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1.
Signal Transduct Target Ther ; 7(1): 257, 2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1967591

ABSTRACT

Highly divergent SARS-CoV-2 variants have continuously emerged and spread around the world, and updated vaccines and innovative vaccination strategies are urgently needed to address the global SARS-COV2 pandemic. Here, we established a series of Ad5-vectored SARS-CoV-2 variant vaccines encoding multiple spike proteins derived from the Alpha, Beta, Gamma, Epsilon, Kappa, Delta and Omicron lineages and analyzed the antibody immune responses induced by single-dose and prime-boost vaccination strategies against emerging SARS-CoV-2 variants of concern (VOCs). Single-dose vaccination with SARS-CoV-2 variant vaccines tended to elicit the optimal self-matched neutralizing effects, and Ad5-B.1.351 produced more broad-spectrum cross-neutralizing antibodies against diverse variants. In contrast, prime-boost vaccination further strengthened and broadened the neutralizing antibody responses against highly divergent SARS-CoV-2 variants. The heterologous administration of Ad5-B.1.617.2 and Ad5-B.1.429 to Ad5-WT-primed mice resulted in superior antibody responses against most VOCs. In particular, the Omicron spike could only stimulate self-matched neutralizing antibodies with infrequent cross-reactivities to other variants used in single-dose vaccination strategies; moreover, with prime-boost regimens, this vaccine elicited an optimal specific neutralizing antibody response to Omicron, and prompted cross-antibody responses against other VOCs that were very similar to those obtained with Ad5-WT booster. Overall, this study delineated the unique characteristics of antibody responses to the SARS-CoV-2 VOC spikes with the single-dose or prime-boost vaccination strategies and provided insight into the vaccine development of next SARS-CoV-2 VOCs.


Subject(s)
COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing/genetics , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , Humans , Mice , RNA, Viral , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
2.
J Nanobiotechnology ; 20(1): 272, 2022 Jun 11.
Article in English | MEDLINE | ID: covidwho-1940509

ABSTRACT

BACKGROUND: Acute lung injury (ALI), a severe health-threatening disease, has a risk of causing chronic pulmonary fibrosis. Informative and powerful evidence suggests that inflammation and oxidative stress play a central role in the pathogenesis of ALI. Quercetin is well recognized for its excellent antioxidant and anti-inflammatory properties, which showed great potential for ALI treatment. However, the application of quercetin is often hindered by its low solubility and bioavailability. Therefore, to overcome these challenges, an inhalable quercetin-alginate nanogel (QU-Nanogel) was fabricated, and by this special "material-drug" structure, the solubility and bioavailability of quercetin were significantly enhanced, which could further increase the activity of quercetin and provide a promising therapy for ALI. RESULTS: QU-Nanogel is a novel alginate and quercetin based "material-drug" structural inhalable nanogel, in which quercetin was stabilized by hydrogen bonding to obtain a "co-construct" water-soluble nanogel system, showing antioxidant and anti-inflammatory properties. QU-Nanogel has an even distribution in size of less than 100 nm and good biocompatibility, which shows a stronger protective and antioxidant effect in vitro. Tissue distribution results provided evidence that the QU-Nanogel by ultrasonic aerosol inhalation is a feasible approach to targeted pulmonary drug delivery. Moreover, QU-Nanogel was remarkably reversed ALI rats by relieving oxidative stress damage and acting the down-regulation effects of mRNA and protein expression of inflammation cytokines via ultrasonic aerosol inhalation administration. CONCLUSIONS: In the ALI rat model, this novel nanogel showed an excellent therapeutic effect by ultrasonic aerosol inhalation administration by protecting and reducing pulmonary inflammation, thereby preventing subsequent pulmonary fibrosis. This work demonstrates that this inhalable QU-Nanogel may function as a promising drug delivery strategy in treating ALI.


Subject(s)
Acute Lung Injury , Pulmonary Fibrosis , Acute Lung Injury/drug therapy , Alginates , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/chemistry , Inflammation , Nanogels , Particle Size , Quercetin/pharmacology , Quercetin/therapeutic use , Rats
3.
Sci Rep ; 12(1): 12596, 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1956423

ABSTRACT

Low power microwave can effectively deactivate influenza type A virus through the nonthermal structure-resonant energy transfer effect, at a frequency matching the confined-acoustic dipolar mode frequency of the virus. Currently, aerosol is considered the major route for SARS-CoV-2 transmission. For the potential microwave-based sterilization, the microwave-resonant frequency of SARS-CoV-2 must be unraveled. Here we report a microwave absorption spectroscopy study of the SARS-CoV-2 and HCoV-229E viruses through devising a coplanar-waveguide-based sensor. Noticeable microwave absorption can be observed, while we identified the resonant frequencies of the 1st and 2nd dipolar modes of SARS-CoV-2 virus as 4 and 7.5 GHz respectively. We further found that the resonant frequencies are invariant to the virus titer, and we also studied the microwave absorption of HCoV-229E in weak acidity medium to simulate the common pH value in fluid secretion. Our results suggest the possible radiation frequency for the recently proposed microwave sterilization devices to inactivate SARS-CoV-2 virus through a nonthermal mechanism so as to control the disease transmission in the post-pandemic era.


Subject(s)
COVID-19 , Coronavirus 229E, Human , Humans , Microwaves , Pandemics , SARS-CoV-2
4.
Front Public Health ; 10: 890960, 2022.
Article in English | MEDLINE | ID: covidwho-1952849

ABSTRACT

With Western therapeutic techniques prevailing in Chinese therapies, some techniques that include Chinese traditional cultural features are required since some cultural factors are not considered in the Western method. Our study introduced a new technique, the moving to emptiness technique (MET), which combines Western structural progress and core factors of Chinese culture. Seventeen therapists treated 107 clients with the MET. Clients reported their target symptoms initially, and therapists helped them transfer invisible symptoms to perceivable stuff and remove their jarring stuff using the psychological emptiness area. At the end of the consultations, we found that MET could eliminate symptoms immediately. By grouping target symptoms according to their frequency, the results showed that clients in the high-frequency symptom group had higher rehabilitation rates than those in the low-frequency symptom group. Additionally, the results of the bereavement group were better than those of the non-bereavement group, indicating that the MET can significantly alleviate clients' target symptoms. In future studies, the replication and stability of the MET can be assessed by integrating questionnaires, experimental designs, and neurological equipment.


Subject(s)
COVID-19 , Humans , Pandemics , Surveys and Questionnaires
5.
Psychol Res Behav Manag ; 15: 1731-1740, 2022.
Article in English | MEDLINE | ID: covidwho-1951821

ABSTRACT

Purpose: This study explored the relationship between emotion and death-thought accessibility (DTA) in individuals experiencing true mortality salience (MS), specifically, patients with cancer. Patients and Methods: The study included 255 participants; among them, 132 patients had cancer and represented the MS group, and 123 had dental pain and served as a control group. Participants completed the Projective Diseases Attitude Assessment Questionnaire to induce priming, completed an affect scale, completed one of four calculation tasks as manipulation of cognitive load (all four were done over several sessions), and performed a Pinyin-Chinese characters exercise to measure DTA. Results: MS was associated with strong negative emotional arousal. When these negative emotions are generated, they enter an individual's consciousness and activate proximal defense mechanisms. At this point, DTA can be measured. Patients with cancer had significantly higher levels of DTA in the high-frequency cognitive load condition than in the other three conditions (no task, simple delay task, and single cognitive load task). Patients with dental pain had significantly higher levels of DTA in the no task and simple delay conditions than in the single cognitive load or high-frequency cognitive load conditions. This study also found that negative experiences without MS (specifically, dental pain) are associated with higher levels of DTA. Conclusion: These findings suggest that in addition to death-related events, both negative and stress-inducing events can produce DTA.

6.
World J Pediatr ; 18(8): 545-552, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1943236

ABSTRACT

BACKGROUND: Human adenovirus (HAdV) infection can cause a variety of diseases. It is a major pathogen of pediatric acute respiratory tract infections (ARIs) and can be life-threatening in younger children. We described the epidemiology and subtypes shifting of HAdV among children with ARI in Guangzhou, China. METHODS: We conducted a retrospective study of 161,079 children diagnosed with acute respiratory illness at the Guangzhou Women and Children's Medical Center between 2010 and 2021. HAdV specimens were detected by real-time PCR and the hexon gene was used for phylogenetic analysis. RESULTS: Before the COVID-19 outbreak in Guangzhou, the annual frequency of adenovirus infection detected during this period ranged from 3.92% to 13.58%, with an epidemic peak every four to five years. HAdV demonstrated a clear seasonal distribution, with the lowest positivity in March and peaking during summer (July or August) every year. A significant increase in HAdV cases was recorded for 2018 and 2019, which coincided with a shift in the dominant HAdV subtype from HAdV-3 to HAdV-7. The latter was associated with a more severe disease compared to HAdV-3. The average mortality proportion for children infected with HAdV from 2016 to 2019 was 0.38% but increased to 20% in severe cases. After COVID-19 emerged, HAdV cases dropped to 2.68%, suggesting that non-pharmaceutical interventions probably reduced the transmission of HAdV in the community. CONCLUSION: Our study provides the foundation for the understanding of the epidemiology of HAdV and its associated risks in children in Southern China.


Subject(s)
Adenovirus Infections, Human , Adenoviruses, Human , COVID-19 , Respiratory Tract Infections , Adenovirus Infections, Human/diagnosis , Adenovirus Infections, Human/epidemiology , Adenoviruses, Human/genetics , Child , China/epidemiology , Female , Humans , Infant , Molecular Epidemiology , Phylogeny , Respiratory Tract Infections/diagnosis , Retrospective Studies
7.
Database (Oxford) ; 20222022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1948247

ABSTRACT

In this research, we explored various state-of-the-art biomedical-specific pre-trained Bidirectional Encoder Representations from Transformers (BERT) models for the National Library of Medicine - Chemistry (NLM CHEM) and LitCovid tracks in the BioCreative VII Challenge, and propose a BERT-based ensemble learning approach to integrate the advantages of various models to improve the system's performance. The experimental results of the NLM-CHEM track demonstrate that our method can achieve remarkable performance, with F1-scores of 85% and 91.8% in strict and approximate evaluations, respectively. Moreover, the proposed Medical Subject Headings identifier (MeSH ID) normalization algorithm is effective in entity normalization, which achieved a F1-score of about 80% in both strict and approximate evaluations. For the LitCovid track, the proposed method is also effective in detecting topics in the Coronavirus disease 2019 (COVID-19) literature, which outperformed the compared methods and achieve state-of-the-art performance in the LitCovid corpus. Database URL: https://www.ncbi.nlm.nih.gov/research/coronavirus/.


Subject(s)
COVID-19 , Data Mining , Data Mining/methods , Humans , Machine Learning , Medical Subject Headings , PubMed
8.
Diabetes ; 71, 2022.
Article in English | ProQuest Central | ID: covidwho-1923920

ABSTRACT

Introduction: The use of telemedicine exponentially increased during the COVID-pandemic as it provided easier access as well as the provision of safety via social distancing. A 12-week intense telemedicine diabetic Bootcamp was therefore launched for patients with uncontrolled DM intended for high-quality outpatient diabetic care. Methods: Patients with DM seen at ambulatory clinics with HbA1c > 8.0%, were voluntarily enrolled from September 2020 to November 2021. The dietitians and diabetic educators conducted biweekly visits via telehealth. Patient demographics, HbA1c, BMI, BP were compared before and after the intervention. Results: A total of 134 patients were included for analysis and 94 patients (70.2%) completed the visits. Mean HbA1c change was -2.09% ± 2.4%, and HbA1c reduction was similarly observed across different age groups, gender, ethnicity, BMI, referred clinic types [Table 1]. A greater HbA1c reduction in patients who completed the visits was noted although it was not statistically significant. We found a negative correlation between the initial HbA1c and the change of HbA1c (coefficient -0.7709, p<0.0001, r2= 0.3899) . No significant BMI or MAP change was observed. Conclusions: This quality improvement project demonstrated an improvement in HbA1c for all poorly controlled diabetic patients, regardless of patient characteristics. Moreover, higher initial HbA1c was associated with a greater HbA1c reduction.

9.
J Fungi (Basel) ; 8(7)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1917570

ABSTRACT

The risk of developing coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) depends on factors related to the host, virus, and treatment. However, many hospitals have modified their existing rooms and adjusted airflow to protect healthcare workers from aerosolization, which may increase the risk of Aspergillus exposure. This study aimed to quantitatively investigate airborne fungal levels in negative and slightly negative pressure rooms for COVID-19 patients. The air in neutral pressure rooms in ordinary wards and a liver intensive care unit with high-efficiency particulate air filter was also assessed for comparison. We found the highest airborne fungal burden in recently renovated slightly negative air pressure rooms, and a higher airborne fungal concentration in both areas used to treat COVID-19 patients. The result provided evidence of the potential environmental risk of CAPA by quantitative microbiologic air sampling, which was scarcely addressed in the literature. Enhancing environmental infection control measures to minimize exposure to fungal spores should be considered. However, the clinical implications of a periodic basis to determine indoor airborne fungal levels and further air sterilization in these areas remain to be defined.

10.
Sustainability ; 14(13):7843, 2022.
Article in English | MDPI | ID: covidwho-1911583

ABSTRACT

The COVID-19 pandemic has left more than 1.6 billion children and young people in 161 countries, nearly 80% of students enrolled in education systems globally, out of school. Many countries have resorted to online learning to reduce the repercussions of this shutdown. Many challenges have emerged, the most important of which are infrastructure and communication, and the knowledge of teachers and administrators of the necessary tools and processes are also key factors in providing online learning. In fact, nationwide lockdowns could have been an opportunity to test technological interventions for distance learning. Unfortunately, few systems have reached this point and are ready for implementation. The current study aimed to propose a strategy for distance education using the focus group method to gather the opinions of experts in the field of learning technologies and analyze their responses using text analysis software considering the McKinsey 7S Framework. The study found that the proposed strategy based on instructional design models that use OERs, i.e., blogs, audio recordings, and other resources, can improve the quality and efficiency of learning, provide students with skills, and achieve sustainable development goals in education in the Kingdom of Saudi Arabia.

11.
12.
JAMA Netw Open ; 5(6): e2217004, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1898501

ABSTRACT

Importance: COVID-19 morbidity is highest in Black and Latino older adults. These racial and ethnic groups initially had lower vaccination uptake than others, and rates in Black adults continue to lag. Objectives: To evaluate the effect of outreach via electronic secure messages and mailings from primary care physicians (PCPs) on COVID-19 vaccination uptake among Black and Latino older adults and to compare the effects of culturally tailored and standard PCP messages. Design, Setting, and Participants: This randomized clinical trial was conducted from March 29 to May 20, 2021, with follow-up surveys through July 31, 2021. Latino and Black individuals aged 65 years and older from 4 Kaiser Permanente Northern California (KPNC) service areas were included. Data were analyzed from May 27, 2021, to September 28, 2021. Interventions: Individuals who had not received COVID-19 vaccination after previous outreach were randomized to electronic secure message and/or mail outreach from their PCP, similar outreach with additional culturally tailored content, or usual care. Outreach groups were sent a secure message or letter in their PCP's name, followed by a postcard to those still unvaccinated after 4 weeks. Main Outcomes and Measures: The primary outcome was time to receipt of COVID-19 vaccination during the 8 weeks after initial study outreach. KPNC data were supplemented with state data from external sources. Intervention effects were evaluated via proportional hazards regression. Results: Of 8287 included individuals (mean [SD] age, 72.6 [7.0] years; 4665 [56.3%] women), 2434 (29.4%) were Black, 3782 (45.6%) were Latino and preferred English-language communications, and 2071 (25.0%) were Latino and preferred Spanish-language communications; 2847 participants (34.4%) had a neighborhood deprivation index at the 75th percentile or higher. A total of 2767 participants were randomized to culturally tailored PCP outreach, 2747 participants were randomized to standard PCP outreach, and 2773 participants were randomized to usual care. Culturally tailored PCP outreach led to higher COVID-19 vaccination rates during follow-up compared with usual care (664 participants [24.0%] vs 603 participants [21.7%]; adjusted hazard ratio (aHR), 1.22; 95% CI, 1.09-1.37), as did standard PCP outreach (635 participants [23.1%]; aHR, 1.17; 95% CI, 1.04-1.31). Individuals who were Black (aHR, 1.19; 95% CI, 1.06-1.33), had high neighborhood deprivation (aHR, 1.17; 95% CI, 1.03-1.33), and had medium to high comorbidity scores (aHR, 1.19; 95% CI, 1.09-1.31) were more likely to be vaccinated during follow-up. Conclusions and Relevance: This randomized clinical trial found that PCP outreach using electronic and mailed messages increased COVID-19 vaccination rates among Black and Latino older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT05096026.


Subject(s)
COVID-19 , Physicians, Primary Care , Aged , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Electronics , Female , Hispanic or Latino , Humans , Male , Postal Service , Vaccination
13.
PLoS One ; 17(3): e0263688, 2022.
Article in English | MEDLINE | ID: covidwho-1896443

ABSTRACT

BACKGROUND: During the COVID-19 surge in Taiwan, the Far East Memorial Hospital established a system including a centralized quarantine unit and triage admission protocol to facilitate acute care surgical inpatient services, prevent nosocomial COVID-19 infection and maintain the efficiency and quality of health care service during the pandemics. MATERIALS AND METHODS: This retrospective cohort study included patients undergoing acute care surgery. The triage admission protocol was based on rapid antigen tests, Liat® PCR and RT-PCT tests. Type of surgical procedure, patient characteristics, and efficacy indices of the centralized quarantine unit and emergency department (ED) were collected and analyzed before (Phase I: May 11 to July 2, 2021) and after (Phase II: July 3 to July 31, 2021) the system started. RESULTS: A total of 287 patients (105 in Phase I and 182 in Phase II) were enrolled. Nosocomial COVID-19 infection occur in 27 patients in phase I but zero in phase II. More patients received traumatological, orthopedic, and neurologic surgeries in phase II than in phase I. The patients' surgical risk classification, median total hospital stay, intensive care unit (ICU) stay, intraoperative blood loss, operation time, and the number of patients requiring postoperative ICU care were similar in both groups. The duration of ED stay and waiting time for acute care surgery were longer in Phase II (397 vs. 532 minutes, p < 0.0001). The duration of ED stay was positively correlated with the number of surgical patients visiting the ED (median = 66 patients, Spearman's ρ = 0.207) and the occupancy ratio in the centralized quarantine unit on that day (median = 90.63%, Spearman's ρ = 0.191). CONCLUSIONS: The triage admission protocol provided resilient quarantine needs and sustainable acute care surgical services during the COVID-19 pandemic. The efficiency was related to the number of medical staff dedicated to the centralized quarantine unit and number of surgical patients visited in ED.


Subject(s)
COVID-19/epidemiology , Critical Care/methods , Triage/methods , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/virology , Female , Humans , Length of Stay , Male , Middle Aged , Pandemics , Patient Admission/standards , Quarantine , Retrospective Studies , SARS-CoV-2/isolation & purification , Surgical Procedures, Operative , Taiwan/epidemiology , Tertiary Care Centers , Time-to-Treatment , Young Adult
15.
J Biomed Sci ; 29(1): 37, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1883528

ABSTRACT

BACKGROUND: Calls for the coronavirus to be treated as an endemic illness, such as the flu, are increasing. After achieving high coverage of COVID-19 vaccination, therapeutic drugs have become important for future SARS-CoV-2 variant outbreaks. Although many monoclonal antibodies have been approved for emergency use as treatments for SARS-CoV-2 infection, some monoclonal antibodies are not authorized for variant treatment. Broad-spectrum monoclonal antibodies are unmet medical needs. METHODS: We used a DNA prime-protein boost approach to generate high-quality monoclonal antibodies. A standard ELISA was employed for the primary screen, and spike protein-human angiotensin-converting enzyme 2 blocking assays were used for the secondary screen. The top 5 blocking clones were selected for further characterization, including binding ability, neutralization potency, and epitope mapping. The therapeutic effects of the best monoclonal antibody against SARS-CoV-2 infection were evaluated in a hamster infection model. RESULTS: Several monoclonal antibodies were selected that neutralize different SARS-CoV-2 variants of concern (VOCs). These VOCs include Alpha, Beta, Gamma, Delta, Kappa and Lambda variants. The high neutralizing antibody titers against the Beta variant would be important to treat Beta-like variants. Among these monoclonal antibodies, mAb-S5 displays the best potency in terms of binding affinity and neutralizing capacity. Importantly, mAb-S5 protects animals from SARS-CoV-2 challenge, including the Wuhan strain, D614G, Alpha and Delta variants, although mAb-S5 exhibits decreased neutralization potency against the Delta variant. Furthermore, the identified neutralizing epitopes of monoclonal antibodies are all located in the receptor-binding domain (RBD) of the spike protein but in different regions. CONCLUSIONS: Our approach generates high-potency monoclonal antibodies against a broad spectrum of VOCs. Multiple monoclonal antibody combinations may be the best strategy to treat future SARS-CoV-2 variant outbreaks.


Subject(s)
Antibodies, Monoclonal , COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/drug therapy , COVID-19 Vaccines , Cricetinae , Humans , Spike Glycoprotein, Coronavirus/genetics
16.
Frontiers in public health ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1871840

ABSTRACT

With Western therapeutic techniques prevailing in Chinese therapies, some techniques that include Chinese traditional cultural features are required since some cultural factors are not considered in the Western method. Our study introduced a new technique, the moving to emptiness technique (MET), which combines Western structural progress and core factors of Chinese culture. Seventeen therapists treated 107 clients with the MET. Clients reported their target symptoms initially, and therapists helped them transfer invisible symptoms to perceivable stuff and remove their jarring stuff using the psychological emptiness area. At the end of the consultations, we found that MET could eliminate symptoms immediately. By grouping target symptoms according to their frequency, the results showed that clients in the high-frequency symptom group had higher rehabilitation rates than those in the low-frequency symptom group. Additionally, the results of the bereavement group were better than those of the non-bereavement group, indicating that the MET can significantly alleviate clients' target symptoms. In future studies, the replication and stability of the MET can be assessed by integrating questionnaires, experimental designs, and neurological equipment.

17.
Front Mol Biosci ; 9: 871499, 2022.
Article in English | MEDLINE | ID: covidwho-1834465

ABSTRACT

Epidemics caused by coronaviruses (CoVs), namely the severe acute respiratory syndrome (SARS) (2003), Middle East respiratory syndrome (MERS) (2012), and coronavirus disease 2019 (COVID-19) (2019), have triggered a global public health emergency. Drug development against CoVs is inherently arduous. The nucleocapsid (N) protein forms an oligomer and facilitates binding with the viral RNA genome, which is critical in the life cycle of the virus. In the current study, we found a potential allosteric site (Site 1) using PARS, an online allosteric site predictor, in the CoV N-N-terminal RNA-binding domain (NTD) to modulate the N protein conformation. We identified 5-hydroxyindole as the lead via molecular docking to target Site 1. We designed and synthesized four 5-hydroxyindole derivatives, named P4-1 to P4-4, based on the pose of 5-hydroxyindole in the docking model complex. Small-angle X-ray scattering (SAXS) data indicate that two 5-hydroxyindole compounds with higher hydrophobic R-groups mediate the binding between N-NTD and N-C-terminal dimerization domain (CTD) and elicit high-order oligomerization of the whole N protein. Furthermore, the crystal structures suggested that these two compounds act on this novel cavity and create a flat surface with higher hydrophobicity, which may mediate the interaction between N-NTD and N-CTD. Taken together, we discovered an allosteric binding pocket targeting small molecules that induces abnormal aggregation of the CoV N protein. These novel concepts will facilitate protein-protein interaction (PPI)-based drug design against various CoVs.

18.
Int J Mol Sci ; 23(9)2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1820291

ABSTRACT

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 µg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 µg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing.


Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Th1 Cells , Adjuvants, Immunologic/pharmacology , Adjuvants, Pharmaceutic , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/pharmacology , Cricetinae , Emulsions , Humans , Mice , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology
19.
Signal Transduct Target Ther ; 7(1): 139, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1815514

ABSTRACT

The SARS-CoV-2 Omicron variant shows substantial resistance to neutralization by infection- and vaccination-induced antibodies, highlighting the demands for research on the continuing discovery of broadly neutralizing antibodies (bnAbs). Here, we developed a panel of bnAbs against Omicron and other variants of concern (VOCs) elicited by vaccination of adenovirus-vectored COVID-19 vaccine (Ad5-nCoV). We also investigated the human longitudinal antibody responses following vaccination and demonstrated how the bnAbs evolved over time. A monoclonal antibody (mAb), named ZWD12, exhibited potent and broad neutralization against SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa, Delta, and Omicron by blocking the spike protein binding to the angiotensin-converting enzyme 2 (ACE2) and provided complete protection in the challenged prophylactic and therapeutic K18-hACE2 transgenic mouse model. We defined the ZWD12 epitope by determining its structure in complex with the spike (S) protein via cryo-electron microscopy. This study affords the potential to develop broadly therapeutic mAb drugs and suggests that the RBD epitope bound by ZWD12 is a rational target for the design of a broad spectrum of vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal/genetics , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Cryoelectron Microscopy , Epitopes , Humans , Mice , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Viral Envelope Proteins
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