A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing ...the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain.
We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127.
Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 46%), fatigue (47 44%), headache (42 39%), and muscle pain (18 17%. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination.
The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation.
National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an ...appropriate dose of the candidate vaccine for an efficacy study.
This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.
603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented.
The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.
National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.
We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). ...Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.
The triglyceride-glucose (TyG) index has been proposed as a surrogate marker of insulin resistance. However, the relationship between the TyG index and central blood pressure (BP), has not been well ...studied in adults.
A total of 715 Chinese adult participants were enrolled in this study. Anthropometric and BP were assessed. The TyG index was calculated as lnfasting triglycerides(mg/dL) × fasting glucose(mg/dL)/2. Central BP was measured using SphygmoCor system.
The participants were stratified into three groups based on the TyG index, and significant differences were observed in metabolic and cardiovascular parameters and the prevalence of hypertension among the groups. Both brachial (β = 1.38, P = 0.0310; group highest vs. lowest, β = 2.66, P = 0.0084) and aortic (β = 2.38, P = 0.0002; group highest vs. lowest, β = 3.96, P = 0.0001) diastolic BP were significantly and independently associated with the TyG index and increasing TyG index tertile. However, there was no independent association between the TyG index and systolic BP. A one-unit increase in the TyG index was associated with a 46% higher risk of hypertension (P = 0.0121), and compared with the lowest group, participants in the highest group had a 95% higher risk of hypertension (P = 0.0057).
Our study demonstrates a significant and independent association between the TyG index and both brachial and aortic diastolic BP in Chinese adults. Furthermore, the TyG index was found to be an independent predictor of hypertension.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy ...Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. Methods We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone–China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18–50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 1011 viral particles), low-dose vaccine (8·0 × 1010 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. Findings During Oct 10–28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 26% in high-dose group and 31 25% in low-dose group) than in those receiving placebo (17 14%; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 95% CI 976·6–1602·5 in low-dose group and 1728·4 1459·4–2047·0 in high-dose group) and peaked at day 28 (1471·8 1151·0–1881·8 and 2043·1 1762·4–2368·4), but declined quickly in the following months (223·3 148·2–336·4 and 254·2 185·0–349·5 at day 168). Geometric mean titres in the placebo group remained around 6·0–6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. Interpretation The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 1010 viral particles was the optimal dose. Funding Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.
Zeolite Beta single crystals with intracrystalline hierarchical porosity at macro‐, meso‐, and micro‐length scales can effectively overcome the diffusion limitations in the conversion of bulky ...molecules. However, the construction of large zeolite Beta single crystals with such porosity is a challenge. We report herein the synthesis of hierarchically ordered macro‐mesoporous single‐crystalline zeolite Beta (OMMS‐Beta) with a rare micron‐scale crystal size by an in situ bottom‐up confined zeolite crystallization strategy. The fully interconnected intracrystalline macro‐meso‐microporous hierarchy and the micron‐sized single‐crystalline nature of OMMS‐Beta lead to improved accessibility to active sites and outstanding (hydro)thermal stability. Higher catalytic performances in gas‐phase and liquid‐phase acid‐catalyzed reactions involving bulky molecules are obtained compared to commercial Beta and nanosized Beta zeolites. The strategy has been extended to the synthesis of other zeolitic materials, including ZSM‐5, TS‐1, and SAPO‐34.
An in situ bottom‐up confined zeolite crystallization strategy is developed to construct micron‐sized hierarchically ordered macro‐mesoporous single‐crystalline zeolite Beta with improved accessibility to active sites and outstanding (hydro)thermal stability for both gas‐phase and liquid‐phase acid‐catalyzed reactions of bulky molecules.
Klotho, an important anti-aging protein, may be related to elevated blood pressure (BP) and arterial stiffness. We aimed to investigate associations between the serum klotho concentration and ...peripheral/central BP and arterial stiffness based on the carotid-femoral pulse wave velocity (cfPWV) in a Chinese population. We invited all inhabitants aged ≥ 18 years in two Dali communities for participation. The SphygmoCor system was used to record radial arterial waveforms. Aortic waveforms were derived using a generalized transfer function. The central BP was assessed by calibrating the brachial BP, which was measured using an oscillometric device. The serum klotho concentration was measured using an enzyme-linked immunosorbent assay and logarithmically transformed. Of the 716 participants (mean age: 51.9 ± 12.6 years), 467 (65.2%) were women. The median serum klotho concentration was 381.8 pg/mL. The serum klotho concentration did not significantly differ between patients with and without hypertension (P > 0.05) and between those with and without arterial stiffness (cfPWV ≥ 10 m/s) (P > 0.05). After adjusting for confounders, the serum klotho concentration was not significantly associated with the peripheral or central BP (P > 0.05) and cfPWV (P > 0.05). Our data indicated that the serum klotho concentration was not associated with BP or cfPWV in the general Chinese population.
Macrocyclic delivery and therapeutics are two significant topics in supramolecular biomedicine. The functional integration of these topics would open new avenues for treating diseases ...synergistically. However, these two individual topics have only been occasionally merged, probably because of the lack of functionalized design of macrocyclic host and the lack of efficient recognition between host and guest drugs. Herein, a “drug‐in‐drug” strategy is proposed, in which an active drug is encapsulated by a macrocycle possessing therapeutic activity to form a multifunctional supramolecular active pharmaceutical ingredient. As a proof‐of‐concept, a complex of hydroxychloroquine (HCQ) with sulfonated azocalix4arene (HCQ@SAC4A) is prepared to treat rheumatoid arthritis (RA) in a combined fashion. SAC4A is a therapeutic agent that exhibits scavenging capacity for reactive oxygen species and exerts an anti‐inflammatory effect. It is also a hypoxia‐responsive carrier that can deliver HCQ directly to the inflammatory articular cavity. Consequently, HCQ@SAC4A achieves the synergistic anti‐inflammatory effect on both inflamed RAW 264.7 cells and RA rats. This effect is attributed to the temporal and spatial consistency of the two active ingredients of the complex. As a new paradigm for combinational therapy, the drug‐in‐drug strategy advances in easy preparation, mix‐and‐match combination, and precise ratiometric control.
Macrocyclic delivery and therapeutics are two hotspots in supramolecular biomedicine that have only been occasionally merged. In this work, a “drug‐in‐drug” strategy is proposed, in which an active drug is encapsulated by a therapeutically active macrocycle, forming a multifunctional supramolecular active ingredient. This drug‐in‐drug formulation achieves the advantages of macrocycles acting as both carriers and therapeutic agents to realize combinational therapy.
The lithium-selenium (Li-Se) battery has attracted growing interest recently due to its high energy density and theoretical capacity. However, the shuttle effect and volume change during cycling ...severely hinder its further application. In this work, we report a metal-organic framework (MOF)-derived nitrogen-doped core-shell hierarchical porous carbon (N-CSHPC) with interconnected meso/micropores to effectively confine Se for high-performance Li-Se batteries. The micropores were located at the ZIF-8-derived core and the ZIF-67-derived shell, while mesopores appeared at the core-shell interface after the pyrolysis of the core-shell ZIF-8@ZIF-67 precursor. Such a special hierarchical porous structure effectively confined selenium and polyselenides to prevent their dissolution from the pores and also alleviated the volume change. In particular, in situ nitrogen doping, which afforded N-CSHPC, not only improved the electrical conductivity of Se but also provided strong chemical adsorption on Li2Se, as confirmed by density functional theory calculations. On the basis of dual-physical confinement and strong chemisorption, Se/N-CSHPC-II (molar ratio of Co source to Zn source of 1.0 in the core-shell ZIF-8@ZIF-67 precursor) exhibited reversible capacities of up to 555 mA h g-1 after 150 cycles at 0.2 C and 462 mA h g-1 after 200 cycles at 0.5 C and even a discharge capacity of 432 mA h g-1 after 200 cycles at 1 C. Our demonstration here suggests that the carefully designed Se/C composite can improve the reversible capacity and cycling stability of Se cathodes for Li-Se batteries.
Long-term couplings between the subducting and overlying plates are very important to understanding plate tectonics, in particular intraplate evolutions. Geological records of this coupling however, ...are usually not well preserved. Here we show a good example in eastern China where Cretaceous tectonic evolution matches remarkably well with the drifting history of the Pacific plate. The most pronounced phenomenon is that the eastern China large-scale orogenic lode gold (Au) mineralization occurred contemporaneously with an abrupt change of ~
80° in the drifting direction of the subducting Pacific plate, concurrent with the formation of the Ontong Java Plateau. Given that lode Au deposits usually form at the onset of compressional or transpressional deformations, the Au deposits dated the major tectonic change from extension to transpression in eastern China, coherent with the subduction regime. The Cretaceous drifting history of the Pacific plate also tallies with other major geological events in eastern China, e.g., the evolution of the Tan-Lu fault and magmatic activities, suggesting that the major geological events in eastern China in the Cretaceous were mainly controlled by the subduction of the Pacific plate, and that plate interactions during subduction are important driving forces for geological evolution in eastern China and intraplate tectonics in general.
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