Antibiotic resistomes in face-mask biofilm along an urban river: Multiple drivers and co-occurrence with human opportunistic pathogens.

Discarded face masks from the global COVID-19 pandemic have contributed significantly to plastic pollution in surface water, whereas their potential as a reservoir for aquatic pollutants is not well understood. Herein, we conducted a field experiment along a human-impacted urban river, investigating the variations of antibiotic resistance genes (ARGs), pathogens, and water-borne contaminants in commonly-used face masks. Results showed that high-biomass biofilms formed on face masks selectively enriched more ARGs than stone biofilm (0.08-0.22 vs 0.07-0.15 copies/16 S rRNA gene copies) from bulk water, which mainly due to unique microbial communities, enhanced horizontal gene transfer, and selective pressure of accumulated contaminants based on redundancy analysis and variation partitioning analysis. Several human opportunistic pathogens (e.g., Acinetobacter, Escherichia-Shigella, Bacillus, and Klebsiella), which are considered potential ARG carriers, were also greatly concentrated in face-mask biofilms, imposing a potential threat to aquatic ecological environment and human health. Moreover, wastewater treatment plant effluents, as an important source of pollutants to urban rivers, further aggravated the abundances of ARGs and opportunistic pathogens in face-mask biofilms. Our findings demonstrated that discarded face masks provide a hotspot for the proliferation and spread of ARGs and pathogens in urban water, highlighting the urgent requirement for implementing stricter regulations in face mask disposal.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults.

INTRODUCTION: Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful "cytokine and chemokine storm" in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). METHODS: Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. RESULTS: The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration-time curve from time zero to 480 h (AUC0-480h), that from time zero to infinity (AUCinf), and peak plasma concentration ©max) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. CONCLUSION: The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. TRIAL REGISTRATION NUMBER: CTR20200429.

Use of temporal contact graphs to understand the evolution of COVID-19 through contact tracing data.

Digital contact tracing has been recently advocated by China and many countries as part of digital prevention measures on COVID-19. Controversies have been raised about their effectiveness in practice as it remains open how they can be fully utilized to control COVID-19. In this article, we show that an abundance of information can be extracted from digital contact tracing for COVID-19 prevention and control. Specifically, we construct a temporal contact graph that quantifies the daily contacts between infectious and susceptible individuals by exploiting a large volume of location-related data contributed by 10,527,737 smartphone users in Wuhan, China. The temporal contact graph reveals five time-varying indicators can accurately capture actual contact trends at population level, demonstrating that travel restrictions (e.g., city lockdown) in Wuhan played an important role in containing COVID-19. We reveal a strong correlation between the contacts level and the epidemic size, and estimate several significant epidemiological parameters (e.g., serial interval). We also show that user participation rate exerts higher influence on situation evaluation than user upload rate does, indicating a sub-sampled dataset would be as good at prediction. At individual level, however, the temporal contact graph plays a limited role, since the behavior distinction between the infected and uninfected individuals are not substantial. The revealed results can tell the effectiveness of digital contact tracing against COVID-19, providing guidelines for governments to implement interventions using information technology.

Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

Gut mycobiota alterations in patients with COVID-19 and H1N1 infections and their associations with clinical features.

The relationship between gut microbes and COVID-19 or H1N1 infections is not fully understood. Here, we compared the gut mycobiota of 67 COVID-19 patients, 35 H1N1-infected patients and 48 healthy controls (HCs) using internal transcribed spacer (ITS) 3-ITS4 sequencing and analysed their associations with clinical features and the bacterial microbiota. Compared to HCs, the fungal burden was higher. Fungal mycobiota dysbiosis in both COVID-19 and H1N1-infected patients was mainly characterized by the depletion of fungi such as Aspergillus and Penicillium, but several fungi, including Candida glabrata, were enriched in H1N1-infected patients. The gut mycobiota profiles in COVID-19 patients with mild and severe symptoms were similar. Hospitalization had no apparent additional effects. In COVID-19 patients, Mucoromycota was positively correlated with Fusicatenibacter, Aspergillus niger was positively correlated with diarrhoea, and Penicillium citrinum was negatively correlated with C-reactive protein (CRP). In H1N1-infected patients, Aspergillus penicilloides was positively correlated with Lachnospiraceae members, Aspergillus was positively correlated with CRP, and Mucoromycota was negatively correlated with procalcitonin. Therefore, gut mycobiota dysbiosis occurs in both COVID-19 patients and H1N1-infected patients and does not improve until the patients are discharged and no longer require medical attention.