Optimization of Population-Level Testing, Contact Tracing, and Isolation in Emerging COVID-19 Outbreaks: a Mathematical Modeling Study - Tonghua City and Beijing Municipality, China, 2021-2022.

Introduction: The transmissibility of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant poses challenges for the existing measures containing the virus in China. In response, this study investigates the effectiveness of population-level testing (PLT) and contact tracing (CT) to help curb coronavirus disease 2019 (COVID-19) resurgences in China. Methods: Two transmission dynamic models (i.e. with and without age structure) were developed to evaluate the effectiveness of PLT and CT. Extensive simulations were conducted to optimize PLT and CT strategies for COVID-19 control and surveillance. Results: Urban Omicron resurgences can be controlled by multiple rounds of PLT, supplemented by CT - as long as testing is frequent. This study also evaluated the time needed to detect COVID-19 cases for surveillance under different routine testing rates. The results show that there is a 90% probability of detecting COVID-19 cases within 3 days through daily testing. Otherwise, it takes around 7 days to detect COVID-19 cases at a 90% probability level if biweekly testing is used. Routine testing applied to the age group 21-60 for COVID-19 surveillance would achieve similar performance to that applied to all populations. Discussion: Our analysis evaluates potential PLT and CT strategies for COVID-19 control and surveillance.

Knowledge Graph: Applications in Tracing the Source of Large-Scale Outbreak - Beijing Municipality, China, 2020-2021.

Introduction: Tracing transmission paths and identifying infection sources have been effective in curbing the spread of coronavirus disease 2019 (COVID-19). However, when facing a large-scale outbreak, this is extremely time-consuming and labor-intensive, and resources for infection source tracing become limited. In this study, we aimed to use knowledge graph (KG) technology to automatically infer transmission paths and infection sources. Methods: We constructed a KG model to automatically extract epidemiological information and contact relationships from case reports. We then used an inference engine to identify transmission paths and infection sources. To test the model's performance, we used data from two COVID-19 outbreaks in Beijing. Results: The KG model performed well for both outbreaks. In the first outbreak, 20 infection relationships were identified manually, while 42 relationships were determined using the KG model. In the second outbreak, 32 relationships were identified manually and 31 relationships were determined using the KG model. All discrepancies and omissions were reasonable. Discussion: The KG model is a promising tool for predicting and controlling future COVID-19 epidemic waves and other infectious disease pandemics. By automatically inferring the source of infection, limited resources can be used efficiently to detect potential risks, allowing for rapid outbreak control.

Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.

BACKGROUND: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. METHODS: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. FINDINGS: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. CONCLUSIONS: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials. FUNDING: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560).

Trivalent NDV-HXP-S Vaccine Protects against Phylogenetically Distant SARS-CoV-2 Variants of Concern in Mice.

Equitable access to vaccines is necessary to limit the global impact of the coronavirus disease 2019 (COVID-19) pandemic and the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. In previous studies, we described the development of a low-cost vaccine based on a Newcastle Disease virus (NDV) expressing the prefusion-stabilized spike protein from SARS-CoV-2, named NDV-HXP-S. Here, we present the development of next-generation NDV-HXP-S variant vaccines, which express the stabilized spike protein of the Beta, Gamma, and Delta variants of concerns (VOC). Combinations of variant vaccines in bivalent, trivalent, and tetravalent formulations were tested for immunogenicity and protection in mice. We show that the trivalent preparation, composed of the ancestral Wuhan, Beta, and Delta vaccines, substantially increases the levels of protection and of cross-neutralizing antibodies against mismatched, phylogenetically distant variants, including the currently circulating Omicron variant. IMPORTANCE This manuscript describes an extended work on the Newcastle disease virus (NDV)-based vaccine focusing on multivalent formulations of NDV vectors expressing different prefusion-stabilized versions of the spike proteins of different SARS-CoV-2 variants of concern (VOC). We demonstrate here that this low-cost NDV platform can be easily adapted to construct vaccines against SARS-CoV-2 variants. Importantly, we show that the trivalent preparation, composed of the ancestral Wuhan, Beta, and Delta vaccines, substantially increases the levels of protection and of cross-neutralizing antibodies against mismatched, phylogenetically distant variants, including the currently circulating Omicron variant. We believe that these findings will help to guide efforts for pandemic preparedness against new variants in the future.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial.

Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg, 1 µg+CpG1018 (a toll-like receptor 9 agonist), 3 µg, 3 µg+CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation's immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 international units per mL (IU/mL; 1 µg, 95% confidence interval (CI) 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥ 4-fold increase over baseline. Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2. Funding: National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA).

A Newcastle disease virus expressing a stabilized spike protein of SARS-CoV-2 induces protective immune responses.

Rapid development of COVID-19 vaccines has helped mitigating SARS-CoV-2 spread, but more equitable allocation of vaccines is necessary to limit the global impact of the COVID-19 pandemic and the emergence of additional variants of concern. We have developed a COVID-19 vaccine candidate based on Newcastle disease virus (NDV) that can be manufactured at high yields in embryonated eggs. Here, we show that the NDV vector expressing an optimized spike antigen (NDV-HXP-S) is a versatile vaccine inducing protective antibody responses. NDV-HXP-S can be administered intramuscularly as inactivated vaccine or intranasally as live vaccine. We show that NDV-HXP-S GMP-produced in Vietnam, Thailand and Brazil is effective in the hamster model. Furthermore, we show that intramuscular vaccination with NDV-HXP-S reduces replication of tested variants of concerns in mice. The immunity conferred by NDV-HXP-S effectively counteracts SARS-CoV-2 infection in mice and hamsters.

New Tetramic Acid Derivatives From the Deep-Sea-Derived Fungus Penicillium sp. SCSIO06868 With SARS-CoV-2 Mpro Inhibitory Activity Evaluation.

Three new tetramic acid derivatives (1-3) and a new polyketide (4) along with eight known compounds (5-12) were isolated from cultures of the deep-sea-derived fungus Penicillium sp. SCSIO06868. Four new structures were elucidated by analysis of one-dimensional/two-dimensional nuclear magnetic resonance (NMR) data and high-resolution electrospray ionization mass spectrometry. Their absolute configurations were established by X-ray crystallography analysis and comparison of the experimental and reported electronic circular dichroism (ECD) values or specific optical rotation. Compound 3 exhibited potent, selective inhibitory activities against Staphylococcus aureus and methicillin-resistant S. aureus with minimum inhibitory concentration values of both 2.5 µg/ml. Also, compound 3 showed weak antiviral activity against severe acute respiratory syndrome coronavirus 2 main protease, which was responsible for the coronavirus disease 2019 pandemic.

Associations between changes in population mobility in response to the COVID-19 pandemic and socioeconomic factors at the city level in China and country level worldwide: a retrospective, observational study.

BACKGROUND: Until broad vaccination coverage is reached and effective therapeutics are available, controlling population mobility (ie, changes in the spatial location of a population that affect the spread and distribution of pathogens) is one of the major interventions used to reduce transmission of SARS-CoV-2. However, population mobility differs across locations, which could reduce the effectiveness of pandemic control measures. Here we assess the extent to which socioeconomic factors are associated with reductions in population mobility during the COVID-19 pandemic, at both the city level in China and at the country level worldwide. METHODS: In this retrospective, observational study, we obtained anonymised daily mobile phone location data for 358 Chinese cities from Baidu, and for 121 countries from Google COVID-19 Community Mobility Reports. We assessed the intra-city movement intensity, inflow intensity, and outflow intensity of each Chinese city between Jan 25 (when the national emergency response was implemented) and Feb 18, 2020 (when population mobility was lowest) and compared these data to the corresponding lunar calendar period from the previous year (Feb 5 to March 1, 2019). Chinese cities were classified into four socioeconomic index (SEI) groups (high SEI, high-middle SEI, middle SEI, and low SEI) and the association between socioeconomic factors and changes in population mobility were assessed using univariate and multivariable linear regression. At the country level, we compared six types of mobility (residential, transit stations, workplaces, retail and recreation, parks, and groceries and pharmacies) 35 days after the implementation of the national emergency response in each country and compared these to data from the same day of the week in the baseline period (Jan 3 to Feb 6, 2020). We assessed associations between changes in the six types of mobility and the country's sociodemographic index using univariate and multivariable linear regression. FINDINGS: The reduction in intra-city movement intensity in China was stronger in cities with a higher SEI than in those with a lower SEI (r=-0·47, p<0·0001). However, reductions in inter-city movement flow (both inflow and outflow intensity) were not associated with SEI and were only associated with government control measures. In the country-level analysis, countries with higher sociodemographic and Universal Health Coverage indexes had greater reductions in population mobility (ie, in transit stations, workplaces, and retail and recreation) following national emergency declarations than those with lower sociodemographic and Universal Health Coverage indexes. A higher sociodemographic index showed a greater reduction in mobility in transit stations (r=-0·27, p=0·0028), workplaces (r=-0·34, p=0·0002), and areas retail and recreation (rxs=-0·30, p=0·0012) than those with a lower sociodemographic index. INTERPRETATION: Although COVID-19 outbreaks are more frequently reported in larger cities, our analysis shows that future policies should prioritise the reduction of risks in areas with a low socioeconomic level-eg, by providing financial assistance and improving public health messaging. However, our study design only allows us to assess associations, and a long-term study is needed to decipher causality. FUNDING: Chinese Ministry of Science and Technology, Research Council of Norway, Beijing Municipal Science & Technology Commission, Beijing Natural Science Foundation, Beijing Advanced Innovation Program for Land Surface Science, National Natural Science Foundation of China, China Association for Science and Technology.

A follow-up study shows that recovered patients with re-positive PCR test in Wuhan may not be infectious.

BACKGROUND: Previous studies showed that recovered coronavirus disease 2019 (COVID-19) patients can have a subsequent positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after they are discharged from the hospital. Understanding the epidemiological characteristics of recovered COVID-19 patients who have a re-positive test is vital for preventing a second wave of COVID-19. METHODS: This retrospective study analyzed the epidemiological and clinical features of 20,280 COVID-19 patients from multiple centers in Wuhan who had a positive PCR test between December 31, 2019, and August 4, 2020. The RT-PCR test results for 4079 individuals who had close contact with the re-positive cases were also obtained. RESULTS: In total, 2466 (12.16%) of the 20,280 patients had a re-positive SARS-CoV-2 PCR test after they were discharged from the hospital, and 4079 individuals had close contact with members of this patient group. All of these 4079 individuals had a negative SARS-CoV-2 PCR test. CONCLUSIONS: This retrospective study in Wuhan analyzed the basic characteristics of recovered COVID-19 patients with re-positive PCR test and found that these cases may not be infectious.

Association between coronavirus disease 2019 (COVID-19) and long-term exposure to air pollution: Evidence from the first epidemic wave in China.

People with chronic obstructive pulmonary disease, cardiovascular disease, or hypertension have a high risk of developing severe coronavirus disease 2019 (COVID-19) and of COVID-19 mortality. However, the association between long-term exposure to air pollutants, which increases cardiopulmonary damage, and vulnerability to COVID-19 has not yet been fully established. We collected data of confirmed COVID-19 cases during the first wave of the epidemic in mainland China. We fitted a generalized linear model using city-level COVID-19 cases and severe cases as the outcome, and long-term average air pollutant levels as the exposure. Our analysis was adjusted using several variables, including a mobile phone dataset, covering human movement from Wuhan before the travel ban and movements within each city during the period of the emergency response. Other variables included smoking prevalence, climate data, socioeconomic data, education level, and number of hospital beds for 324 cities in China. After adjusting for human mobility and socioeconomic factors, we found an increase of 37.8% (95% confidence interval [CI]: 23.8%-52.0%), 32.3% (95% CI: 22.5%-42.4%), and 14.2% (7.9%-20.5%) in the number of COVID-19 cases for every 10-µg/m3 increase in long-term exposure to NO2, PM2.5, and PM10, respectively. However, when stratifying the data according to population size, the association became non-significant. The present results are derived from a large, newly compiled and geocoded repository of population and epidemiological data relevant to COVID-19. The findings suggested that air pollution may be related to population vulnerability to COVID-19 infection, although the extent to which this relationship is confounded by city population density needs further exploration.

A Newcastle Disease Virus (NDV) Expressing a Membrane-Anchored Spike as a Cost-Effective Inactivated SARS-CoV-2 Vaccine.

A successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine must not only be safe and protective, but must also meet the demand on a global scale at a low cost. Using the current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent coronavirus disease 2019 (COVID-19) vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.

Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate.

BACKGROUND: Due to the lack of protective immunity of humans towards the newly emerged SARS-CoV-2, this virus has caused a massive pandemic across the world resulting in hundreds of thousands of deaths. Thus, a vaccine is urgently needed to contain the spread of the virus. METHODS: Here, we describe Newcastle disease virus (NDV) vector vaccines expressing the spike protein of SARS-CoV-2 in its wild type format or a membrane-anchored format lacking the polybasic cleavage site. All described NDV vector vaccines grow to high titers in embryonated chicken eggs. In a proof of principle mouse study, the immunogenicity and protective efficacy of these NDV-based vaccines were investigated. FINDINGS: We report that the NDV vector vaccines elicit high levels of antibodies that are neutralizing when the vaccine is given intramuscularly in mice. Importantly, these COVID-19 vaccine candidates protect mice from a mouse-adapted SARS-CoV-2 challenge with no detectable viral titer and viral antigen in the lungs. INTERPRETATION: The results suggested that the NDV vector expressing either the wild type S or membrane-anchored S without the polybasic cleavage site could be used as live vector vaccine against SARS-CoV-2. FUNDING: This work is supported by an NIAID funded Center of Excellence for Influenza Research and Surveillance (CEIRS) contract, the Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract, philanthropic donations and NIH grants.

An investigation of transmission control measures during the first 50 days of the COVID-19 epidemic in China.

Responding to an outbreak of a novel coronavirus [agent of coronavirus disease 2019 (COVID-19)] in December 2019, China banned travel to and from Wuhan city on 23 January 2020 and implemented a national emergency response. We investigated the spread and control of COVID-19 using a data set that included case reports, human movement, and public health interventions. The Wuhan shutdown was associated with the delayed arrival of COVID-19 in other cities by 2.91 days. Cities that implemented control measures preemptively reported fewer cases on average (13.0) in the first week of their outbreaks compared with cities that started control later (20.6). Suspending intracity public transport, closing entertainment venues, and banning public gatherings were associated with reductions in case incidence. The national emergency response appears to have delayed the growth and limited the size of the COVID-19 epidemic in China, averting hundreds of thousands of cases by 19 February (day 50).