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1.
Toxics ; 11(2):87, 2023.
Article in English | MDPI | ID: covidwho-2200840

ABSTRACT

Wearing masks has become the norm during the Coronavirus disease pandemic. Masks can reportedly interface with air pollutants and release microplastics and plastic additives such as phthalates. In this study, an experimental device was set up to simulate the impact of five kinds of masks (activated-carbon, N95, surgical, cotton, and fashion masks) on the risk of humans inhaling microplastics and phthalates during wearing. The residual concentrations of seven major phthalates ranged from 296 to 72,049 ng/g (median: 1242 ng/g), with the lowest and the highest concentrations detected in surgical (median: 367 ng/g) and fashion masks (median: 37,386 ng/g), respectively. During the whole inhalation simulation process, fragmented and 20-100 μm microplastics accounted for the largest, with a rapid release during the first six hours. After one day's wearing, that of 6 h, while wearing different masks, 25-135 and 65-298 microplastics were inhaled indoors and outdoors, respectively. The total estimated daily intake of phthalates with indoor and outdoor conditions by inhalation and skin exposure ranged from 1.2 to 13 and 0.43 to 14 ng/kg bw/d, respectively. Overall, surgical masks yield a protective effect, while cotton and fashion masks increase human exposure to microplastics and phthalates both indoors and outdoors compared to no mask wearing. This study observed possible risks from common facemasks and provided suggestions to consumers for selecting suitable masks to reduce exposure risks from microplastics and phthalate acid.

2.
Cell Reports Medicine ; : 100918, 2023.
Article in English | ScienceDirect | ID: covidwho-2184477

ABSTRACT

Summary With the wide vaccinations against coronavirus disease 2019 (COVID-19), we are witnessing gradually waning neutralizing antibodies and increasing cases of breakthrough infections, necessitating the development of drugs aside from vaccines, particularly ones that can be administered outside of hospitals. Here, we present two cross-reactive nanobodies (R14 and S43) and their multivalent derivatives, including decameric ones (fused to the IgM Fc) that maintain potent neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after aerosolization and display pan-SARS-CoV-2 but varied pan-sarbecovirus activities. Through respiratory administration to mice, monovalent and decameric R14 significantly reduce the lung viral RNAs at low dose and display potent pre- and post-exposure protection. Furthermore, structural studies reveal the neutralizing mechanisms of R14 and S43 and the multiple inhibition effects that the multivalent derivatives exert. Our work demonstrates promising convenient drug candidates via respiratory administration against SARS-CoV-2 infection, which can contribute to contain the COVID-19 pandemic.

3.
Frontiers in public health ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-2147764

ABSTRACT

Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.617.2 (also named the Delta variant) was declared as a variant of concern by the World Health Organization (WHO). This study aimed to describe the outbreak that occurred in Nanjing city triggered by the Delta variant through the epidemiological parameters and to understand the evolving epidemiology of the Delta variant. Methods We collected the data of all COVID-19 cases during the outbreak from 20 July 2021 to 24 August 2021 and estimated the distribution of serial interval, basic and time-dependent reproduction numbers (R0 and Rt), and household secondary attack rate (SAR). We also analyzed the cycle threshold (Ct) values of infections. Results A total of 235 cases have been confirmed. The mean value of serial interval was estimated to be 4.79 days with the Weibull distribution. The R0 was 3.73 [95% confidence interval (CI), 2.66–5.15] as estimated by the exponential growth (EG) method. The Rt decreased from 4.36 on 20 July 2021 to below 1 on 1 August 2021 as estimated by the Bayesian approach. We estimated the household SAR as 27.35% (95% CI, 22.04–33.39%), and the median Ct value of open reading frame 1ab (ORF1ab) genes and nucleocapsid protein (N) genes as 25.25 [interquartile range (IQR), 20.53–29.50] and 23.85 (IQR, 18.70–28.70), respectively. Conclusions The Delta variant is more aggressive and transmissible than the original virus types, so continuous non-pharmaceutical interventions are still needed.

4.
PLoS Comput Biol ; 18(10): e1010636, 2022 10.
Article in English | MEDLINE | ID: covidwho-2112639

ABSTRACT

Early and accurate detection of viruses in clinical and environmental samples is essential for effective public healthcare, treatment, and therapeutics. While PCR detects potential pathogens with high sensitivity, it is difficult to scale and requires knowledge of the exact sequence of the pathogen. With the advent of next-gen single-cell sequencing, it is now possible to scrutinize viral transcriptomics at the finest possible resolution-cells. This newfound ability to investigate individual cells opens new avenues to understand viral pathophysiology with unprecedented resolution. To leverage this ability, we propose an efficient and accurate computational pipeline, named Venus, for virus detection and integration site discovery in both single-cell and bulk-tissue RNA-seq data. Specifically, Venus addresses two main questions: whether a tissue/cell type is infected by viruses or a virus of interest? And if infected, whether and where has the virus inserted itself into the human genome? Our analysis can be broken into two parts-validation and discovery. Firstly, for validation, we applied Venus on well-studied viral datasets, such as HBV- hepatocellular carcinoma and HIV-infection treated with antiretroviral therapy. Secondly, for discovery, we analyzed datasets such as HIV-infected neurological patients and deeply sequenced T-cells. We detected viral transcripts in the novel target of the brain and high-confidence integration sites in immune cells. In conclusion, here we describe Venus, a publicly available software which we believe will be a valuable virus investigation tool for the scientific community at large.


Subject(s)
HIV Infections , Liver Neoplasms , Viruses , Humans , RNA-Seq , Sequence Analysis, RNA , Software
5.
Sci Rep ; 12(1): 18168, 2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2096749

ABSTRACT

SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in the airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments have not been fully characterized using matched samples from large cohorts. Gene expression data from 793 nasal and 1673 bronchial brushes obtained from individuals participating in lung cancer screening or diagnostic workup revealed that smoking status (current versus former) was the only clinical factor significantly and reproducibly associated with VE gene expression. The expression of ACE2 and TMPRSS2 was higher in smokers in the bronchus but not in the nose. scRNA-seq of nasal brushings indicated that ACE2 co-expressed genes were highly expressed in club and C15orf48+ secretory cells while TMPRSS2 co-expressed genes were highly expressed in keratinizing epithelial cells. In contrast, these ACE2 and TMPRSS2 modules were highly expressed in goblet cells in scRNA-seq from bronchial brushings. Cell-type deconvolution of the gene expression data confirmed that smoking increased the abundance of several secretory cell populations in the bronchus, but only goblet cells in the nose. The association of ACE2 and TMPRSS2 with smoking in the bronchus is due to their high expression in goblet cells which increase in abundance in current smoker airways. In contrast, in the nose, these genes are not predominantly expressed in cell populations modulated by smoking. In individuals with elevated lung cancer risk, smoking-induced VE gene expression changes in the nose likely have minimal impact on SARS-CoV-2 infection, but in the bronchus, smoking may lead to higher viral loads and more severe disease.


Subject(s)
COVID-19 , Lung Neoplasms , Humans , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Early Detection of Cancer , Peptidyl-Dipeptidase A/metabolism , Lung Neoplasms/metabolism , Bronchi/metabolism , Smoking/adverse effects , Smoking/genetics
6.
Elife ; 112022 08 25.
Article in English | MEDLINE | ID: covidwho-2025329

ABSTRACT

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein ­ the so-called spike protein ­ all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , Humans , Rats , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
7.
Financ Res Lett ; 50: 103289, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2004077

ABSTRACT

This paper examines implied volatility spillovers and connectedness between Bitcoin and a broad range of traditional financial assets (U.S. equity market, gold, crude oil, emerging markets and developing markets) from January 8, 2019 to January 20, 2022. Vector Auto-Regression and Generalized Forecast Error Variance Decomposition are used to compare results before COVID-19, during COVID-19 and after the vaccine becomes available. Results indicate higher connectedness during COVID-19 but very low connectedness after the vaccine is available, signaling recovery in financial markets. We also find that Bitcoin is a strong transmitter of volatility during COVID-19.

8.
BMC Infect Dis ; 22(1): 632, 2022 Jul 20.
Article in English | MEDLINE | ID: covidwho-1935459

ABSTRACT

BACKGROUND: The outbreak of SARS-CoV-2 at the end of 2019 sounded the alarm for early inspection on acute respiratory infection (ARI). However, diagnosis pathway of ARI has still not reached a consensus and its impact on prognosis needs to be further explored. METHODS: ESAR is a multicenter, open-label, randomized controlled, non-inferiority clinical trial on evaluating the diagnosis performance and its impact on prognosis of ARI between mNGS and multiplex PCR. Enrolled patients will be divided into two groups with a ratio of 1:1. Group I will be directly tested by mNGS. Group II will firstly receive multiplex PCR, then mNGS in patients with severe infection if multiplex PCR is negative or inconsistent with clinical manifestations. All patients will be followed up every 7 days for 28 days. The primary endpoint is time to initiate targeted treatment. Secondary endpoints include incidence of significant events (oxygen inhalation, mechanical ventilation, etc.), clinical remission rate, and hospitalization length. A total of 440 participants will be enrolled in both groups. DISCUSSION: ESAR compares the efficacy of different diagnostic strategies and their impact on treatment outcomes in ARI, which is of great significance to make precise diagnosis, balance clinical resources and demands, and ultimately optimize clinical diagnosis pathways and treatment strategies. Trial registration Clinicaltrial.gov, NCT04955756, Registered on July 9th 2021.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Hospitalization , Humans , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiration, Artificial , Treatment Outcome
9.
NPJ Vaccines ; 7(1): 84, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-1960375

ABSTRACT

As the world continues to experience the COVID-19 pandemic, seasonal influenza remain a cause of severe morbidity and mortality globally. Worse yet, coinfection with SARS-CoV-2 and influenza A virus (IAV) leads to more severe clinical outcomes. The development of a combined vaccine against both COVID-19 and influenza is thus of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we developed and characterized a novel mRNA vaccine encoding the HA antigen of influenza A (H1N1) virus, termed ARIAV. Then, ARIAV was combined with our COVID-19 mRNA vaccine ARCoV, which encodes the receptor-binding domain (RBD) of the SARS-CoV-2 S protein, to formulate the final combined vaccine, AR-CoV/IAV. Further characterization demonstrated that immunization with two doses of AR-CoV/IAV elicited robust protective antibodies as well as antigen-specific cellular immune responses against SARS-CoV-2 and IAV. More importantly, AR-CoV/IAV immunization protected mice from coinfection with IAV and the SARS-CoV-2 Alpha and Delta variants. Our results highlight the potential of the LNP-mRNA vaccine platform in preventing COVID-19 and influenza, as well as other respiratory diseases.

10.
Psychol Res Behav Manag ; 15: 1783-1796, 2022.
Article in English | MEDLINE | ID: covidwho-1951831

ABSTRACT

Background: Employees in high-risk occupations are exposed to tremendous work stress that hinders organizational effectiveness and personal mental health. Based on positive psychology, courage can be considered a protective factor that buffers the adverse effect of high-risk surroundings on employees. However, little is known about the way courage is simulated or evaluated in response to safety concerns. Virtual reality (VR) is an accessible tool for courage simulation due to its immersive qualities, presence and interactive features and may provide a promising pathway to achieve a scientific, accurate and ecologically valid evaluation of high-risk employees. Methods: The sample consisted of 51 high-risk employees who were recruited voluntarily. Before and after experiencing the VR courage scenarios, the participants completed the VR features questionnaire, the Physical Courage at Work Scale (PCWS), the Courage Measure (CM), and the Positive and Negative Affect Scale (PANAS). During the process of watching the VR courage scenarios, the participants' heart rate and skin conductance at resting-state baseline and during virtual courage scenarios were recorded through HTC VIVE Pro Eye and BioGraph Infiniti 8. Results: The results support the hypothesis and reveal that the interaction, immersion and presence scores of the scenarios were all significantly higher than the median 4 points. The score for the CM in the posttest was significantly higher than that in the pretest. The scared and afraid scores for the posttest were significantly higher than those for the pretest. The heart rate and skin conductance of each scenario showed an increase compared with the baseline. The Pearson's correlation between physiological indicators and the score of the PCWS was 0.28~0.54. Conclusion: This study developed virtual courage for high-risk occupations based on well-established theory and VR technology. Experimental data revealed that the paradigm conformed to the requirements of VR features and was able to activate fear and evoke the quality of courage. Thus, the virtual courage paradigms have good validity in simulating scenarios for high-risk employees, which might accelerate organizational effectiveness while buffering working stress.

12.
Nat Commun ; 13(1): 3654, 2022 Jun 27.
Article in English | MEDLINE | ID: covidwho-1908175

ABSTRACT

NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluate the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in BBIBP-CorV recipients in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who have administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, are randomized 1:1 to receive either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The incidence of adverse reactions is low, and the overall safety profile is quite similar between two booster regimens. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster are significantly higher than those by BBIBP-CorV booster against not only SARS-CoV-2 prototype strain but also multiple variants of concerns (VOCs). Especially, the neutralizing antibody GMT against Omicron variant induced by heterologous NVSI-06-08 booster reaches 367.67, which is substantially greater than that boosted by BBIBP-CorV (GMT: 45.03). In summary, NVSI-06-08 is safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which is immunogenically superior to the homologous boost with another dose of BBIBP-CorV.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Immunogenicity, Vaccine , Adult , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Humans , Immunoglobulin G , SARS-CoV-2
13.
Signal Transduct Target Ther ; 7(1): 172, 2022 06 06.
Article in English | MEDLINE | ID: covidwho-1878517

ABSTRACT

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1-3 months, 4-6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01-63.85 folds on day 28 after vaccination, whereas only 4.20-16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , SARS-CoV-2
14.
Support Care Cancer ; 30(9): 7469-7479, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1877840

ABSTRACT

Autologous stem cell transplantation (ASCT) is standard of care in biologically fit, newly diagnosed multiple myeloma (MM) patients, offering better therapeutic outcomes and improved quality of life (QoL). However, with the UK's 1st national lockdown on 23/03/2020, several guidelines recommended deferring ASCT due to risks of infection, with resource limitations forcing some units to suspend ASCT entirely. Such changes to patients' treatment plans inevitably altered their lived experience during these uncertain times with expected impact on QoL. We conducted a qualitative study using semi-structured interviews to gain insight into MM patients' understanding of their disease, initial therapy and ASCT, and their response to therapy changes. A clinical snapshot of how COVID-19 affected the MM ASCT service in a single UK institution is also provided, including changes to chemotherapy treatment plans, timing, and prioritisation of ASCT. Framework analysis identified 6 overarching themes: (1) beliefs about ASCT, (2) perceptions of information provided about MM and ASCT, (3) high levels of fear and anxiety due to COVID-19, (4) feelings about ASCT disruption or delay due to COVID-19, (5) perceptions of care, and (6) importance of social support. Example subthemes were beliefs that ASCT would provide a long-remission/best chance of normality including freedom from chemotherapy and associated side-effects, disappointment, and devastation at COVID-related treatment delays (despite high anxiety about infection) and exceptionally high levels of trust in the transplant team. Such insights will help us adjust our service and counselling approaches to be more in tune with patients' priorities and expectations.


Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Communicable Disease Control , Humans , Multiple Myeloma/drug therapy , Quality of Life , Retrospective Studies , Stem Cell Transplantation , Transplantation, Autologous
15.
Viruses ; 14(5)2022 05 12.
Article in English | MEDLINE | ID: covidwho-1869809

ABSTRACT

A new antibody diagnostic assay with more rapid and robust properties is demanded to quantitatively evaluate anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity in a large population. Here, we developed a nanometer-scale fluorescent biosensor system consisting of CdSe-ZnS quantum dots (QDs) coupled with the highly sensitive B-cell epitopes of SARS-CoV-2 that could remarkably identify the corresponding antibody with a detection limit of 100 pM. Intriguingly, we found that fluorescence quenching of QDs was stimulated more obviously when coupled with peptides than the corresponding proteins, indicating that the energy transfer between QDs and peptides was more effective. Compared to the traditional enzyme-linked immunosorbent assay (ELISA), the B-cell-epitope-based QD-biosensor could robustly distinguish coronavirus disease 2019 (COVID-19) antibody-positive patients from uninfected individuals with a higher sensitivity (92.3-98.1% positive rates by QD-biosensor vs. 78.3-83.1% positive rates by ELISAs in 207 COVID-19 patients' sera) in a more rapid (5 min) and labor-saving manner. Taken together, the 'QD-peptides' biosensor provided a novel real-time, quantitative, and high-throughput method for clinical diagnosis and home-use tests.


Subject(s)
Biosensing Techniques , COVID-19 , Quantum Dots , Antibodies , COVID-19/diagnosis , Epitopes, B-Lymphocyte , Humans , Peptides , SARS-CoV-2
16.
Viruses ; 14(5)2022 04 28.
Article in English | MEDLINE | ID: covidwho-1820410

ABSTRACT

New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.


Subject(s)
COVID-19 , Dihydroorotate Dehydrogenase , Virus Diseases , Viruses , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Dihydroorotate Dehydrogenase/antagonists & inhibitors , Humans , Pyrimidines , SARS-CoV-2/drug effects , Virus Diseases/drug therapy , Virus Replication/drug effects , Viruses/drug effects
17.
Cell ; 185(13): 2265-2278.e14, 2022 06 23.
Article in English | MEDLINE | ID: covidwho-1803705

ABSTRACT

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.


Subject(s)
COVID-19 , Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Mice , SARS-CoV-2/genetics
18.
Gen Hosp Psychiatry ; 77: 80-87, 2022.
Article in English | MEDLINE | ID: covidwho-1800043

ABSTRACT

OBJECTIVE: The COVID-19 pandemic is a traumatic stressor resulting in anxiety, depression, post-traumatic stress, and burnout among healthcare workers. We describe an intervention to support the health workforce and summarize results from its 40-week implementation in a large, tri-state health system during the COVID-19 pandemic. METHOD: We conducted 121 virtual and interactive Stress and Resilience Town Halls attended by 3555 healthcare workers. Town hall participants generated 1627 stressors and resilience strategies that we coded and analyzed using rigorous qualitative methods (Kappa = 0.85). RESULTS: We identify six types of stressors and eight types of resilience strategies reported by healthcare workers, how these changed over time, and how town halls were responsive to emerging health workforce needs. We show that town halls dedicated to groups working together yielded 84% higher mean attendance and more sharing of stressors and resilience strategies than those offered generally across the health system, and that specific stressors and strategies are reported consistently while others vary markedly over time. CONCLUSIONS: The virtual and interactive Stress and Resilience Town Hall is an accessible, scalable, and sustainable intervention to build mutual support, wellness, and resilience among healthcare workers and within hospitals and health systems responding to emerging crises, pandemics, and disasters.


Subject(s)
Burnout, Professional , COVID-19 , Resilience, Psychological , Burnout, Professional/epidemiology , Health Personnel , Health Workforce , Humans , Pandemics
19.
Research Square ; 2022.
Article in English | EuropePMC | ID: covidwho-1786456

ABSTRACT

As the world continues to experience the COVID-19 pandemic, seasonal influenza remain a cause of severe morbidity and mortality globally. Worse yet, coinfection with SARS-CoV-2 and influenza A virus (IAV) leads to more severe clinical outcomes. The development of a combined vaccine against both COVID-19 and influenza is thus of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we developed and characterized a novel mRNA vaccine encoding the HA antigen of influenza A (H1N1) virus, termed ARIAV. Then, ARIAV was combined with our COVID-19 mRNA vaccine ARCoV, which encodes the receptor binding domain (RBD) of the SARS-CoV-2 S protein, to formulate the final combined vaccine, AR-CoV/IAV. Further characterization demonstrated that immunization with two doses of AR-CoV/IAV elicited robust protective antibodies as well as antigen-specific cellular immune responses against SARS-CoV-2 and IAV. More importantly, AR-CoV/IAV immunization protected mice from coinfection with IAV and the SARS-CoV-2 Alpha and Delta variants. Our results highlight the potential of the LNP-mRNA vaccine platform in preventing COVID-19 and influenza, as well as other respiratory diseases.

20.
Nat Immunol ; 23(3): 423-430, 2022 03.
Article in English | MEDLINE | ID: covidwho-1713201

ABSTRACT

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.


Subject(s)
Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/genetics , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Cloning, Molecular , Disease Models, Animal , Dose-Response Relationship, Immunologic , Epitopes , Humans , Macaca mulatta , Mice , Neutralization Tests , Protein Engineering/methods , Structure-Activity Relationship
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