Safety and immunogenicity of the COVID-19 mRNA vaccine CS-2034: A randomized, double-blind, dose-exploration, placebo-controlled multicenter Phase I clinical trial in healthy Chinese adults.

BACKGROUND: The novel coronavirus pneumonia (COVID-19) is an infectious disease caused by the infection of a novel coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths. We aimed to evaluate the safety and immunogenicity of the COVID-19 mRNA vaccine (CS-2034, CanSino, Shanghai, China) in adults without COVID-19 infection from China. METHOD: This is a multicenter Phase I clinical trial with a randomized, double-blinded, dose-exploration, placebo-controlled design. The trial recruited 40 seronegative participants aged 18-59 years who had neither received any COVID-19 vaccine nor been infected before. They were divided into a low-dose group (administered with either the CS-2034 vaccine containing 30 µg of mRNA or a placebo of 0.3 ml type 5 adenovirus vector) and a high-dose group (administered with either the CS-2034 vaccine containing 50 µg of mRNA or a placebo of 0.5 ml type 5 adenovirus vector). Participants were randomly assigned in a 3:1 ratio to receive either the mRNA vaccine or a placebo on days 0 and 21 according to a two-dose immunization schedule. The first six participants in each dosage group were assigned as sentinel subjects. Participants were sequentially enrolled in a dose-escalation manner from low to high dose and from sentinel to non-sentinel subjects. Blood samples were collected from all participants on the day before the first dose (Day 0), the day before the second dose (day 21), 14 days after the second dose (day 35), and 28 days after the second dose (day 49) to evaluate the immunogenicity of the CS-2034 vaccine. Participants were monitored for safety throughout the 28-day follow-up period, including solicited adverse events, unsolicited adverse events, adverse events of special interest (AESI), and medically attended adverse events (MAE). This report focuses solely on the safety and immunogenicity analysis of adult participants aged 18-59 years, while the long-term phase of the study is still ongoing. This study is registered at ClinicalTrials.gov, NCT05373485. FINDINGS: During the period from May 17, 2022, to August 8, 2022, a total of 155 participants aged 18-59 years were screened for this study. Among them, 115 participants failed the screening process, and 40 participants were randomly enrolled (15 in the low-dose group, 15 in the high-dose group, and 10 in the placebo group). Throughout the 28-day follow-up period, the overall incidence of adverse reactions (related to vaccine administration) in the low-dose group, high-dose group, and placebo group was 93.33% (14/15), 100.00% (15/15), and 80.00% (8/10), respectively. There was a statistically significant difference in the incidence of local adverse reactions (soreness, pruritus, swelling at the injection site) among the low-dose group, high-dose group, and placebo group (P = 0.002). All adverse reactions were mainly of severity grade 1 (mild) or 2 (moderate), and no adverse events of severity grade 4 or higher occurred. Based on the analysis of Spike protein Receptor Binding Domain (S-RBD) IgG antibodies against the BA.1 strain, the seroconversion rates of antibodies at day 21 after the first dose were 86.67%, 93.33%, and 0.00% in the low-dose group, high-dose group, and placebo group, respectively. The geometric mean titer (GMT) of antibodies was 61.2(95%CI 35.3-106.2), 55.4(95%CI 36.3-84.4), and 15.0(95%CI 15.0-15.0), and the geometric mean fold increase (GMI) was 4.08(95%CI 2.35-7.08), 3.69(95%CI 2.42-5.63), and 1.00(95%CI 1.00-1.00) for each group. At day 28 after the full vaccination, the seroconversion rates of antibodies were 100.00%, 93.33%, and 0.00%, and the GMT of antibodies was 810.0(95%CI 511.4-1283.0), 832.2(95%CI 368.1-1881.6), and 15.0(95%CI 15.0-15.0), and the GMI was 54.00(95%CI 34.09-85.53), 55.48(95%CI 24.54-125.44), and 1.00(95%CI 1.00-1.00) for each group, respectively. Based on the analysis of CD3+/CD4+ cell cytokine response, the percentages of IL-2+, IL-4+, IFN-γ+, and TNF-α+ cells increased after 14 days and 28 days of full vaccination in both the low-dose group and high-dose group. The increase was most pronounced in the high-dose group. INTERPRETATION: At day 28 after the full vaccination, both the low-dose and the high-dose CS-2034 vaccine were able to induce the production of high titers of S-RBD IgG antibodies against the BA.1 strain. Adverse reactions in the low-dose and high-dose groups were mainly of severity grade 1 or 2, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.

The influence of rainfall and catchment characteristics on runoff generation in urban catchments-a case study in Hebi City of China.

An in-depth understanding of the rainfall-runoff process is essential for effective stormwater management. However, the understanding of the hierarchy of rainfall characteristics in terms of their importance in influencing runoff generation is limited. This paper investigates the influence of rainfall characteristics and catchment characteristics on runoff generation in urban catchments. The outcomes showed that there are 4 dominant factors affecting runoff generation: total precipitation TP and maximum 60-min rainfall intensity MAX60 are the two top-ranked factors while average rainfall intensity RI and maximum 5-min rainfall intensity MAX5 are ranked second. Additionally, compared to the moderate rainfall regime (MR), the heavy rainfall regime (HR) tends to produce higher peak flow rates, higher total inflow per unit area, and lower runoff control effect. Note that the antecedent precipitation has a more significant effect on runoff generation and is even the dominant factor when rainstorm events with daily rainfall larger than 50 mm are not considered. The results of analyzing the influence of catchment characteristics suggest that only under HR regime conditions do the catchment characteristics have an impact on runoff generation and behave as smaller catchment areas, and higher proportions of green landscapes always lead lower peak flow rates, lower total inflows per unit area, and higher runoff control effects.

Bullying Victimization Heightens Cortisol Response to Psychosocial Stress in Chinese Children.

Childhood adverse experiences have been consistently documented to engender persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis reactivity to chronic stress. However, there has been very little research examining whether this effect can be elicited among children when using a standardized laboratory stress test, or whether such effects are found in non-Western youth. In the current study, 80 10-year-old Chinese children (45% girls, 4-5th grades) were selected from 970 students based on the experience of being bullied, resulting in a sample of 59 victims (physical, verbal, and relational/social), and a group of 21 nonbullied children with distributions of age and gender that were comparable. We examined the association between bullying victimization and cortisol reactivity to the Trier Social Stress Test (TSST) at six time points using repeated-measures analyses of variance. The results showed that the TSST was a valid protocol among Chinese children for testing the functioning of HPA axis, based on two indicators: cortisol increase in response to stressor, and cortisol decrease after stressor removal. Based on the TSST, both cortisol reactivity and total cortisol concentration over the course of TSST were higher in bullied children relative to nonbullied children. Moreover, there were no differences in cortisol levels between victimization sub-types. Our study extended prior findings, by showing that cortisol dysregulation in response to stress may be related to bullying victimization.

Occurrence and possible sources of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) along the Chao River, China.

To analyze the possible influence of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) on Miyun Reservoir, 14 soil samples and 1 water sample were collected along the Chao River, which is the main upstream source of the reservoir. A total of 24 kinds of OCPs and 12 kinds of dioxin-like PCBs were measured. Results showed that the ∑OCPs concentration ranged from 0.8145 to 16.8524 ng g(-1), and the ∑PCBs ranged from 0.0039 to 0.0365 ng g(-1). Dichlorodiphenyltrichloroethanes (DDTs), hexachlorocyclohexanes (HCHs) and hexachlorobenzene (HCB) were the three dominant kinds of OCPs in this region, and the majority component of the PCBs was PCB-118 in both water and soil samples. The OCP ratios suggest that new inputs of lindane exist. DDTs mainly come from old technical inputs. HCHs might come from a new application of lindane, which highlights the importance of prohibited pesticide control. OCP concentrations were higher in corn fields and orchards and lower in forest lands and grasslands, which indicated that OCPs were very much influenced by human activities. The proportion of PCB components in this study area suggested that they mainly came from atmospheric deposition.

[Analysis and evaluation of heavy metals along the Chaohe River in Miyun County].

In order to explore the heavy metal concentrations in soils surrounding the Chaohe River, 15 soil samples were collected along the Chaohe River. Results show that average concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb, Zn are 7.94, 0.16, 127.71, 38.45, 0.22, 45.97, 21.98, 81.06 microg x g(-1), respectively. The mean concentrations of 15 samples for most heavy metals are higher than the background values of Beijing soil except Pb. Compared to the heavy metal concentrations in the soil of Shanghai Huangpu River water resource area, the mean concentrations of Cr, Cu and Ni are higher and concentrations of other heavy metals are at a moderate level. Geo-accumulation index method was used to evaluate the pollution status of different heavy metals. Results show that the pollution of Cr and Hg is moderate. The pollution of Cu and Ni is between no to moderate. There is no pollution of As, Cd, Pb and Zn in the study area. Ecological risk index method was also used to evaluate the ecological impact. Results show that the pollution level of Hg is strong and Cu is medium. Other heavy metals are at a slight pollution level. The samplings region as a whole is at a medium ecological pollution level. In a word, Hg, Cr, Ni, and Cu need to be controlled.

Enhanced protein production by engineered zinc finger proteins.

Increasing the yield of therapeutic proteins from mammalian production cell lines reduces costs and decreases the time to market. To this end, we engineered a zinc finger protein transcription factor (ZFP TF) that binds a DNA sequence within the promoter driving transgene expression. This ZFP TF enabled >100% increase in protein yield from CHO cells in transient, stable, and fermentor production run settings. Expression vectors engineered to carry up to 10 ZFP binding sites further enhanced ZFP-mediated increases in protein production up to approximately 500%. The multimerized ZFP binding sites function independently of the promoter, and therefore across vector platforms. CHO cell lines stably expressing ZFP TFs demonstrated growth characteristics similar to parental cell lines. ZFP TF expression and gains in protein production were stable over >30 generations in the absence of antibiotic selection. Our results demonstrate that ZFP TFs can rapidly and stably increase protein production in mammalian cells.

Gene regulation in planta by plant-derived engineered zinc finger protein transcription factors.

The ability to modify plant traits is of great commercial potential in agricultural biotechnology. To this end we have engineered plant-based zinc finger protein transcription factors (ZFP TFs) that minimize the use of non-plant DNA sequences. This novel architecture supports the use of tandem arrays of zinc-finger DNA recognition domains such that the ZFP TF binds a contiguous DNA target site - thus emulating the design of ZFP TFs described previously for mammalian gene regulation. We show that this plant-based ZFP TF architecture supports high affinity DNA binding while allowing the specificity of the DNA-protein interaction to be determined by the amino acid sequences of the recognition helices. This plant-based backbone thus supports the use of previously characterized DNA recognition helices originally identified in a mammalian ZFP context without using mammalian DNA sequences. Moreover, we show that plant-based ZFP TFs employing this new architecture can up-regulate endogenous ADH activity by > 20-fold in transgenic Arabidopsis. Thus plant-based ZFP TFs are shown to be potent regulators of gene expression in vivo.