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The coronavirus disease 2019 (COVID-19) pandemic and the measures taken by authorities to control its spread had altered human behavior and mobility patterns in an unprecedented way. However, it remains unclear whether the population response to a COVID-19 outbreak varies within a city or among demographic groups. Here we utilized passively recorded cellular signaling data at a spatial resolution of 1km × 1km for over 5 million users and epidemiological surveillance data collected during the SARS-CoV-2 Omicron BA.2 outbreak from February to June 2022 in Shanghai, China, to investigate the heterogeneous response of different segments of the population at the within-city level and examine its relationship with the actual risk of infection. Changes in behavior were spatially heterogenous within the city and population groups, and associated with both the infection incidence and adopted interventions. We also found that males and individuals aged 30-59 years old traveled more frequently, traveled longer distances, and their communities were more connected; the same groups were also associated with the highest SARS-CoV-2 incidence. Our results highlight the heterogeneous behavioral change of the Shanghai population to the SARS-CoV-2 Omicron BA.2 outbreak and the its effect on the heterogenous spread of COVID-19, both spatially and demographically. These findings could be instrumental for the design of targeted interventions for the control and mitigation of future outbreaks of COVID-19 and, more broadly, of respiratory pathogens.Significance StatementOur study utilized passively recorded cellular signaling data and epidemiological surveillance data to investigate the changes human mobility to a COVID-19 outbreak at an unprecedented within-city level and examine its relationship with the actual risk of infection. Our findings highlight the heterogeneous behavioral change of the Shanghai population to the 2022 SARS-CoV-2 Omicron BA.2 outbreak and its heterogenous effect on the SARS-CoV-2 spread, both spatially and demographically. The implications of our findings could be instrumental to inform spatially targeted interventions at the within-city scale to mitigate possible new surges of COVID-19 cases as well as fostering preparedness for future respiratory infections disease outbreaks.

Having adopted a dynamic zero-COVID strategy to respond to SARS-CoV-2 variants with higher transmissibility since August 2021, China is now considering whether, and for how long, this policy can remain in place. The debate has thus shifted towards the identification of mitigation strategies for minimizing disruption to the healthcare system in the case of a nationwide epidemic. To this aim, we developed an age-structured stochastic compartmental susceptible-latent-infectious-removed-susceptible model of SARS-CoV-2 transmission calibrated on the initial growth phase for the 2022 Omicron outbreak in Shanghai, to project COVID-19 burden (that is, number of cases, patients requiring hospitalization and intensive care, and deaths) under hypothetical mitigation scenarios. The model also considers age-specific vaccine coverage data, vaccine efficacy against different clinical endpoints, waning of immunity, different antiviral therapies and nonpharmaceutical interventions. We find that the level of immunity induced by the March 2022 vaccination campaign would be insufficient to prevent an Omicron wave that would result in exceeding critical care capacity with a projected intensive care unit peak demand of 15.6 times the existing capacity and causing approximately 1.55 million deaths. However, we also estimate that protecting vulnerable individuals by ensuring accessibility to vaccines and antiviral therapies, and maintaining implementation of nonpharmaceutical interventions could be sufficient to prevent overwhelming the healthcare system, suggesting that these factors should be points of emphasis in future mitigation policies.

Background Large-scale vaccination against COVID-19 is being implemented in many countries with CoronaVac, an inactivated vaccine. We aimed to assess the immune persistence of a two-dose schedule of CoronaVac, and the immunogenicity and safety of a third dose of CoronaVac, in healthy adults aged 18 years and older. Methods In the first of two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials, adults aged 18–59 years in Jiangsu, China, were initially allocated (1:1) into two vaccination schedule cohorts: a day 0 and day 14 vaccination cohort (cohort 1) and a day 0 and day 28 vaccination cohort (cohort 2); each cohort was randomly assigned (2:2:1) to either a 3 μg dose or 6 μg dose of CoronaVac or a placebo group. Following a protocol amendment on Dec 25, 2020, half of the participants in each cohort were allocated to receive an additional dose 28 days (window period 30 days) after the second dose, and the other half were allocated to receive a third dose 6 months (window period 60 days) after the second dose. In the other phase 2 trial, in Hebei, China, participants aged 60 years and older were assigned sequentially to receive three injections of either 1·5 μg, 3 μg, or 6 μg of vaccine or placebo, administered 28 days apart for the first two doses and 6 months (window period 90 days) apart for doses two and three. The main outcomes of the study were geometric mean titres (GMTs), geometric mean increases (GMIs), and seropositivity of neutralising antibody to SARS-CoV-2 (virus strain SARS-CoV-2/human/CHN/CN1/2020, GenBank accession number MT407649.1), as analysed in the per-protocol population (all participants who completed their assigned third dose). Our reporting is focused on the 3 μg groups, since 3 μg is the licensed formulation. The trials are registered with ClinicalTrials.gov, NCT04352608 and NCT04383574. Findings 540 (90%) of 600 participants aged 18–59 years were eligible to receive a third dose, of whom 269 (50%) received the primary third dose 2 months after the second dose (cohorts 1a-14d-2m and 2a-28d-2m) and 271 (50%) received a booster dose 8 months after the second dose (cohorts 1b-14d-8m and 2b-28d-8m). In the 3 μg group, neutralising antibody titres induced by the first two doses declined after 6 months to near or below the seropositive cutoff (GMT of 8) for cohort 1b-14d-8m (n=53; GMT 3·9 [95% CI 3·1–5·0]) and for cohort 2b-28d-8m (n=49; 6·8 [5·2–8·8]). When a booster dose was given 8 months after a second dose, GMTs assessed 14 days later increased to 137·9 (95% CI 99·9–190·4) for cohort 1b-14d-8m and 143·1 (110·8–184·7) 28 days later for cohort 2b-28d-8m. GMTs moderately increased following a primary third dose, from 21·8 (95% CI 17·3–27·6) on day 28 after the second dose to 45·8 (35·7–58·9) on day 28 after the third dose in cohort 1a-14d-2m (n=54), and from 38·1 (28·4–51·1) to 49·7 (39·9–61·9) in cohort 2a-28d-2m (n=53). GMTs had decayed to near the positive threshold by 6 months after the third dose: GMT 9·2 (95% CI 7·1–12·0) in cohort 1a-14d-2m and 10·0 (7·3–13·7) in cohort 2a-28d-2m. Similarly, in adults aged 60 years and older who received booster doses (303 [87%] of 350 participants were eligible to receive a third dose), neutralising antibody titres had declined to near or below the seropositive threshold by 6 months after the primary two-dose series. A third dose given 8 months after the second dose significantly increased neutralising antibody concentrations: GMTs increased from 42·9 (95% CI 31·0–59·4) on day 28 after the second dose to 158·5 (96·6–259·2) on day 28 following the third dose (n=29). All adverse reactions reported within 28 days after a third dose were of grade 1 or 2 severity in all vaccination cohorts. There were three serious adverse events (2%) reported by the 150 participants in cohort 1a-14d-2m, four (3%) by 150 participants from cohort 1b-14d-8m, one (1%) by 150 participants in each of cohorts 2a-28d-2m and 2b-28d-8m, and 24 (7%) by 349 participants from cohort 3-28d-8m. Interpretation A third dose of CoronaVac in adults administered 8 months after a second dose effectively recalled specific immune responses to SARS-CoV-2, which had declined substantially 6 months after two doses of CoronaVac, resulting in a remarkable increase in the concentration of antibodies and indicating that a two-dose schedule generates good immune memory, and a primary third dose given 2 months after the second dose induced slightly higher antibody titres than the primary two doses. Funding National Key Research and Development Program, Beijing Science and Technology Program, and Key Program of the National Natural Science Foundation of China. Translation For the Mandarin translation of the abstract see Supplementary Materials section.

Genomic surveillance has shaped our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. We performed a global landscape analysis on SARS-CoV-2 genomic surveillance and genomic data using a collection of country-specific data. Here, we characterize increasing circulation of the Alpha variant in early 2021, subsequently replaced by the Delta variant around May 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 45 countries performing a high level of routine genomic surveillance and 96 countries with a high availability of SARS-CoV-2 sequencing. We also observed a marked heterogeneity of sequencing percentage, sequencing technologies, turnaround time and completeness of released metadata across regions and income groups. A total of 37% of countries with explicit reporting on variants shared less than half of their sequences of variants of concern (VOCs) in public repositories. Our findings indicate an urgent need to increase timely and full sharing of sequences, the standardization of metadata files and support for countries with limited sequencing and bioinformatics capacity.

SummaryBackgroundThe kinetics of the neutralizing antibody response against SARS-CoV-2 is crucial for responding to the pandemic as well as developing vaccination strategies. We aimed to fit the antibody curves in symptomatic and asymptomatic individuals.MethodsWe systematically searched PubMed, Embase, Web of Science, and Europe PMC for articles published in English between Jan 1, 2020, and Oct 2, 2022. Studies evaluating neutralizing antibody from people who had a natural SARS-CoV-2 infection history were included. Study quality was assessed using a modified standardized scoring system. We fitted dynamic patterns of neutralizing antibody using a generalized additive model and a generalized additive mixed model. We also used linear regression model to conduct both univariate and multivariable analyses to explore the potential affecting factors on antibody levels. This study is registered with PROSPERO, CRD42022348636.Results7,343 studies were identified in the initial search, 50 were assessed for eligibility after removal of duplicates as well as inappropriate titles, abstracts and full-text review, and 48 studies (2,726 individuals, 5,670 samples) were included in the meta-analysis after quality assessment. The neutralization titer of people who infected with SARS-CoV-2 prototype strain peaked around 27 days (217.4, 95%CI: 187.0-252.9) but remained below the Omicron BA.5 protection threshold all the time after illness onset or confirmation. Furthermore, neither symptomatic infections nor asymptomatic infections could provide over 50% protection against Omicron BA.5 sub-lineage. It also showed that the clinical severity and the type of laboratory assays may significantly correlated with the level of neutralizing antibody.ConclusionsThis study provides a comprehensive mapping of the dynamic of neutralizing antibody against SARS-CoV-2 prototype strain induced by natural infection and compared the dynamic patterns between prototype and variant strains. It suggests that the protection probability provided by natural infection is limited. Therefore, timely vaccination is necessary for both previously infected symptomatic and asymptomatic individuals.

Background A rapidly increasing number of serological surveys for antibodies to SARS-CoV-2 have been reported worldwide. We aimed to synthesise, combine, and assess this large corpus of data. Methods In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and five preprint servers for articles published in English between Dec 1, 2019, and Dec 22, 2020. Studies evaluating SARS-CoV-2 seroprevalence in humans after the first identified case in the area were included. Studies that only reported serological responses among patients with COVID-19, those using known infection status samples, or any animal experiments were all excluded. All data used for analysis were extracted from included papers. Study quality was assessed using a standardised scale. We estimated age-specific, sex-specific, and race-specific seroprevalence by WHO regions and subpopulations with different levels of exposures, and the ratio of serology-identified infections to virologically confirmed cases. This study is registered with PROSPERO, CRD42020198253. Findings 16 506 studies were identified in the initial search, 2523 were assessed for eligibility after removal of duplicates and inappropriate titles and abstracts, and 404 serological studies (representing tests in 5 168 360 individuals) were included in the meta-analysis. In the 82 studies of higher quality, close contacts (18·0%, 95% CI 15·7–20·3) and high-risk health-care workers (17·1%, 9·9–24·4) had higher seroprevalence than did low-risk health-care workers (4·2%, 1·5–6·9) and the general population (8·0%, 6·8–9·2). The heterogeneity between included studies was high, with an overall I2 of 99·9% (p

The current global demand for novel anti-TB drugs has drawn urgent attention on the discovery of natural product compounds with anti-TB activity. Lots of efforts have emphasized on environmental samples from unexplored or underexplored natural habits and identified numerous rare actinomycete taxa producing structurally diverse bioactive natural products. Herein, we report a survey of the rare actinobacteria diversity in Xinjiang region together with the discovery of anti-TB active natural products from these strains. We have collected 17 soil samples at different sites with different environmental conditions, from which 39 rare actinobacteria were identified by using a selective isolation strategy with 5 media variations. Among those isolated strains, XJ31 was identified as a new Nocardia sp. based on 16S rRNA gene analysis. Through one strain-many compounds (OSMAC) strategy combined with anti-Bacillus Calmette-Guérin bioassay-guided isolation, two groups of compounds were identified. They were twelve siderophores (nocardimicins, 1-12) and two anthraquinones (brasiliquinones, 13 and 14) and ten of them were identified as new compounds. The structures of the purified compounds were elucidated using HR-ESI-MS, 1D NMR, and 2D NMR techniques. The anti-TB bioassays revealed that the two benz[α]anthraquinones have potent activity against BCG (MICs = 25 μM), which can be used as a promising start point for further anti-TB drug development. Key points • Ten new natural products were identified from Nocardia sp. XJ31. • Brasiliquinones 13 and 14 showed moderate anti-BCG activity. Electronic supplementary material The online version of this article (10.1007/s00253-020-10842-2) contains supplementary material, which is available to authorized users.

After the adoption of a dynamic zero-COVID strategy in China for nearly two years, whether and for how long this policy can remain in place is unclear. The debate has thus shifted towards the identification of mitigation strategies capable to prevent the disruption of the healthcare system, should a nationwide epidemic caused by the SARS-CoV-2 Omicron variant start to unfold. To this aim, we developed a mathematical model of SARS-CoV-2 transmission tailored to the unique immunization and epidemiological situation of China. We find that the level of immunity induced by the current vaccination campaign would be insufficient to prevent overwhelming the healthcare system and major losses of human lives. Instead, a synergetic strategy would be needed and based on 1) a heterologous booster vaccination campaign, 2) treating 50% of symptomatic cases with an antiviral with an 80% efficacy in preventing severe outcomes, and 3) the adoption of non-pharmaceutical interventions (NPIs) capable of reducing Rt to ≤2. Protecting vulnerable individuals by ensuring accessibility to vaccines and antivirals, and maintaining a certain degree of NPIs should be emphasised in a future mitigation policy, possibly supported by strengthening critical care capacity and the development of highly efficacious vaccines with long-lasting immunity.

Determining the duration of immunity induced by booster doses of CoronaVac is crucial for informing recommendations for booster regimens and adjusting immunization strategies. In two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials, immunogenicity and safety of four immunization regimens are assessed in adults aged 18 to 59 years and one immunization regimen in adults aged 60 years and older, respectively. Serious adverse events occurring within 6 months after booster doses are recorded as pre-specified secondary endpoints, geometric mean titres (GMTs) of neutralising antibodies one year after the 3-dose schedule immunization and 6 months after the booster doses are assessed as pre-specified exploratory endpoints, GMT fold-decreases in neutralization titres are assessed as post-hoc analyses. Neutralising antibody titres decline approximately 4-fold and 2.5-fold from day 28 to day 180 after third doses in adults aged 18–59 years of age and in adults aged 60 years and older, respectively. No safety concerns are identified during the follow-up period. There are increases in the magnitude and duration of humoral response with homologous booster doses of CoronaVac given 8 months after a primary two-dose immunization series, which could prolong protection and contribute to building our wall of population immunity. Trial number: NCT04352608 and NCT04383574.

Genomic surveillance has shaped our understanding of SARS-CoV-2 variants, which have proliferated globally in 2021.We collected country-specific data on SARS-CoV-2 genomic surveillance, sequencing capabilities, public genomic data from multiple public repositories, and aggregated publicly available variant data. Then, different proxies were used to estimate the sequencing coverage and public availability extent of genomic data, in addition to describing the global dissemination of variants. We found that the COVID-19 global epidemic clearly featured increasing circulation of Alpha since the start of 2021, which was rapidly replaced by the Delta variant starting around May 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 63 countries performing routine genomic surveillance and 79 countries with high availability of SARS-CoV-2 sequencing. We also observed a marked heterogeneity of sequenced coverage across regions and countries. Across different variants, 21-46% of countries with explicit reporting on variants shared less than half of their variant sequences in public repositories. Our findings indicated an urgent need to expand sequencing capacity of virus isolates, enhance the sharing of sequences, the standardization of metadata files, and supportive networks for countries with no sequencing capability.

Background Evidence on vaccine-specific protection over time, in particular against the Delta variant, and protection afforded by a homologous third dose is urgently needed. Methods We used a previously published model and neutralization data for five vaccines—mRNA-1273, BNT162b2, NVX-CoV2373, V01, and CoronaVac— to evaluate long-term neutralizing antibody dynamics and predict time-varying efficacy against the Delta variant by specific vaccine, age group, and clinical severity. Results We found that homologous third-dose vaccination produces higher neutralization titers compared with titers observed following primary-series vaccination for all vaccines studied. We estimate the efficacy of mRNA-1273 and BNT162b2 against Delta variant infection to be 63.5% (95% CI: 51.4–67.3%) and 78.4% (95% CI: 72.2–83.5%), respectively, 14–30 days after the second dose, and that efficacy decreases to 36.0% (95% CI: 24.1–58.0%) and 38.5% (95% CI: 28.7–49.1%) 6–8 months later. Fourteen to 30 days after administration of homologous third doses, efficacy against the Delta variant would be 97.0% (95% CI: 96.4–98.5%) and 97.2% (95.7–98.1%). All five vaccines are predicted to provide good protection against severe illness from the Delta variant after both primary and homologous third dose vaccination. Conclusions Timely administration of third doses of SARS-CoV-2-prototype-based vaccines can provide protection against the Delta variant, with better performance from mRNA vaccines than from protein and inactivated vaccines. Irrespective of vaccine technology, a homologous third dose for all types of vaccines included in the study will effectively prevent symptomatic and severe COVID-19 caused by the Delta variant. Long-term monitoring and surveillance of antibody dynamics and vaccine protection, as well as further validation of neutralizing antibody levels or other markers that can serve as correlates of protection against SARS-CoV-2 and its variants, are needed to inform COVID-19 pandemic responses.

BackgroundGenomic surveillance has shaped our understanding of SARS-CoV-2 variants, which have proliferated globally in 2021. Characterizing global genomic surveillance, sequencing coverage, the extent of publicly available genomic data coupled with traditional epidemiologic data can provide evidence to inform SARS-CoV-2 surveillance and control strategies.MethodsWe collected country-specific data on SARS-CoV-2 genomic surveillance, sequencing capabilities, public genomic data, and aggregated publicly available variant data. We divided countries into three levels of genomic surveillance and sequencing availability based on predefined criteria. We downloaded the merged and deduplicated SARS-CoV-2 sequences from multiple public repositories, and used different proxies to estimate the sequencing coverage and public availability extent of genomic data, in addition to describing the global dissemination of variants.FindingsSince the start of 2021, the COVID-19 global epidemic clearly featured increasing circulation of Alpha, which was rapidly replaced by the Delta variant starting around May 2021 and reaching a global prevalence of 96.6% at the end of July 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 63 countries performing routine genomic surveillance and 79 countries with high availability of SARS-CoV-2 sequencing. Less than 3.5% of confirmed SARS-CoV-2 infections were sequenced globally since September 2020, with the lowest sequencing coverage in the WHO regions of Eastern Mediterranean, South East Asia, and Africa. Across different variants, 28-52% of countries with explicit reporting on variants shared less than half of their variant sequences in public repositories. More than 60% of demographic and 95% of clinical data were absent in GISAID metadata accompanying sequences.InterpretationOur findings indicated an urgent need to expand sequencing capacity of virus isolates, enhance the sharing of sequences, the standardization of metadata files, and supportive networks for countries with no sequencing capability.Research in contextEvidence before this studyOn September 3, 2021, we searched PubMed for articles in any language published after January 1, 2020, using the following search terms: (“COVID-19” OR “SARS-CoV-2”) AND (“Global” OR “Region”) AND (“genomic surveillance” OR “sequencing” OR “spread”). Among 43 papers identified, few papers discussed the global diversity in genomic surveillance, sequencing, public availability of genomic data, as well as the global spread of SARS-CoV-2 variants. A paper from Furuse employed the publicly GISAID data to evaluate the SARS-CoV-2 sequencing effort by country from the perspectives of “fraction”, “timeliness”, and “openness”. Another viewpoint paper by Case Western Reserve University’s team discussed the impediments of genomic surveillance in several countries during the COVID-19 pandemic. The paper as reported by Campbell and colleagues used the GISAID data to present the global spread and estimated transmissibility of recently emerged SARS-CoV-2 variants. We also found several studies that reported the country-level genomic surveillance and spread of variants. To our knowledge, no research has quantitatively depicted the global SARS-CoV-2 genomic surveillance, sequencing ability, and public availability extent of genomic data.Added value of this studyThis study collected country-specific data on SARS-CoV-2 genomic surveillance, sequencing capabilities, public genomic data, and aggregated publicly available variant data as of 20 August 2021. We found that genomic surveillance strategies and sequencing availability is globally diverse. Less than 3.5% of confirmed SARS-CoV-2 infections were sequenced globally since September 2020. Our analysis of publicly deposited SARS-CoV-2 sequences and officially reported number of variants implied that the public availability extent of genomic data is low in some countries, and more than 60% of demographic and 95% of clinical data were absent in GISAID metadata accompanying sequences. We also described the pandemic dynamics shaped by VOCs.Implications of all the available evidenceOur study provides a landscape for global sequencing coverage and public availability extent of sequences, as well as the evidence for rapid spread of SRAS-CoV-2 variants. The pervasive spread of Alpha and Delta variants further highlights the threat of SARS-CoV-2 mutations despite the availability of vaccines in many countries. It raised an urgent need to do more work on defining the ideal sampling schemes for different purposes (e.g., identifying new variants) with an additional call to share these data in public repositories to allow for further rapid scientific discovery.

ImportanceWhether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults ≥60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults≥60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses.InterventionsTwo formulations (3 μg, and 6 μg) were used in phase 1 trial, and an additional formulation of 1.5 μg was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose.Main outcomes and measuresGeometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination.ResultsNeutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 μg group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity.Conclusion and relevanceNeutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults.Trial registrationClinicalTrials.gov(NCT04383574).

Two pairs of dibenzospiroketal racemates, (±)-epicospirocin A (1a/1b) and (±)-1-epi-epicospirocin A (2a/2b), and two (+)-enantiomers of aspermicrones, ent-aspermicrone B (3b) and ent-aspermicrone C (4b), together with two hemiacetal epimeric mixtures, epicospirocin B/1-epi-epicospirocin B (5/6) and epicospirocin C/1-epi-epicospirocin C (7/8), were investigated from the phytopathogenic fungus Epicoccum nigrum 09116 via MS/MS molecular networking guided isolation and chiral separation for the first time. A plausible epicospirocin biosynthetic pathway was elucidated through in silico gene function annotation together with knock-out experiments. This is the first report that has applied MS/MS molecular networking to identify intermediates correlated with a biosynthetic pathway.

BACKGROUND: Immunity after SARS-CoV-2 infection or vaccination has been threatened by recently emerged SARS-CoV-2 variants. A systematic summary of the landscape of neutralizing antibodies against emerging variants is needed. METHODS: We systematically searched PubMed, Embase, Web of Science, and 3 pre-print servers for studies that evaluated neutralizing antibodies titers induced by previous infection or vaccination against SARS-CoV-2 variants and comprehensively collected individual data. We calculated lineage-specific GMTs across different study participants and types of neutralization assays. FINDINGS: We identified 56 studies, including 2,483 individuals and 8,590 neutralization tests, meeting the eligibility criteria. Compared with lineage B, we estimate a 1.5-fold (95% CI: 1.0–2.2) reduction in neutralization against the B.1.1.7, 8.7-fold (95% CI: 6.5–11.7) reduction against B.1.351 and 5.0-fold (95% CI: 4.0–6.2) reduction against P.1. The estimated neutralization reductions for B.1.351 compared to lineage B were 240.2-fold (95% CI: 124.0–465.6) reduction for non-replicating vector platform, 4.6-fold (95% CI: 4.0–5.2) reduction for RNA platform, and 1.6-fold (95% CI: 1.2–2.1) reduction for protein subunit platform. The neutralizing antibodies induced by administration of inactivated vaccines and mRNA vaccines against lineage P.1 were also remarkably reduced by an average of 5.9-fold (95% CI: 3.7–9.3) and 1.5-fold (95% CI: 1.2–1.9). INTERPRETATION: Our findings indicate that the antibody response established by natural infection or vaccination might be able to effectively neutralize B.1.1.7, but neutralizing titers against B.1.351 and P.1 suffered large reductions. Standardized protocols for neutralization assays, as well as updating immune-based prevention and treatment, are needed. FUNDING: Chinese National Science Fund for Distinguished Young Scholars

BackgroundImmunity after SARS-CoV-2 infection or vaccination has been threatened by recently emerged SARS-CoV-2 variants. A systematic summary of the landscape of neutralizing antibodies against emerging variants is needed.MethodsWe systematically searched PubMed, Embase, Web of Science, and 3 pre-print servers for studies that evaluated neutralizing antibodies titers induced by previous infection or vaccination against SARS-CoV-2 variants and comprehensively collected individual data. We calculated lineage-specific GMTs across different study participants and types of neutralization assays.FindingsWe identified 56 studies, including 2,483 individuals and 8,590 neutralization tests, meeting the eligibility criteria. Compared with lineage B, we estimate a 1.5-fold (95% CI: 1.0-2.2) reduction in neutralization against the B.1.1.7, 8.7-fold (95% CI: 6.5-11.7) reduction against B.1.351 and 5.0-fold (95% CI: 4.0-6.2) reduction against P.1. The estimated neutralization reductions for B.1.351 compared to lineage B were 240.2-fold (95% CI: 124.0-465.6) reduction for non-replicating vector platform, 4.6-fold (95% CI: 4.0-5.2) reduction for RNA platform, and 1.6-fold (95% CI: 1.2-2.1) reduction for protein subunit platform. The neutralizing antibodies induced by administration of inactivated vaccines and mRNA vaccines against lineage P.1 were also remarkably reduced by an average of 5.9-fold (95% CI: 3.7-9.3) and 1.5-fold (95% CI: 1.2-1.9).InterpretationOur findings indicate that the antibody response established by natural infection or vaccination might be able to effectively neutralize B.1.1.7, but neutralizing titers against B.1.351 and P.1 suffered large reductions. Standardized protocols for neutralization assays, as well as updating immune-based prevention and treatment, are needed.FundingChinese National Science Fund for Distinguished Young ScholarsResearch in contextEvidence before this studySeveral newly emerged SARS-CoV-2 variants have raised significant concerns globally, and there is concern that SARS-CoV-2 variants can evade immune responses that are based on the prototype strain. It is not known to what extent do emerging SARS-CoV-2 variants escape the immune response induced by previous infection or vaccination. However, existing studies of neutralizing potency against SARS-CoV-2 variants are based on limited numbers of samples and lack comparability between different laboratory methods. Furthermore, there are no studies providing whole picture of neutralizing antibodies induced by prior infections or vaccination against emerging variants. Therefore, we systematically reviewed and quantitively synthesized evidence on the degree to which antibodies from previous SARS-CoV-2 infection or vaccination effectively neutralize variants.Added value of this studyIn this study, 56 studies, including 2,483 individuals and 8,590 neutralization tests, were identified. Antibodies from natural infection or vaccination are likely to effectively neutralize B.1.1.7, but neutralizing titers against B.1.351 and P.1 suffered large reductions. Lineage B.1.351 escaped natural-infection-mediated neutralization the most, with GMT of 79.2 (95% CI: 68.5-91.6), while neutralizing antibody titers against the B.1.1.7 variant were largely preserved (254.6, 95% CI: 214.1-302.8). Compared with lineage B, we estimate a 1.5-fold (95% CI: 1.0-2.2) reduction in neutralization against the B.1.1.7, 8.7-fold (95% CI: 6.5-11.7) reduction against B.1.351 and 5.0-fold (95% CI: 4.0-6.2) reduction against P.1. The neutralizing antibody response after vaccinating with non-replicating vector vaccines against lineage B.1.351 was worse than responses elicited by vaccines on other platforms, with levels lower than that of individuals who were previously infected. The neutralizing antibodies induced by administration of inactivated vaccines and mRNA vaccines against lineage P.1 were also remarkably reduced by an average of 5.9-fold (95% CI: 3.7-9.3) and 1.5-fold (95% CI: 1.2-1.9).Implications of all the available evidenceOur findings indicate that antibodies from natural infection of the parent lineage of SARS-CoV-2 or vaccination may be less able to neutralize some emerging variants, and antibody-based therapies may need to be updated. Furthermore, standardized protocols for neutralizing antibody testing against SARS-CoV-2 are needed to reduce lab-to-lab variations, thus facilitating comparability and interpretability across studies.

Background: Recently emerged SARS-CoV-2 variants may pose a threat to immunity derived from prototypical SARS-CoV-2 infection or vaccination. A systematic summary of the landscape of neutralizing antibodies against emerging variants is needed. Methods: We systematically searched PubMed, Embase, Web of Science, and 3 pre-print servers for studies that evaluated neutralizing antibodies titers induced by previous infection or vaccination against SARS-CoV-2 variants and comprehensively collected individual data. Through pooled analyses we estimated lineage-specific GMTs across different study participants and types of neutralization assays. Findings: We identified 76 studies, including 2,876 individuals and 10,526 neutralization tests, meeting the eligibility criteria. Compared with reference lineage B, B.1.351 and B.1.617 significantly escaped natural-infection-mediated neutralization, with an average of 3.8-fold (95% CI: 3.4-4.4) and 4.0-fold (95% CI: 2.3-6.9) reduction in live virus neutralization assay, while neutralizing antibody titers against B.1.1.7 decreased slightly (1.3-fold, 95%CI: 1.1-1.6). Serum from vaccinees also led to significant reductions in neutralization of B.1.351 and B.1.617, with a 32.6-fold (95% CI: 18.7-56.9) and 11.4-fold (95% CI: 8.6-15.2) for non-replicating vector vaccines, while 4.4-fold (95% CI: 4.0-5.0) and 2.1-fold (95%CI: 1.6-2.8) for mRNA platform vaccine. Neutralizing antibodies levels induced mRNA vaccines against SARS-CoV-2 variants were similar, or higher, than that derived from naturally-infected individuals. Interpretation: Antibody responses established by natural infection or vaccination have similar ability to neutralize B.1.1.7, but neutralizing titers against B.1.351 and B.1.617 were significantly reduced. Standardized protocols for neutralization assays, as well as updating immune-based prevention and treatment, are needed. Registration Information: The study has been registered with PROSPERO and is awaiting approval (ID: 256932). Funding Information: This study was funded by the National Science Fund for Distinguished Young Scholars (grant no. 81525023), Program of Shanghai Academic/Technology Research Leader (grant no.18XD1400300), National Science and Technology Major project of China (grant no. 2018ZX10713001-007, 2017ZX10103009-005, 2018ZX10201001-010), the US National Institutes of Health (R01 AI135115 to D.T.L. and A.S.A.) Declaration of Interests: H.Y. has received research funding from Sanofi Pasteur, and Shanghai Roche Pharmaceutical Company; D.T.L. and A.S.A. has received research funding from the US National Institutes of Health. None of those research funding is related to COVID-19. All other authors report no competing interests.

BackgroundA rapidly increasing number of serological surveys for anti-SARS-CoV-2 antibodies have been reported worldwide. A synthesis of this large corpus of data is needed.PurposeTo evaluate the quality of serological studies and provide a global picture of seroprevalence across demographic and occupational groups, and to provide guidance for conducting better serosurveys.Data sourcesPubMed, Embase, Web of Science, medRxiv, bioRxiv, SSRN and Wellcome were searched for English-language papers published from December 1, 2019 to August 28, 2020.Study selectionSerological studies that evaluated seroprevalence of SARS-CoV-2 infections in humans.Data extractionTwo investigators independently extracted data from included studies.Data SynthesisMost of 178 serological studies, representing tests in >800,000 individuals, identified were of low quality. Close contacts and high-risk healthcare workers had higher seroprevalence of 22.9% (95% CI: 11.1-34.7%) and 14.9% (4.8-25.0%), compared to low-risk healthcare workers and general population of 5.5% (4.6-6.4%) and 6.3% (5.5-7.1%). Generally, young people (0-20 yrs) were less likely to be seropositive compared to the middle-aged (21-55 yrs) populations (RR, 0.8, 95% CI: 0.7-0.8). Seroprevalence correlated with clinical COVID-19 reports with 10 (range: 2 to 34) infections per confirmed COVID-19 case.LimitationsSome heterogeneity cannot be well explained quantitatively.ConclusionsThe overall quality of seroprevalence studies examined was low. The relatively low seroprevalence among general populations suggest that in most settings, antibody-mediated herd immunity is far from being reached. Given that ratio of infections to confirmed cases is on the same order of magnitude across different locales, reported case numbers may help provide insights into the proportion of the population infected.Primary Funding sourceNational Science Fund for Distinguished Young Scholars (PROSPERO: CRD42020198253).

Ethnopharmacological relevance Gegen Qinlian Decoction (GQD) is a classic traditional Chinese medicine prescription that is widely used to clinically treat diabetes mellitus. It is composed of Pueraria lobata (Willd.) Ohwi (ge gen), Scutellaria baicalensis Georgi (huang qin), Coptidis chinensis Franch. (huang lian), and Glycyrrhiza uralensis Fisch. (gan cao). However, the active ingredients in GQD and their mechanism of action are unclear. Aim of the study In this study, we aimed to verify the efficacy of GQD in improving insulin resistance (IR) in diabetic mice and used network pharmacology to identify potential targets and pathways underlying its mechanism of action. Materials and methods A mouse model of diabetes was created by feeding mice a high-fat diet followed by an intraperitoneal injection of streptozotocin. These type II diabetic mice were administered either a clinical dose or a high dose of GQD, after which blood glucose and serum insulin levels were measured to assess its effects on IR. Network pharmacology was used to construct a ‘component-pathway-target’ network to elucidate the likely targets and pathways modulated in common by GQD components. Furthermore, mRNA transcript levels and protein expression levels of oestrogen receptor alpha (ESR1) were determined. Results The in vivo experiment showed that GQD markedly decreased blood glucose and increased serum insulin levels in type II diabetic mice. Network pharmacology and bioinformatics analysis indicated that GQD regulated 82 corresponding proteins and 59 relevant biological pathways associated with diabetes. One such target was ESR1, which was significantly decreased at both the mRNA and protein levels in diabetic mice, but whose levels were significantly increased by GQD treatment. Conclusions This project provides a scientific basis for understanding the effectiveness of multi-component, multi-target compound formulas, as well as a new strategy for investigating therapeutic drugs for type II diabetes and other diseases.

Datura metel L. has been frequently used in Chinese traditional medicine. However, little is known on the chemical composition and in vivo metabolism of its seeds. In this study, using the strategy “chemical analysis, metabolism of single representative compounds, and metabolism of extract at clinical dosage” that we propose here, 42 constituents were characterized from D. metel seeds water extract. Furthermore, the metabolic pathways of 13 representative bioactive compounds of D. metel seeds were studied in rats after the oral administration of D. metel seeds water extract at a clinical dosage (0.15 g/kg). These included three withanolides, two withanolide glucosides, four amides, one indole, one triterpenoid, one steroid, and one sesquiterpenoid, and with regard to phase II metabolism, hydroxylation, (de)methylation, and dehydrogenation reactions were dominant. Furthermore, the metabolism of D. metel seeds water extract provided to rats at a clinical dosage was investigated by liquid chromatography-tandem mass spectrometry based on the above metabolic pathways. Sixty-one compounds were detected in plasma, 83 in urine, and 76 in fecal samples. Among them, withanolides exhibited higher plasma exposure than the other types. To our knowledge, this is the first systematic study on the chemical profiling and metabolite identification of D. metel seeds, including all compounds instead of single constituents.

Datura metel L. has been frequently used in Chinese traditional medicine. However, little is known on the chemical composition and in vivo metabolism of its seeds. In this study, using the strategy “chemical analysis, metabolism of single representative compounds, and metabolism of extract at clinical dosage” that we propose here, 42 constituents were characterized from D. metel seeds water extract. Furthermore, the metabolic pathways of 13 representative bioactive compounds of D. metel seeds were studied in rats after the oral administration of D. metel seeds water extract at a clinical dosage (0.15 g/kg). These included three withanolides, two withanolide glucosides, four amides, one indole, one triterpenoid, one steroid, and one sesquiterpenoid, and with regard to phase II metabolism, hydroxylation, (de)methylation, and dehydrogenation reactions were dominant. Furthermore, the metabolism of D. metel seeds water extract provided to rats at a clinical dosage was investigated by liquid chromatography-tandem mass spectrometry based on the above metabolic pathways. Sixty-one compounds were detected in plasma, 83 in urine, and 76 in fecal samples. Among them, withanolides exhibited higher plasma exposure than the other types. To our knowledge, this is the first systematic study on the chemical profiling and metabolite identification of D. metel seeds, including all compounds instead of single constituents.

In pursuit of more sustainable development of industry, China has been actively developing eco-industrial parks (EIPs) for more than a decade. However, the environmental value of these EIPs remains largely unverified. This study aimed to evaluate the environmental performance of national EIPs in China using data envelopment analysis. Eco-efficiency and environmental performance indices were used to represent the static and dynamic environmental performance of EIPs, respectively. An environmental performance index was formed by combining measures of eco-efficiency in a dynamic setting with the sequential Malmquist index approach. We obtained three main empirical findings. First, 34 national EIPs exhibited a cumulative environmental performance improvement of 89.4% from 2007 to 2010, which is primarily the result of eco-efficiency change rather than environmental technical change. Second, compared with the trial EIPs, the demonstration EIPs had a higher average eco-efficiency (0.611 vs. 0.446 in 2010) and experienced greater average environmental performance improvement (129% vs. 60%). Third, the EIPs retrofitted from high-tech industrial development zones exhibited much higher average eco-efficiency (0.798 vs. 0.440 in 2010) than those retrofitted from economic and technical development zones. The key measures supporting the performance improvement and policy implications for the development of EIPs are also discussed

Lysostaphin is a peptidoglycan hydrolase secreted by Staphylococcus simulans . It can specifically lyse Staphylococcus aureus and is being tested as a novel antibacterial agent. The protein contains an N-terminal catalytic domain and a C-terminal cell wall targeting domain. Although the two domains from homologous enzymes were structurally determined, the structural organization of lysostaphin domains remains unknown. We used hydrogen/deuterium exchange mass spectrometry (H/DX-MS) and site-directed disulfide cross-linking to probe the interface between the lysostaphin catalytic and targeting domains. H/DX-MS-mediated comparison of peptides from full-length lysostaphin and the separated domains identified four peptides of lower solvent accessibility in the full-length protein. Cross-linking analysis using cysteine pair substitutions within those peptides showed that two pairs of cysteines can form disulfide bonds, supporting the domain association role of the targeted peptides. The cross-linked mutant exhibited a binding capacity to S. aureus that was similar to that of the wild-type protein but reduced bacteriolytic activity probably because of restraint in conformation. The diminished activity was further reduced with increasing NaCl concentrations that can cause contractions of bacterial peptidoglycan. The lytic activity, however, could be fully recovered by reducing the disulfide bonds. These results suggest that lysostaphin may require dynamic association of the two domains for coordinating substrate binding and target cleavage on the elastic peptidoglycan. Our study will help develop site-specific PEGylated lysostaphin to treat systemic S. aureus infections.

Methicillin-resistant Staphylococcus aureus (MRSA) have become increasingly prevalent as nosocomial pathogens, especially in burn patients, which is the leading cause of their death. A drug delivery system of chitosan-collagen hydrogel incorporated with lysostaphin (CCHL) based on the lysostaphin gauze was developed for MRSA infected burn wounds. CCHL scaffold consisted of numerous interconnected sphericles and tubular bodies with an average diameter of 100–200 µm, 20–60-fold swelling, high water retention capacity, and cell proliferation properties. The minimal inhibitory concentration of CCHL was 0.053 U/mL. By the second week after its application on MRSA infected third-degree burn wounds, no bacteria could be detected and the burn wounds had started healing. Therefore, CCHL should be studied further as a promising candidate of burn treatment dressing against MRSA infections for clinics.

Nasal colonization of Staphylococcus aureus (S.aureus) is known as a significant risk factor for nosocomial infections, and clearance of its nasal colonization greatly reduces the risk. In the present study the preparation and characterizations of the chitosan-o/w cream incorporated with lysostaphin (CCL) were described. It showed that the concentration of incorporated lysostaphin had a direct relationship with its release behavior from the cream. It was rapid at 2 and 3.5 mg lysostaphin/g cream and of a more sustained pattern at 5 mg lysostaphin/g cream. Efficacy of lysostaphin released from the CCL cream to inhibit S.aureus growth was higher than that of lysostaphin delivery routinely treated, as demonstrated by the reduction of the mucociliary transport rate (MTR) in contrast to the control graphite particles (p