drug Delivery Studies.

With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that they can be delivered promptly to the market is critically acknowledged. There have been attempts to manufacture anatomically relevant 3D replicas of the human nasal cavity for in vitro IN drug tests, and a couple of organ-on-chip (OoC) models, which mimic some key features of the nasal mucosa, have been proposed. However, these models are still in their infancy, and have not completely recapitulated the critical characteristics of the human nasal mucosa, including its biological interactions with other organs, to provide a reliable platform for preclinical IN drug tests. While the promising potential of OoCs for drug testing and development is being extensively investigated in recent research, the applicability of this technology for IN drug tests has barely been explored. This review aims to highlight the importance of using OoC models for in vitro IN drug tests and their potential applications in IN drug development by covering the background information on the wide usage of IN drugs and their common side effects where some classical examples of each area are pointed out. Specifically, this review focuses on the major challenges of developing advanced OoC technology and discusses the need to mimic the physiological and anatomical features of the nasal cavity and nasal mucosa, the performance of relevant drug safety assays, as well as the fabrication and operational aspects, with the ultimate goal to highlight the much-needed consensus, to converge the effort of the research community in this area of work.

The impact of primary immunization route on the outcome of infection with SARS-CoV-2 in a hamster model of COVID-19.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has resulted in over 6.7 million deaths worldwide. COVID-19 vaccines administered parenterally via intramuscular or subcutaneous (SC) routes have reduced the severity of respiratory infections, hospitalization rates, and overall mortality. However, there is a growing interest in developing mucosally delivered vaccines to further enhance the ease and durability of vaccination. This study compared the immune response in hamsters immunized with live SARS-CoV-2 virus via SC or intranasal (IN) routes and assessed the outcome of a subsequent IN SARS-CoV-2 challenge. Results showed that SC-immunized hamsters elicited a dose-dependent neutralizing antibody response but of a significantly lower magnitude than that observed in IN-immunized hamsters. The IN challenge with SARS-CoV-2 in SC-immunized hamsters resulted in body weight loss, increased viral load, and lung pathology than that observed in IN-immunized and IN-challenged counterparts. These results demonstrate that while SC immunization renders some degree of protection, IN immunization induces a stronger immune response and better protection against respiratory SARS-CoV-2 infection. Overall, this study provides evidence that the route of primary immunization plays a critical role in determining the severity of a subsequent respiratory infection caused by SARS-CoV-2. Furthermore, the findings suggest that IN route of immunization may be a more effective option for COVID-19 vaccines than the currently used parenteral routes. Understanding the immune response to SARS-CoV-2 elicited via different immunization routes may help guide more effective and long-lasting vaccination strategies.

Evaluation of Chronic Rhinosinusitis Symptoms' Severity Following COVID-19 Infection: A Retrospective Analysis.

Objectives This study aims to compare the severity of chronic rhinosinusitis (CRS) symptoms pre- and post-COVID-19 infection and estimate the impact of the COVID-19 pandemic on the use of intranasal corticosteroids (ICS) among adult CRS patients. Methods This was an observational retrospective cohort study conducted at King Abdulaziz University Hospital, Riyadh, Saudi Arabia, between July 2022 and October 2022. Adult CRS patients with sino-nasal outcomes test-22 (SNOT-22) scores documented prior to March 2020, marking the occurrence of Saudi Arabia's initial reported case of COVID-19, were requested to complete the SNOT-22 questionnaire following COVID-19 infection. A comparison was subsequently made between the two scores obtained. Results The study enrolled a total of 33 patients, with 16 assigned to the control group and 17 with a history of COVID-19 infection. The mean age of the patients was 43 years, and the majority (52%) were males. Statistical analysis did not reveal any statistically significant differences in the total SNOT-22 scores or domain-level scores between the two groups. Furthermore, the use of ICS during the COVID-19 pandemic did not show any significant associations, except for patients with asthma, where 80% of them used ICS during the pandemic (p=0.0073). Conclusion There was no statistically significant disparity observed in the SNOT-22 scores between patients who tested positive for COVID-19 and those who did not. The use of corticosteroids during the COVID-19 pandemic was found to be more prevalent in this study compared to previous studies conducted before the pandemic, particularly among patients with asthma. The use of ICS during the pandemic was not associated with the presence of polyps, functional endoscopic sinus surgery (FESS), allergic rhinitis, or eczema.

HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration.

The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs, this necessitates the development of broad-spectrum antiviral drugs. In the previous study, we designed a recombinant protein, heptad repeat (HR) 121, as a variant-proof vaccine. Here, we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants. Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike (S) 2 subunit to block virus-cell fusion. Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH, highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route. Importantly, HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells, as well as block authentic SARS-CoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells. After intranasal administration to Syrian golden hamsters, it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection. Together, our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.

Localized delivery of nanomedicine and antibodies for combating COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been a major health burden in the world. So far, many strategies have been investigated to control the spread of COVID-19, including social distancing, disinfection protocols, vaccines, and antiviral treatments. Despite the significant achievement, due to the constantly emerging new variants, COVID-19 is still a great challenge to the global healthcare system. It is an urgent demand for the development of new therapeutics and technology for containing the wild spread of SARS-CoV-2. Inhaled administration is useful for the treatment of lung and respiratory diseases, and enables the drugs to reach the site of action directly with benefits of decreased dose, improved safety, and enhanced patient compliance. Nanotechnology has been extensively applied in the prevention and treatment of COVID-19. In this review, the inhaled nanomedicines and antibodies, as well as intranasal nanodrugs, for the prevention and treatment of COVID-19 are summarized.

Role of Famotidine and Other Acid Reflux Medications for SARS-CoV-2: A Pilot Study.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus-19 disease (COVID-19) pandemic. The H-2 blocker famotidine has been suggested as an FDA-approved drug that could potentially be repurposed for treatment of COVID-19. Famotidine has since been shown to improve patient outcomes and reduce symptom severity in patients acutely ill with COVID-19. Other studies have suggested that proton pump inhibitors (PPIs) might have an association with COVID-19. OBJECTIVE: The purpose of the present study was to determine whether famotidine or any other antireflux medications have a prophylactic or detrimental effect for SARS-CoV-2 infection when taken regularly for the management of acid reflux. METHODS: An anonymous, web-based survey was distributed via email to adult otolaryngology patients to collect demographic data, past medical history, medication history, incidence of symptoms associated with COVID-19, potential exposure to SARS-CoV-2, and results of any PCR or serological testing. Associations between reflux medications and incidence of COVID-19 cases were analyzed. Statistical analysis was performed using SPSS. Chi-square with Fisher's exact test, Point-Biserial correlation, Kendall's-tau-b, independent samples t test, and the Mann-Whitney U test were used as appropriate. A binary logistic regression model was fit to determine probability of COVID-19 cases after adjustment for other risk factors. RESULTS: There were 307 patients who responded to the survey. The average age of respondents was 52.63 ± 17.03. Famotidine use was not associated with incidence of laboratory-confirmed (P= 0.717) or symptomatically suspected (P= 0.876) COVID-19. No other reflux medications were found to be significant predictors for laboratory-confirmed or suspected COVID-19 (P> 0.05). Younger age (odds ratio [OR] = 1.043, 95% CI: 1.020-1.065, P< 0.001), high risk obesity (OR = 4.005, 95% CI: 1.449-11.069, P= 0.007), and use of a corticosteroid nasal spray (OR = 3.529, 95% CI: 1.352-9.211, P= 0.010) were significant predictors for symptomatically suspected COVID-19 cases. CONCLUSIONS: There was no association between incidence of COVID-19 and use of reflux medications, including famotidine at doses used orally to manage reflux and high dose PPIs. Reflux medications did not protect against or increase the risk of COVID-19.

Intranasal administration of convalescent plasma protects against SARS-CoV-2 infection in hamsters.

BACKGROUND: Convalescent plasma (CP) transfusion is an early option for treating infections with pandemic potential, often preceding vaccine or antiviral drug rollout. Heterogenous findings from randomized clinical trials on transfusion of COVID-19 CP (CCP) have been reported. However, meta-analysis suggests that transfusion of high titer CCP is associated with a mortality benefit for COVID-19 outpatients or inpatients treated within 5 days after symptom onset, indicating the importance of early administration. METHODS: We tested if CCP is an effective prophylactic against SARS-CoV-2 infection by the intranasal administration of 25 µL CCP/nostril (i.e. 0.01-0.06 mg anti-RBD antibodies/kg) in hamsters exposed to infected littermates. FINDINGS: In this model, 40% of CCP treated hamsters were fully protected and 40% had significantly reduced viral loads, the remaining 20% was not protected. The effect seems dose-dependent because high-titer CCP from a vaccinated donor was more effective than low-titer CCP from a donation prior to vaccine rollout. Intranasal administration of human CCP resulted in a reactive (immune) response in hamster lungs, however this was not observed upon administration of hamster CCP. INTERPRETATION: We conclude that CCP is an effective prophylactic when used directly at the site of primary infection. This option should be considered in future prepandemic preparedness plans. FUNDING: Flanders Innovation & Entrepreneurship (VLAIO) and the Foundation for Scientific Research of the Belgian Red Cross Flanders.

Pharmacokinetic Study of Intranasal Dexamethasone and Methylprednisolone Compared with Intravenous Administration: Two Open-Label, Single-Dose, Two-Period, Two-Sequence, Cross-Over Study in Healthy Volunteers.

Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers direct access to the brain as it bypasses the blood-brain barrier. The Mucosal Atomization Device is an optimal tool that can achieve rapid absorption into the CNS and the bloodstream across mucosal membranes. This study was designed to evaluate and compare the bioavailability of DXM and MEP after intranasal versus intravenous administration. Two open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover studies were conducted, which involved healthy male and female adult volunteers. After intranasal administration, DXM and MEP were detected in plasma after the first sampling time. Mean peak concentrations of DXM and MEP were 86.61 ng/mL at 60 min and 843.2 ng/mL at 1.5 h post-administration, respectively. DXM and MEP showed high absolute bioavailability, with values of 80% and 95%, respectively. No adverse effects were observed. DXM and MEP systemic bioavailability by intranasal administration was comparable with the intravenous one, suggesting that the intranasal route can be used as a non-invasive and appropriate alternative for systemic drug delivery.

Advances and challenges in intranasal vaccines development for respiratory infectious diseases

The great challenge to prevent transmission makes widespread of respiratory infectious diseases easily occur. Intranasal immunization is considered to be a promising route of vaccination to prevent it. Different from parenteral vaccines, intranasal vaccines can induce mucosal immune in respiratory tracts in addition to systemic immune, which provide the first line of defense against respiratory pathogen infection and further prevent transmission. Safe and effective intranasal spray flu vaccines have been licensed. Since the outbreak of COVID-19, intranasal administration has been applied in different vaccine platforms. This article has reviewed the progress of intranasal vaccines for respiratory infectious diseases that have been licensed or are under evaluation in the clinical trials, meanwhile discusses its unique advantages and challenges faced. © 2023, Publication Centre of Anhui Medical University. All rights reserved.

SARS-CoV-2: Immunity, Challenges with Current Vaccines, and a Novel Perspective on Mucosal Vaccines.

The global rollout of COVID-19 vaccines has played a critical role in reducing pandemic spread, disease severity, hospitalizations, and deaths. However, the first-generation vaccines failed to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and transmission, partially due to the limited induction of mucosal immunity, leading to the continuous emergence of variants of concern (VOC) and breakthrough infections. To meet the challenges from VOC, limited durability, and lack of mucosal immune response of first-generation vaccines, novel approaches are being investigated. Herein, we have discussed the current knowledge pertaining to natural and vaccine-induced immunity, and the role of the mucosal immune response in controlling SARS-CoV2 infection. We have also presented the current status of the novel approaches aimed at eliciting both mucosal and systemic immunity. Finally, we have presented a novel adjuvant-free approach to elicit effective mucosal immunity against SARS-CoV-2, which lacks the safety concerns associated with live-attenuated vaccine platforms.

Neutralisation of SARS-CoV-2 by monoclonal antibody through dual targeting powder formulation.

Neutralising monoclonal antibody (mAb) is an important weapon in our arsenal for combating respiratory viral infections. However, the effectiveness of neutralising mAb has been impeded by the rapid emergence of mutant variants. Early administration of broad-spectrum mAb with improved delivery efficiency can potentially enhance efficacy and patient outcomes. WKS13 is a humanised mAb which was previously demonstrated to exhibit broad-spectrum activity against SARS-CoV-2 variants. In this study, a dual targeting formulation strategy was designed to deliver WKS13 to both the nasal cavity and lower airways, the two critical sites of infection caused by SARS-CoV-2. Dry powders of WKS13 were first prepared by spray drying, with cyclodextrin used as stabiliser excipient. Two-fluid nozzle (TFN) was used to produce particles below 5 µm for lung deposition (C-TFN formulation) and ultrasonic nozzle (USN) was used to produce particles above 10 µm for nasal deposition (C-USN formulation). Gel electrophoresis and size exclusion chromatography studies showed that the structural integrity of mAb was successfully preserved with no sign of aggregation after spray drying. To achieve dual targeting property, C-TFN and C-USN were mixed at various ratios. The aerosolisation property of the mixed formulations dispersed from a nasal powder device was examined using a Next Generation Impactor (NGI) coupled with a glass expansion chamber. When the ratio of C-TFN in the mixed formulation increased, the fraction of particles deposited in the lung increased proportionally while the fraction of particles deposited in the nasal cavity decreased correspondingly. A customisable aerosol deposition profile could therefore be achieved by manipulating the mixing ratio between C-TFN and C-USN. Dual administration of C-TFN and C-USN powders to the lung and nasal cavity of hamsters, respectively, was effective in offering prophylactic protection against SARS-CoV-2 Delta variant. Viral loads in both the lung tissues and nasal wash were significantly reduced, and the efficacy was comparable to systemic administration of unformulated WKS13. Overall, dual targeting powder formulation of neutralising mAb is a promising approach for prophylaxis of respiratory viral infections. The ease and non-invasive administration of dual targeting nasal powder may facilitate the widespread distribution of neutralising mAb during the early stage of unpredictable outbreaks.

Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models.

The ongoing SARS-CoV-2 pandemic is controlled but not halted by public health measures and mass vaccination strategies which have exclusively relied on intramuscular vaccines. Intranasal vaccines can prime or recruit to the respiratory epithelium mucosal immune cells capable of preventing infection. Here we report a comprehensive series of studies on this concept using various mouse models, including HLA class II-humanized transgenic strains. We found that a single intranasal (i.n.) dose of serotype-5 adenoviral vectors expressing either the receptor binding domain (Ad5-RBD) or the complete ectodomain (Ad5-S) of the SARS-CoV-2 spike protein was effective in inducing i) serum and bronchoalveolar lavage (BAL) anti-spike IgA and IgG, ii) robust SARS-CoV-2-neutralizing activity in the serum and BAL, iii) rigorous spike-directed T helper 1 cell/cytotoxic T cell immunity, and iv) protection of mice from a challenge with the SARS-CoV-2 beta variant. Intramuscular (i.m.) Ad5-RBD or Ad5-S administration did not induce serum or BAL IgA, and resulted in lower neutralizing titers in the serum. Moreover, prior immunity induced by an intramuscular mRNA vaccine could be potently enhanced and modulated towards a mucosal IgA response by an i.n. Ad5-S booster. Notably, Ad5 DNA was found in the liver or spleen after i.m. but not i.n. administration, indicating a lack of systemic spread of the vaccine vector, which has been associated with a risk of thrombotic thrombocytopenia. Unlike in otherwise genetically identical HLA-DQ6 mice, in HLA-DQ8 mice Ad5-RBD vaccine was inferior to Ad5-S, suggesting that the RBD fragment does not contain a sufficient collection of helper-T cell epitopes to constitute an optimal vaccine antigen. Our data add to previous promising preclinical results on intranasal SARS-CoV-2 vaccination and support the potential of this approach to elicit mucosal immunity for preventing transmission of SARS-CoV-2.

A Phase 1, Randomized, Double-Blinded, Placebo-Controlled and Dose-Escalation Study to Evaluate the Safety and Immunogenicity of the Intranasal DelNS1-nCoV-RBD LAIV for COVID-19 in Healthy Adults.

An intranasal COVID-19 vaccine, DelNS1-based RBD vaccines composed of H1N1 subtype (DelNS1-nCoV-RBD LAIV) was developed to evaluate the safety and immunogenicity in healthy adults. We conducted a phase 1 randomized, double-blinded, placebo-controlled study on healthy participants, age 18-55 and COVID-19 vaccines naïve, between March and September 2021. Participants were enrolled and randomly assigned (2:2:1) into the low and high dose DelNS1-nCoV-RBD LAIV manufactured in chicken embryonated eggs or placebo groups. The low and high-dose vaccine were composed of 1 × 107 EID50/ dose and 1 × 107.7 EID50/ dose in 0.2 mL respectively. The placebo vaccine was composed of inert excipients/dose in 0.2 mL. Recruited participants were administered the vaccine intranasally on day 0 and day 28. The primary end-point was the safety of the vaccine. The secondary endpoints included cellular, humoral, and mucosal immune responses post-vaccination at pre-specified time-points. The cellular response was measured by the T-cell ELISpot assay. The humoral response was measured by the serum anti-RBD IgG and live-virus neutralizing antibody against SARS-CoV-2. The saliva total Ig antibody responses in mucosal secretion against SARS-CoV-2 RBD was also assessed. Twenty-nine healthy Chinese participants were vaccinated (low-dose: 11; high-dose: 12 and placebo: 6). The median age was 26 years. Twenty participants (69%) were male. No participant was discontinued due to an adverse event or COVID-19 infection during the clinical trial. There was no significant difference in the incidence of adverse events (p = 0.620). For the T-cell response elicited after full vaccination, the positive PBMC in the high-dose group increased to 12.5 SFU/106 PMBC (day 42) from 0 (baseline), while it increased to 5 SFU/106 PBMC (day 42) from 2.5 SFU/106 PBMC (baseline) in the placebo group. The high-dose group showed a slightly higher level of mucosal Ig than the control group after receiving two doses of the vaccine (day 31, 0.24 vs. 0.21, p = 0.046; day 56 0.31 vs. 0.15, p = 0.45). There was no difference in the T-cell and saliva Ig response between the low-dose and placebo groups. The serum anti-RBD IgG and live virus neutralizing antibody against SARS-CoV-2 were undetectable in all samples. The high-dose intranasal DelNS1-nCoV-RBD LAIV is safe with moderate mucosal immunogenicity. A phase-2 booster trial with a two-dose regimen of the high-dose intranasal DelNS1-nCoV-RBD LAIV is warranted.

Efficacy of Breathox device inhalation on acute symptoms associated with COVID-19 (BREATH study)

Background: Breathox is a sodium chloride inhaler. Increase of the airway salinity has been proposed to reduce the symptomatic stage of a respiratory viral infection. Objective(s): to evaluate the effectiveness of nasal and inhaled sodium chloride therapy through Breathox on mild COVID-19 symptoms in patients >= 18 years-old compared to usual care. Method(s): a pilot, open, randomized clinical trial, including 100 patients with confirmed and symptomatic COVID-19 within 10 days of symptom onset. All patients received standard of care (SOC), i.e. antipyretic or analgesic. Breathox was administered as two oral inhalations and one nasal instillation in each nostril at each administration with 2mg per inhalation. Patients were randomized 1:1:1 into three groups: Group 1(G1): SOC + Breathox 10 times daily for 10 days;Group 2(G2): SOC + Breathox five times daily for 10 days;Group 3(G3): SOC. Recovery time for symptoms, such as cough was assessed. Result(s): In total 100 of 103 screened patients were included from December 1 2021 to March 03 2022. Of those, 33 from G1 and G3, and 32 from G2 completed the study. Mean age was 40.4/42.2/40.6 years old for G1, G2 and G3, (p=0.96). No patients were hospitalized or died during the study. Time to cough resolution was reduced in G1 (2.8+/-0.66 days) and G2 (2.4+/-0.66 days) compared to G3 (5.39+/-0.79 days) (p=0.001), with a hazard ratio (HR) for G2 of 2.17 (Confidence interval 1.17-4.04) and G3 of 2.01 (1.06-3.81) compared to SOC. Conclusion(s): ten days of Breathox use halved the time for resolution of COVID-19-induced cough.

Features of secretory immunoglobulin A in patients after COVID-19 infection.

Secretory immunoglobulin A, as a marker of the immune response in the mucous membrane, is an available indicator for detecting changes in the local immunity of mucous patients who have undergone COVID-19. Objective. To evaluate the dynamics of changes in the level of sIgA in saliva samples and the effectiveness of the use of interferon alpha-2b in individuals after a coronavirus infection. Patients and methods. Patients aged 18 to 60 years after COVID-19 infection (group 1 on therapy, n = 65;group 2 without therapy, n = 65) and conditionally healthy individuals (control group, n = 15) were monitored. The material is saliva samples, where the sIgA level was determined initially and after a month. The drug - interferon alpha-2b, in the form of a gel for topical use (Viferon, dosage 36,000 IU/g) was administered intranasally 2 times a day, for 1 month. Results. In all groups of patients who underwent COVID-19, the level of saliva sIgA was lower compared to the conditional norm of healthy individuals (6,45 +/- 1,81 mg/ml). A month after the administration of interferon alpha-2b the best effect was observed in patients in the time interval of 1-3 months from the infection, where sIgA was noted a statistically significant increase from 1,84 +/- 0,28 to 5,78 +/- 1,96 mg/ml. In the groups of patients with later terms, a moderate increase in sIgA was determined (3-6 months: 2,83 +/- 0,71 to 3,33 +/- 1,78 mg/ml;6-9 months: 3,53 +/- 0,45 to 4,76 +/- 2,3 mg/ml) and the absence of infectious diseases during rehabilitation period. In the group without therapy, in all temporal aspects, a persistent decrease in sIgA indicators below normal values was revealed, and the frequency of incidence of respiratory viral infections was noted in 9,2% of cases. Conclusions. During the rehabilitation period, the greatest changes in sIgA in saliva were observed in patients in the first 3 months after the COVID infection. The administration of interferon alpha-2b to patients in the post-COVID period is accompanied by the normalization of sIgA and prevents the development of respiratory infections. In similar groups, after COVID-19 without therapy, the indicator tends to decrease, and this category of people is at a higher risk of developing other infectious pathologies.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Anesthetic management of toxic epidermal necrolysis: a report of two cases

Toxic epidermal necrolysis (TEN), is an acute, life-threatening emergent disease involving the skin and mucous membranes with serious systemic complications. It is characterized by widespread epidermal sloughing. Drugs are the most common triggers of TEN, but infection, vaccination, radiation therapy and malignant neoplasms can all induce it in susceptible patients. We report two cases in whom a hair dye and a COVID-19 vaccine (BioNTech, Pfizer) were believed to be the causative agents. These patients have to undergo repeated debridements of the necrotic tissue. In this manuscript the anesthetic management of TEN patients is discussed. Detailed preoperative evaluation, aggressive fluid and electrolyte replacement, avoidance of hypothermia during debridement, minimizing anesthetic agents and limiting traumatic procedures are key points in the management.Copyright © 2023 Faculty of Anaesthesia, Pain and Intensive Care, AFMS. All rights reserved.