First-in-class small molecule drugs in 2022.

2022 is the third year of the global COVID-19 pandemic, and its troubles on new drug discovery are gradually apparent. 37 new drugs were approved by the FDA's Center for Drug Evaluation and Research (CDER) last year, down from the peak of 50 new drug approvals in 2021. Notably, first-in-class drugs still occupy a dominant position this year, with a total of 21 drugs. Among them, 7 are first-in-class small molecule drugs. Although the total number of new drug approvals in 2022 sharply decreased, some first-in-class small molecule drugs were regarded as significant, including mitapivat, the first oral activator targeting the pyruvate kinase (PK);mavacamten, the first selective allosteric inhibitor targeting the myocardial beta myosin ATPase;deucravacitinib, the first deuterated allosteric inhibitor targeting the tyrosine kinase 2 (TYK2);and lenacapavir, the first long-acting inhibitor targeting the HIV capsid. Generally, the research of first-in-class drugs needs to focus on difficult clinical problems and can treat some specific diseases through novel targets and biological mechanisms. There are tremendous challenges in the research processes of new drugs, including biological mechanism research, target selection, molecular screening, lead compound identification and druggability optimization. Therefore, the success of first-in-class drugs development has prominent guidance significance for new drug discovery. This review briefly describes the discovery background, research and development process and therapeutic application of 3 firstin- class small molecule drugs to provide research ideas and methods for more first-in-class drugs.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

EFFICACY AND SAFETY OF DAZODALIBEP (VIB4920/HZN4920) IN SUBJECTS WITH SJÖGREN'S SYNDROME: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF OF CONCEPT STUDY

BackgroundSjögren's syndrome (SS) is a chronic, systemic autoimmune disease affecting exocrine glands, primarily the salivary and tear glands, with potentially severe manifestations in multiple organs. No approved disease-modifying therapies exist. Dazodalibep (DAZ) is a biologic antagonist of CD40L.ObjectivesThe objective of this study was to evaluate the efficacy and safety of DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity (NCT04129164).MethodsWe conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity, as defined by a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ≥ 5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses. Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks. The primary endpoint was the change from Baseline in ESSDAI at Day 169. Safety assessments included the incidence of adverse (AEs), serious AEs (SAEs), and AEs of special interest (AESIs).ResultsThe 74 randomized subjects all received ≥1 dose of study medication (DAZ, N=36;PBO, N=38). The baseline demographics and disease characteristics were balanced between the two groups. The change from Baseline to Day 169 in ESSDAI score (LS mean ± SE), was -6.3 ± 0.6 in DAZ-treated subjects compared to -4.1 ± 0.6 in the PBO group, a difference of -2.2 (p = 0.0167). Compared to the PBO group, the DAZ group showed positive trends in the EULAR Sjögren's Syndrome Patient Reported Index score, and Functional Assessment of Chronic Illness Therapy-Fatigue score at Day 169. A post-hoc responder analysis of subjects achieving high levels (5 and 6 points) of improvement on ESSDAI favored DAZ (61.1% and 60.0%) over PBO (35.1% and 34.3%).The reported AEs were generally mild through Day 169 and similar in frequency between treatment groups. The most frequently reported AEs occurring in ≥5% of DAZ-treated subjects and >PBO were COVID-19, diarrhea, dizziness, ligament sprain, upper respiratory tract infection, contusion, device allergy, fatigue, hypertension, and oropharyngeal pain. Two SAEs were reported in a single DAZ-treated subject: this subject was a 59-year-old female who experienced a grade 3 SAE of COVID-19 infection and later died of unknown cause 46 days after last administration of DAZ (12 days after COVID-19 diagnosis). There was a single AESI of herpes zoster in a DAZ-treated subject.ConclusionDAZ is a potential new therapy for the treatment of systemic disease activity in patients with SS. SS subjects with moderate-to-high systemic disease receiving DAZ experienced a statistically significant reduction in disease activity relative to PBO as measured by the improvement in ESSDAI score. Except for a case of severe COVID-19 infection, DAZ therapy in SS subjects appeared to be well tolerated. Larger controlled trials of DAZ therapy for SS are warranted to further explore its safety profile and confirm its clinical efficacy.Table 1.Efficacy and Safety DataPBO N=38DAZ 1500 mg N=36EfficacyΔESSDAI, LS mean (SE) †-4.1 (0.6)-6.3 (0.6)*ΔESSPRI, LS mean (SE) †-1.12 (0.29)-1.80 (0.31)ΔFACIT-Fatigue, LS mean (SE) †5.8 (1.6)8.1 (1.6)AE Summary, n (%)≥1 AE23 (60.5)28 (77.8)≥1 related AE8 (21)10 (27.8)≥1 SAE01 (2.8)≥1 related SAE00≥1 AE leading to discontinuation00≥1 AESI01 (2.8)≥1 Death01 (2.8)Efficacy endpoints as of Day 169;† Analyzed using MMRM;Comparisons vs PBO;*p<0.05;AE summaries based on AEs that occurred through Day 169;AE, adverse event;AESI, adverse event of special interest;ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index;ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index;FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue;PBO, placebo;SAE, serious adverse eventFigure 1.AcknowledgementsFunded by Horizon herapeutics. Medical writing support provided by B Lujan, PhD, an employee of Horizon Therapeutics.Disclosure of InterestsE. William St. Clair Consultant of: Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics. Royalties: UpToDate, Liangwei Wang Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Ilias Alevizos Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, William Rees Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Alan Baer Consultant of: Bristol Myers Squibb, Wan Fai Ng Consultant of: Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen and UCB, Ghaith Noaiseh Consultant of: Novartis, Chiara Baldini Consultant of: GSK, and Sanofi.

Anesthesia management of athletes' operation in Beijing Olympic Winter Games.

According to literature reports, the injury rate of the athletes in Olympic Winter Games recent years was as high as 10%-14%. Combined with the background of corona virus disease 2019 (COVID-19), the medical insurance work of the 24th Olympic Winter Games held in Beijing had put forward more complicated requirements and more severe challenges. In order to better optimize anesthesia management, this article summarized the perioperative treatment of athletes in Olympic Winter Games, the safety protection strategy of medical staff under general anesthesia, and the potential impact of peri-operative drugs on athletes. Anesthesiologists, as the core members of the rescue team, should be familiar with the particularity of operative anesthesia of athletes, sum up relevant experience to ensure the safety of perioperative patients. So all kinds of technical measures should be taken in the process of operation to minimize the indoor pollution caused by the patient's cough. For example, all the patients should wear N95 masks from the ward to the operating room, and after the operation, wear the N95 masks back to the ward. Although the International Olympic Committee had banned more than 200 drugs for participants and athletes who had to strictly follow International Olympic Committee requirements during anesthesia, the athletes were no longer participating in this Olympic Winter Games, so opioids (sufentanil and remifentanil) and glucocorticoid (dexamethasone) could be used according to the actual needs of surgery and anesthesia. Five athletes in Yanqing competition area underwent surgical anesthesia in Peking University Third Hospital Yanqing Hospital. All the five patients received general anesthesia, of whom four underwent orthopaedic surgery and one underwent laparoscopic cholecystectomy. General anesthesia with laryngeal mask airway was the first choice in the five patients. And the pain after orthopaedic surgery was severe and nerve block technique could effectively relieve the pain after surgery. Three patients received ultrasound-guided nerve block analgesia, the postoperative analgesia lasted 36 h. After the operation, non-steroidal anti-inflammatory drug (NSAID) was infused intravenously in the ward and all the patients recovered uneventfully. As the core member of the trauma rescue team, anesthesiologists should be familiar with the particularity of the athletes' surgical anesthesia, do a good job in medical security, and summarize relevant experience to ensure the life safety of the perioperative patients.

Asian Pacific Journal of Tropical Medicine COVID-19 vaccine uptake and its determinants among teenagers and their parents in Zhejiang, China: An online cross-sectional study

Objective: To examine COVID-19 vaccine uptake and its determinants among teenagers and their parents in Zhejiang, China. Method(s): An online cross-sectional study was conducted among parents of teenagers in Zhejiang, China from May 1 to 31, 2022. Data were interpreted via univariate and multivariate analyses using the statistical package for the social sciences (SPSS) program. Result(s): A total of 11115 (96.11%) participants and 11449 (99.00%) of their children in Zhejiang, China had been vaccinated against COVID-19. Children whose parents did not receive COVID-19 vaccination were 19 times (aOR 18.96, 95%CI 12.36-29.08) more likely to be unvaccinated than their counterparts. In addition, children with no previous influenza vaccination, those whose parents doubted the COVID-19 vaccine's safety or effectiveness, were 6.11 times (aOR 6.11, 95%CI 2.80-13.34), 8.27 times (aOR 8.27, 95%CI 5.33-12.83), and 2.69 times (aOR 2.69, 95%CI 1.11-6.50) more likely to be unvaccinated than their counterparts, respectively. COVID-19 vaccine uptake varied between different sociodemographic groups. However, the odds of receiving the COVID-19 vaccine decreased as age and education level increased. The main refusal reasons claimed by participants were that they had medical conditions that may not qualify them for vaccination (53.78%), followed by safety concerns about the vaccine (13.56%), not knowing where to get vaccinated (6.44%), and concerns about fertility issues (5.56%). Conclusion(s): Despite a highly encouraging level of COVID-19 vaccine uptake in Zhejiang, China, the elderly and highly educated people had lower COVID-19 vaccine uptake. It is suggested that tailored health education strategies should be taken to increase the COVID-19 vaccine uptake in such groups. Furthermore, with vaccination rates at such a high level, the pandemic is still ongoing, and public confidence in vaccines may decline. Thus, sufficient evidence-based information regarding COVID-19 vaccines should be provided to the public. Copyright © 2023 Asian Pacific Journal of Tropical Medicine.

J-wave in a patient with severe COVID-19

In the context of the current COVID-19 epidemic, numerous are the manifestations of the infected patients, including the alterations in the 12-lead electrocardiogram, where the presence ofa J-wave can be found, secondary to the generation ofa transmural voltage gradient, caused by the overexpression of the channels for transient outward potassium current (Ito), in the context of a severe infection with extensive myocardial injury. In this article is presented the case of an 83-year-old patient with a positive diagnosis of COVID-19, who progressed to septic shock, with mixed addosis and mild hyperkalemia. The electrocardiogram showed the presence of a Jwave, probably secondary to the effect ofpro-inflammatory cytokines on potassium channels and extensive areas of myocardial injury.

AI Techniques for Forecasting Epidemic Dynamics: Theory and Practice

Forecasting epidemic dynamics has been an active area of research for at least two decades. The importance of the topic is evident: policy makers, citizens, and scientists would all like to get accurate and timely forecasts. In contrast to physical systems, the co-evolution of epidemics, individual and collective behavior, viral dynamics, and public policies make epidemic forecasting a problematic task. The situation is even more challenging during a pandemic as has become amply clear during the ongoing COVID-19 pandemic. Researchers worldwide have put in extraordinary efforts to try to forecast the time-varying evolution of the pandemic;despite their best efforts, it is fair to say that the results have been mixed. Several teams have done well on average but failed to forecast upsurges in the cases. In this chapter, we describe the state-of-the-art in epidemic forecasting, with a particular emphasis on forecasting during an ongoing pandemic. We describe a range of methods that have been developed and discuss the experience of our team in this context. We also summarize several challenges in producing accurate and timely forecasts. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

COVID-19 vaccine uptake and its determinants among teenagers and their parents in Zhejiang, China: An online cross-sectional study

Objective: To examine COVID-19 vaccine uptake and its determinants among teenagers and their parents in Zhejiang, China. Methods: An online cross-sectional study was conducted among parents of teenagers in Zhejiang, China from May 1 to 31, 2022. Data were interpreted via univariate and multivariate analyses using the statistical package for the social sciences (SPSS) program. Results: A total of 11115 (96.11%) participants and 11449 (99.00%) of their children in Zhejiang, China had been vaccinated against COVID-19. Children whose parents did not receive COVID-19 vaccination were 19 times (aOR 18.96, 95%CI 12.36-29.08) more likely to be unvaccinated than their counterparts. In addition, children with no previous influenza vaccination, those whose parents doubted the COVID-19 vaccine's safety or effectiveness, were 6.11 times (aOR 6.11, 95%CI 2.80-13.34), 8.27 times (aOR 8.27, 95%CI 5.33-12.83), and 2.69 times (aOR 2.69, 95%CI 1.11-6.50) more likely to be unvaccinated than their counterparts, respectively. COVID-19 vaccine uptake varied between different sociodemographic groups. However, the odds of receiving the COVID-19 vaccine decreased as age and education level increased. The main refusal reasons claimed by participants were that they had medical conditions that may not qualify them for vaccination (53.78%), followed by safety concerns about the vaccine (13.56%), not knowing where to get vaccinated (6.44%), and concerns about fertility issues (5.56%). Conclusions: Despite a highly encouraging level of COVID-19 vaccine uptake in Zhejiang, China, the elderly and highly educated people had lower COVID-19 vaccine uptake. It is suggested that tailored health education strategies should be taken to increase the COVID-19 vaccine uptake in such groups. Furthermore, with vaccination rates at such a high level, the pandemic is still ongoing, and public confidence in vaccines may decline. Thus, sufficient evidence-based information regarding COVID-19 vaccines should be provided to the public.

Non-contact sensing system based on GaN optoelectronic chip

As the global spread of COVID-19becomesarapidly19 becomes a rapidly evolvingcrisis,thedevelopmentofcontactlesssharedevolving crisis, the development of contactless shared interactivedisplaysisanurgentiinteractive displays is an urgent issuetoreducetheriskofssue to reduce the risk of viralandbacterialcrosscontaminationduetotheuseofviral and bacterial cross contamination due to the use of touchtouch -operatedshareduserterminals.Here,weoperated shared user terminals. Here, we experimentallydemonstrateacontactlessuserterminalexperimentally demonstrate a contactless user terminal fabricatedwithamonolithicGaNOptoelectronicsystemfabricated with a monolithic GaN Optoelectronic system (MGOS),which(MGOS), which integratesthetransmitterandreceiverintointegrates the transmitter and receiver into asinglechip.a single chip. TheinherentspectralemissionThe inherent spectral emission-responsivenessresponsiveness overlapofGaNQWdiodesgivesthedeviceauniqueabilityoverlap of GaN QW diodes gives the device a unique ability todetectlighttransmittedbydiodesthatsharethesameQWto detect light transmitted by diodes that share the same QW structure.WhentheGaNtransmstructure. When the GaN transm itteremitslighttoitter emits light to illuminateanexternalobject,theintegratedGaNreceiverilluminate an external object, the integrated GaN receiver candetectthereflectedlightencodingtheinformationandcan detect the reflected light encoding the information and converttheopticalsignalintoanelectricalsignal,sothatconvert the optical signal into an electrical signal, so that thenonthe non--contactuserterminalhastheabilitytouselcontact user terminal has the ability to use lightforight for bidirectionaldatacommunication.Comparedtotraditionalbidirectional data communication. Compared to traditional handwritingsystems,theseterminalsoperateascontactlesshandwriting systems, these terminals operate as contactless informationentrydevicesthatcanhelpreducepotentialinformation entry devices that can help reduce potential crosscross--contaminationduetocontactwithhandwritingcontamination due to contact with handwriting terminals,providepterminals, provide precautionstokeeptheenvironmentrecautions to keep the environment clean,andhelppreventvirustransmission.clean, and help prevent virus transmission.

[Research progress on the relationship between low-density neutrophils and infectious diseases]

Neutrophils play an important role in infectious diseases by clearing pathogens in the early stages of the disease and damaging the surrounding tissues along with the disease progress. Low-density neutrophils (LDNs) are a crucial and distinct subpopulation of neutrophils. They are a mixture of activated and degranulated normal mature neutrophils and a considerable number of immature neutrophils prematurely released from the bone marrow. Additionally, they may be involved in the occurrence and development of diseases through the changes in phagocytosis, the generation of reactive oxygen species (ROS), the enhancement of the ability to produce neutrophils extracellular traps and immunosuppression. We summarizes the role of LDNs in the pathogenesis and their correlation with the severity of infectious diseases such as COVID-19, severe fever with thrombocytopenia syndrome (SFTS), AIDS, and tuberculosis.

Real-time Cheating Detection System Based on Sight Detection

Due to the COVID-19 pandemic, many exams, written tests and interviews are conducted online and remotely, which raises a series of questions such as how to prevent cheating. In this project, the methods commonly used in the existing cheating monitoring system are fully investigated and their shortcomings are improved one by one. Finally, a line of sight detection algorithm based on computer vision technology is designed, and a prototype of auxiliary cheating detection system that can get good results only with a small number of samples is developed. © 2022 SPIE.

Multizone Modelling of SARS-CoV-2 Airborne Transmission in Mechanically Ventilated Buildings

This study contributes to a better understanding of the airborne transmission risks in multizone, mechanically ventilated buildings and how to reduce infection risk. A novel modeling approach combining the Wells-Riley and the US National Institute of Standards and Technology (NIST) CONTAM models was applied to a multizone whole building to simulate exposure and assess the effectiveness of different mitigation measures. A case study for the US Department of Energy large office prototype building was conducted to illustrate the approach. © 2022 17th International Conference on Indoor Air Quality and Climate, INDOOR AIR 2022. All rights reserved.

Face mask detection based on improved YOLOv3 algorithm

In the current situation of COVID-19 prevention and control, wearing masks remains an important way to prevent the transmission of the Novel Coronavirus. Aiming at the problem that the detection accuracy of the traditional YOLOv3 algorithm can still be improved, this paper proposes an improved yolov3 algorithm and applies it to the practical problem of detecting whether to wear a mask. Firstly, the algorithm introduces the residual structure of structural reparameterization in the feature extraction network named Darknet53 of YOLOv3 to obtain the input features;Secondly, the SimSPPF (Simplified Spatial Pyramid Pooling-Fast) is introduced to enhance feature extraction;Finally, an improved attention mechanism is introduced to make the model focus on regions with more prominent features. Besides, in order to ensure the accuracy of target detection, CIoU and Focal loss function was used in the training process. The results show that compared with the traditional YOLOv3, the detection accuracy of the improved algorithm for normal face and mask face is improved by 16.98% and 7.30% respectively, and the mAP is improved by 12.14%, which can meet the requirements of daily use and lay a foundation for rapid face recognition when wearing mask. () © 2023 IEEE.

Examining the effects of disinformation and trust on social media users' COVID-19 vaccine decision-making

Purpose: Disinformation on social media is a serious issue. This study examines the effects of disinformation on COVID-19 vaccination decision-making to understand how social media users make healthcare decisions when disinformation is presented in their social media feeds. It examines trust in post owners as a moderator on the relationship between information types (i.e. disinformation and factual information) and vaccination decision-making. Design/methodology/approach: This study conducts a scenario-based web survey experiment to collect extensive survey data from social media users. Findings: This study reveals that information types differently affect social media users' COVID-19 vaccination decision-making and finds a moderating effect of trust in post owners on the relationship between information types and vaccination decision-making. For those who have a high degree of trust in post owners, the effect of information types on vaccination decision-making becomes large. In contrast, information types do not affect the decision-making of those who have a very low degree of trust in post owners. Besides, identification and compliance are found to affect trust in post owners. Originality/value: This study contributes to the literature on online disinformation and individual healthcare decision-making by demonstrating the effect of disinformation on vaccination decision-making and providing empirical evidence on how trust in post owners impacts the effects of information types on vaccination decision-making. This study focuses on trust in post owners, unlike prior studies that focus on trust in information or social media platforms. © 2023, Emerald Publishing Limited.

Investigation on the relationship between the number of coronavirus disease 2019 cases at the beginning of the epidemic and the decrease of PM2.5 in Hubei, China: The role of temperature changes

In response to the coronavirus disease 2019 pandemic, the Chinese government implemented blockade measures in Hubei, which largely affected the emission of pollutants. This work is aimed to explore the effects of epidemics on pollutants at different temperatures in Hubei, China. We applied for a panel nonlinear model with autonomous search thresholds to explore this, using daily average temperature as a threshold variable, and PM2.5 set as the explained variable, and the cumulative number of confirmed coronavirus disease 2019 cases set as the explanatory variable. An empirical analysis was conducted by running the proposed model and using nine cities in China most impacted by the pandemic. The results show that there was a non-linear negative relationship between the cumulative number of confirmed coronavirus disease 2019 cases and PM2.5. A more detailed non-linear relationship between the two was uncovered by the proposed panel threshold regression model. When the temperature crosses the threshold value (12.5 degrees C and 20.5 degrees C) in sequence, the estimated value was -0.0688, -0.0934, and -0.1520 in that order. This means that this negative non-linear relationship increased with increasing temperature. This work helps to explore the effect of coronavirus disease 2019 on pollutions at different temperatures and provides a methodological reference to study their nonlinear relationship.

First-in-class small molecule drugs in 2022

2022 is the third year of the global COVID-19 pandemic, and its troubles on new drug discovery are gradually apparent. 37 new drugs were approved by the FDA's Center for Drug Evaluation and Research (CDER) last year, down from the peak of 50 new drug approvals in 2021. Notably, first-in-class drugs still occupy a dominant position this year, with a total of 21 drugs. Among them, 7 are first-in-class small molecule drugs. Although the total number of new drug approvals in 2022 sharply decreased, some first-in-class small molecule drugs were regarded as significant, including mitapivat, the first oral activator targeting the pyruvate kinase (PK);mavacamten, the first selective allosteric inhibitor targeting the myocardial beta myosin ATPase;deucravacitinib, the first deuterated allosteric inhibitor targeting the tyrosine kinase 2 (TYK2);and lenacapavir, the first long-acting inhibitor targeting the HIV capsid. Generally, the research of first-in-class drugs needs to focus on difficult clinical problems and can treat some specific diseases through novel targets and biological mechanisms. There are tremendous challenges in the research processes of new drugs, including biological mechanism research, target selection, molecular screening, lead compound identification and druggability optimization. Therefore, the success of first-in-class drugs development has prominent guidance significance for new drug discovery. This review briefly describes the discovery background, research and development process and therapeutic application of 3 firstin- class small molecule drugs to provide research ideas and methods for more first-in-class drugs.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

Advances in the evolution and immune escape of SARS-CoV-2 variants

Although most of the mutations in the genome of SARS-CoV-2 are ineffective, rapidly eliminated, or relatively neutral, a small number of mutations will affect its functional characteristics and may change its infectivity, pathogenicity, or interaction with host immunity. Since the emergence of SARS-CoV-2 at the end of 2019, there has been a relative evolution stagnation period lasting about 11 months. However, since the end of 2020, a series of spike protein mutations have occurred in SARS-CoV-2, which affect the characteristics of the virus. The variants of concern (VOC) ranged from Alpha to Omicron. These variants will affect the infectivity and antigenicity of the virus. The evidence has shown that the neutralization effect of serum on some SARS-CoV-2 variants is weakened after vaccination, but a deeper understanding of the relevant factors of protection is still required to assess how this may affect the effectiveness of the vaccine. In this review, we described the evolution of SARS-CoV-2, summarized the literatures on the mutations of SARS-CoV-2 spike protein, and discussed the effects of different variants on the protective effects of vaccines and their coping strategies. © 2023 Editorial Board of Medical Journal of Wuhan University. All rights reserved.

PHASE 1 CLINICAL TRIALS OF A Q-GRIFFITHSIN NASAL SPRAY FOR SARS-CoV-2 PROPHYLAXIS

Background: The currently approved vaccines do not induce sterilizing immunity against SAR-CoV-2 infection, and immunity wanes over time. A robust broad spectrum topical prophylaxis strategy could protect vulnerable populations in the face of continuous evolution of SARS-CoV-2. The algal antiviral lectin Griffithsin (GRFT), and an engineered oxidation-resistant variant Q-GRFT have robust entry inhibitory activity against SARS-CoV variants of concern, in addition to other respiratory viruses with pandemic potential. We designed a nasal spray to deliver Q-GRFT to the upper respiratory tract mucosa for on-demand use as a broad-spectrum prophylactic. Two clinical trials (Phase 1a and 1b) were conducted to assess safety, tolerability, and pharmacokinetics of Q-GRFT nasal spray in healthy adults. Method(s): Healthy adult volunteers were enrolled in a Phase 1a double blinded, randomized study to receive a single dose of either intranasal Q-GRFT (3.0 mg, 2 sprays per nostril) or placebo at 2:1 ratio. Following a safety review, the Phase 1b study was initiated. Eleven volunteers in Group 1 received 3.0 mg dose once daily, for 7 days. After a safety review, 11 volunteers in Group 2 received a total of 6.0 mg Q-GRFT (3.0 mg twice daily for 7 days). Topical Q-GRFT concentrations were measured by ELISA in collected nasal and nasopharyngeal fluids. Drug levels in plasma were assayed to determine systemic exposure. Viral microneutralization cytopathic effect (CPE) assays were performed against SARS-CoV-2 Omicron BA-5 and MERS-CoV. Result(s): Eighteen adults (24-54 years;Males 58.3%, Females 41.7%;12 Q-GRFT, 6 Placebo), and 22 adults (aged 23-59 years;Males 52.4%, Females 47.6%) were enrolled in Phase 1a and 1b, respectively. In Phase 1a, a single dose of Q-GRFT maintained quantifiable levels in nasal passages and nasopharynx for up to 24 hours. Similarly, Q-GRFT was quantifiable in nasal and nasopharyngeal regions in the Phase 1b study. No dose accumulation effect or systemic exposure was observed. Nasal and nasopharyngeal swab eluates inhibited SARS-CoV-2 Omicron BA.5 and MERS-CoV in CPE assays. Q-GRFT did not modify olfactory sensation. No severe adverse events were reported. Thus, the nasal spray was deemed safe. Conclusion(s): Intranasal Q-GRFT was safe and enhanced mucosal SARSCoV-2 inhibitory activity in human volunteers. The results support further development of Q-GRFT as a broad-spectrum prophylactic against coronaviruses to curb ongoing infections, and for future pandemic preparedness.

[Research progress on the relationship between low-density neutrophils and infectious diseases]

Neutrophils play an important role in infectious diseases by clearing pathogens in the early stages of the disease and damaging the surrounding tissues along with the disease progress. Low-density neutrophils (LDNs) are a crucial and distinct subpopulation of neutrophils. They are a mixture of activated and degranulated normal mature neutrophils and a considerable number of immature neutrophils prematurely released from the bone marrow. Additionally, they may be involved in the occurrence and development of diseases through the changes in phagocytosis, the generation of reactive oxygen species (ROS), the enhancement of the ability to produce neutrophils extracellular traps and immunosuppression. We summarizes the role of LDNs in the pathogenesis and their correlation with the severity of infectious diseases such as COVID-19, severe fever with thrombocytopenia syndrome (SFTS), AIDS, and tuberculosis.