Combinative effect of pulsed-light irradiation and solid-state fermentation on ginkgolic acids, ginkgols, ginkgolides, bilobalide, flavonoids, product quality and sensory assessment of Ginkgo biloba dark tea.

Pulsed light (PL) is a prospective non-thermal technology that can improve the degradation of ginkgolic acid (GA) and retain the main bioactive compounds in Ginkgo biloba leaves (GBL). However, only using PL hasn't yet achieved the ideal effect of reducing GA. Fermentation of GBL to make ginkgo dark tea (GDT) could decrease GA. Because different microbial strains are used for fermentation, their metabolites and product quality might differ. However, there is no research on the combinative effect of PL irradiation fixation and microbial strain fermentation on main bioactive compounds and sensory assessment of GDT. In this research, first, Bacillus subtilis and Saccharomyces cerevisiae were selected as fermentation strains that can reduce GA from the five microbial strains. Next, the fresh GBL was irradiated by PL for 200 s (fluences of 0.52 J/cm2), followed by B. subtilis, S. cerevisiae, or natural fermentation to make GDT. The results showed that compared with the control (unirradiated and unfermented GBL) and the only PL irradiated GBL, the GA in GDT using PL + B. subtilis fermentation was the lowest, decreasing by 29.74%; PL + natural fermentation reduced by 24.53%. The total flavonoid content increased by 14.64% in GDT using PL + B. subtilis fermentation, whose phenolic and antioxidant levels also increased significantly. Sensory evaluation showed that the color, aroma, and taste of the tea infusion of PL + B. subtilis fermentation had the highest scores. In conclusion, the combined PL irradiation and solid-state fermentation using B. subtilis can effectively reduce GA and increase the main bioactive compounds, thus providing a new technological approach for GDT with lower GA.

GPS2 promotes erythroid differentiation in K562 erythroleukemia cells primarily via NCOR1.

G protein pathway suppressor 2 (GPS2) has been shown to play a pivotal role in human and mouse definitive erythropoiesis in an EKLF-dependent manner. However, whether GPS2 affects human primitive erythropoiesis is still unknown. This study demonstrated that GPS2 positively regulates erythroid differentiation in K562 cells, which have a primitive erythroid phenotype. Overexpression of GPS2 promoted hemin-induced hemoglobin synthesis in K562 cells as assessed by the increased percentage of benzidine-positive cells and the deeper red coloration of the cell pellets. In contrast, knockdown of GPS2 inhibited hemin-induced erythroid differentiation of K562 cells. GPS2 overexpression also enhanced erythroid differentiation of K562 cells induced by cytosine arabinoside (Ara-C). GPS2 induced hemoglobin synthesis by increasing the expression of globin and ALAS2 genes, either under steady state or upon hemin treatment. Promotion of erythroid differentiation of K562 cells by GPS2 mainly relies on NCOR1, as knockdown of NCOR1 or lack of the NCOR1-binding domain of GPS2 potently diminished the promotive effect. Thus, our study revealed a previously unknown role of GPS2 in regulating human primitive erythropoiesis in K562 cells.

Thermal fixation technologies affect phenolic profile, ginkgolides, bilobalide, product quality, and ginkgolic acids in Ginkgo biloba leaf tea.

Ginkgo biloba leaves (GBLs) contain high phytoconstituents, but ginkgolic acids (GAs, the main toxic compound in GBLs) have limited its applications. Processing Ginkgo biloba dark tea (GBDT) using fixation technology could decrease the toxic compounds; retain flavonoids, ginkgolides, and bilobalide; and improve the product quality. For the first time, various thermal fixations (hot air fixation [HAF], iron pot fixation [IPF], and boiled water fixation [BWF]) followed by rolling, fermentation, and drying were applied to produce GBDT. A comprehensive analysis of the toxicants (GAs), main bioactive compounds (ginkgolides and bilobalide, flavonoids, antioxidants, and phenolic profiles), and product qualities (moisture content, reducing sugar [RS], free amino acids [FAAs], enzyme activity, color properties, antioxidant capacity, etc.) were evaluated. The results revealed that thermal fixations BWF and HAF significantly reduced the GA contents (41.1%-34.6%). Most terpene lactones showed significant differences in control, IPF, and HAF. The HAF had lower total flavonoid content (TFC) than BWF and IPF. The control group (unfixated) had the highest toxic components (GA), terpene trilactones, and TFC compared with various fixations. Adding different fixations to rolling, fermentation, and drying had various impacts on GBDT, and principal component analysis supported the results. Among four thermal fixations, HAF yielded the best results in RS, FAA, total phenolic content, and antioxidant activities, while IPF had the highest TFC. BWF had the lowest content for GA. In conclusion, HAF (6) was chosen as the best technique for producing GBDT since it preserved GBDT's bioactive components while lowering its toxic components.

Separation and purification of polyprenols from Ginkgo biloba leaves by silver ion anchored on imidazole-based ionic liquid functionalized mesoporous MCM-41 sorbent.

Polyprenols (PPs) are compounds with excellent biological activities and are applied in food, pharmaceutical, and cosmetic industries. However, its strong non-polar nature makes it difficult to separate with many saturated impurities (such as saturated fatty acids) extracted together. Complexation extraction is an effective method for separating saturated and polyunsaturated compounds. In this study, mesoporous silica MCM-41 was modified by imidazole-based ionic liquids (IL) followed by coating these MCM-41-supported IL compounds with silver salt to construct π-complexing adsorbent (AgBF4/IL•MCM-41) to enrich PPs from Ginkgo biloba leaves (GBL) extract. The mesoporous π-complexing sorbent was characterized by small-angle X-ray scattering (SAXS), FTIR, and nitrogen adsorption-desorption. The effect of the ratio of silver salt to IL•MCM-41 on the adsorption capacity of polyprenols from GBL was compared, and the dosage of AgBF4 was determined to be 1.5 mmol/g IL•MCM-41. Adsorption isotherms and kinetics indicate that the π-complexing adsorbent has excellent PPs adsorption performance (153 mg/g at 30 °C) and a fast adsorption rate (the time to reach adsorption equilibrium is 210 s). The PPs were separated using the fixed bed after treatment for only one cycle with AgBF4/IL•MCM-41, and the content of PPs in the product was increased from 38.54% to 70.2%, with a recovery rate of 86.6%. The π-complexing adsorbent showed excellent reusability for ≥3 adsorption-desorption cycles.

Development, Validation, and Application of High-Performance Liquid Chromatography with Diode-Array Detection Method for Simultaneous Determination of Ginkgolic Acids and Ginkgols in Ginkgo biloba.

Ginkgo biloba leaves (GBLs), which comprise many phytoconstituents, also contain a toxic substance named ginkgolic acid (GA). Our previous research showed that heating could decarboxylate and degrade GA into ginkgols with high levels of bioactivity. Several methods are available to measure GA in GBLs, but no analytical method has been developed to measure ginkgols and GA simultaneously. Hence, for the first time, an HPLC-DAD method was established to simultaneously determine GA and ginkgols using acetonitrile (0.01% trifluoroacetic acid, v/v) as mobile phase A and water (0.01% trifluoroacetic acid, v/v) as mobile phase B. The gradient elution conditions were: 0-30 min, 75-90% phase A; 30-35 min, 90-90% phase A; 35-36 min, 90-75% phase A; 36-46 min, 75-75% phase A. The detection wavelength of GA and ginkgol were 210 and 270 nm, respectively. The flow rate and injection volume were 1.0 mL/min and 50 µL, respectively. The linearity was excellent (R2 > 0.999), and the RSD of the precision, stability, and repeatability of the total ginkgols was 0.20%, 2.21%, and 2.45%, respectively, in six parallel determinations. The recoveries for the low, medium, and high groups were 96.58%, 97.67%, and 101.52%, respectively. The limit of detection of ginkgol C13:0, C15:1, and C17:1 was 0.61 ppm, 0.50 ppm, and 0.06 ppm, respectively. The limit of quantification of ginkgol C13:0, C15:1, and C17:1 was 2.01 ppm, 1.65 ppm, and 0.20 ppm, respectively. Finally, this method accurately measured the GA and ginkgol content in ginkgo leaves and ginkgo tea products (ginkgo black tea, ginkgo dark tea, ginkgo white tea, and ginkgo green tea), whereas principal component analysis (PCA) was performed to help visualize the association between GA and ginkgols and five different processing methods for GBLs. Thus, this research provides an efficient and accurate quantitative method for the subsequent detection of GA and ginkgols in ginkgo tea.

Immunosuppressants exert antiviral effects against influenza A(H1N1)pdm09 virus via inhibition of nucleic acid synthesis, mRNA splicing, and protein stability.

Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of 10 immunosuppressants, explored the antiviral mechanisms of immunosuppressants, and demonstrated the combined effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibits viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through a proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibits IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG, and filgotinib could be the preferential choices for patients who must take immunosuppressants but are at risk of influenza virus infection.

BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury.

BRISC (BRCC3 isopeptidase complex) is a deubiquitinating enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1ß, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.

Immunogenicity and safety of a new hexavalent rotavirus vaccine in Chinese infants: A randomized, double-blind, placebo-controlled phase 2 clinical trial.

Rotavirus remains a major cause of diarrhea among 5-y-old children, and vaccination is currently the most effective and economical measure. We conducted a randomized, double-blind, placebo-controlled phase II clinical trial designed to determine the dosage, immunogenicity, and safety profile of a novel hexavalent rotavirus vaccine. In total, 480 eligible healthy infants, who were 6-12 weeks of age at the time of randomization were randomly allocated (1:1:1) to receive 105.5 focus-forming unit (FFU) or 106.5FFU of vaccine or placebo on a 0, 28 and 56-d schedule. Blood samples were collected 28 d after the third dose to assess rotavirus immunoglobulin A (IgA) antibody levels. Adverse events (AEs) up to 28 d after each dose and serious adverse events (SAEs) up to 6 months after the third dose were recorded as safety measurements. The anti-rotavirus IgA seroconversion rate of the vaccine groups reached more than 70.00%, ranging from 74.63% to 76.87%. The postdose 3 (PD3) geometric mean concentrations (GMCs) of anti-rotavirus IgA among vaccine recipients ranged from 76.97 U/ml to 84.46 U/ml. At least one solicited AE was recorded in 114 infants (71.25%) in the high-dose vaccine group, 106 infants (66.25%) in the low-dose vaccine group and 104 infants (65.00%) in the placebo group. The most frequently solicited AE was fever. The novel oral hexavalent rotavirus vaccine was safe and immunogenic in infants support the conclusion to advance the candidate vaccine for phase 3 efficacy trials.

Cupric coordination compounds with multiple anions: a promising strategy for the regulation of energetic materials.

To seek new high energetic materials, N-methylene-C-bridged nitrogen-rich heterocycle 1-((4,5-diamino-4H-1,2,4-triazol-3-yl)methyl)-1H-1,2,4-triazol-3,5-diamine (DATMTDA) (2) was first synthesized, and two copper coordination compounds ([Cu12(OH)4(ClO4)4(H2O)4(DATMTDA)12](ClO4)16·12H2O (3) and [Cu3(OH)(ClO4)(DATMTDA)3](ClO4)3(NO3) (4)) based on 2 were formed by introducing different anions. These compounds were characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction analysis. The crystal structures of compounds 3 and 4 are similar and crystallize in monoclinic systems with the P21/c space group, while the central copper atoms show different coordination behaviors. However, the structure of compounds 3 and 4 is analogous to a three dimensional structure owing to the O atom of OH-, forming coordinate bonds with three copper cations. The NBO charge of 2 was calculated using density functional theory to understand its coordination modes. The Hirshfeld surface calculation reveals that 3 and 4 have strong intermolecular interactions. The thermal decomposition processes, non-isothermal kinetics, and enthalpies of formation and sensitivities of these compounds were investigated. By introducing one NO3- of compound 4 to replace one ClO4- in compound 3, compound 4 shows lower density and lower decomposition peak temperature but lower sensitivity and a higher formation enthalpy than compound 3. The complex 4 possesses an outstanding catalytic effect for the decomposition of AP than that of complex 3. The results illustrate the possibility of introducing various anions into energetic coordination compounds for the regulation of energetic materials.

VPS37C facilitates erythroid differentiation by promoting EKLF stability.

The process of erythroid differentiation is orchestrated at the molecular level by a complex network of transcription factors. Erythroid Krüppel-like factor (EKLF/KLF1) is a master erythroid gene regulator that directly regulates most aspects of terminal erythroid differentiation. However, the underlying regulatory mechanisms of EKLF protein stability are still largely unknown. In this study, we identified Vacuolar protein sorting 37 C (VPS37C), a core subunit of the Endosomal sorting complex required for transport-I (ESCRT-I) complex, as an essential regulator of EKLF stability. Our study showed that VPS37C interacts with EKLF and prevents K48-linked polyubiquitination of EKLF and proteasome-mediated EKLF degradation, thus enhancing EKLF protein stability and transcriptional activity. VPS37C overexpression in murine erythroleukemia (MEL) cells promotes hexamethylene bisacetamide (HMBA)-induced erythroid differentiation manifested by up-regulating erythroid-specific EKLF target genes and increasing benzidine-positive cells. In contrast, VPS37C knockdown inhibits HMBA-induced MEL cell erythroid differentiation. Particularly, the restoration of EKLF expression in VPS37C-knockdown MEL cells reverses erythroid-specific gene expression and hemoglobin production. Collectively, our study demonstrated VPS37C is a novel regulator of EKLF ubiquitination and degradation, which plays a positive role in erythroid differentiation of MEL cells by enhancing EKLF protein stability.

Development of an mRNA vaccine against a panel of heterologous H1N1 seasonal influenza viruses using a consensus hemagglutinin sequence.

Seasonal influenza, causes hundreds of thousands of deaths annually, posing a severe threat to human health. Currently available influenza vaccines are targeted only at specific strains or conserved epitopes; however, these vaccines are not completely efficacious because influenza viruses can undergo mutation during circulation, leading to antigenic mismatch between recommended strains and circulating strains and elusion from the immune system. Therefore, developing an influenza vaccine that is quick, effective, and broadly protective has become crucial, and the integral part of hemagglutinin (HA) remains an ideal target for vaccine development. This study developed a lipid nanoparticle-encapsulated nucleoside-modified mRNA vaccine (mRNA-LNPs) encoding a consensus full-length HA sequence (H1c) and evaluated its protective efficacy and immunogenicity through in vitro and in vivo assays. Following two intramuscular immunizations (2, 10 µg, or 20 µg) at a 3-week interval in BALB/c mice, H1c-mRNA-LNP vaccine induced strong antibodies as shown in the hemagglutination-inhibition test and protective neutralizing antibodies against numerous heterologous H1N1 influenza viruses as shown in the microneutralization assay. Additionally, both Th1- and Th2-biased cellular immune responses were elicited, with the Th1-biased response being stronger. Two doses of the H1c-mRNA-LNP vaccine could neutralize a panel of heterologous H1N1 influenza viruses and could confer protection in mice. Taken together, these findings suggest that the H1c-mRNA-LNP vaccine encoding a consensus full-length HA is a feasible strategy for developing a cross-protective vaccine against a panel of heterologous H1N1 influenza viruses.

Effects of processing methods on quality, antioxidant capacity, and cytotoxicity of Ginkgo biloba leaf tea product.

BACKGROUND: Ginkgo biloba leaves contain beneficial flavonoids, bilobalide (BB), and ginkgolides. However, the toxic ginkgolic acid (GA) limit its application. In this study, various traditional processing methods were used to prepare G. biloba leaf tea (GBLT), including white tea, black tea, dark tea, green tea, and freeze-dried as control, followed by investigations of their effects on quality, antioxidant capacity, bioactive components, and cytotoxicity of the tea products. RESULTS: Results showed that different processing methods significantly impact the tea products' quality indexes and the principal component analysis (PCA) and hierarchical cluster analysis (HCA) corroborated it. White tea had the highest total sugar (TS) and GA content and the most potent cytotoxicity on HepG2 cells. However, TS and GA content and the cytotoxicity of GBLT markedly decreased during fermentation and fixation. Moreover, white tea possessed higher total phenolic content (TPC), total flavonoid content (TFC), and more vigorous antioxidant activities than green tea, black tea, and dark tea. Terpene trilactones value was stable, but different catechins contents fluctuated according to the manufacturing process of different GBLTs. Among the four GBLTs, dark tea combining fixation and fermentation had the lowest GA content and cytotoxicity, less bioactive components reduction, appropriate quality, and stronger flavor. CONCLUSION: These findings demonstrate that fixation and fermentation help reduce GAs during the manufacturing of GBLT. However, their ability to retain bioactive substances needs further optimization in future studies. © 2023 Society of Chemical Industry.

Status of epidemic and immunization of diphtheria / 中国生物制品学杂志

@#Abstract：The infection rate and incidence of diphtheria have been controlled effectively under the large⁃scale immunization projects. However，in recent years，cases of diphtheria have occurred frequently at home and abroad. Except for common infection in children，the number of middle⁃aged and elderly patients also increased，indicating that the prevention and control of diphtheria still should not be ignored. This paper reviewed the etiological characteristics，pathogenic mechanism as well as the epidemic and immunization status at home and abroad of diphtheria and looked forward to the above problems.

COVID-19 vaccination boosts the potency and breadth of the immune response against SARS-CoV-2 among recovered patients in Wuhan.

The immunity of patients who recover from coronavirus disease 2019 (COVID-19) could be long lasting but persist at a lower level. Thus, recovered patients still need to be vaccinated to prevent reinfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or its mutated variants. Here, we report that the inactivated COVID-19 vaccine can stimulate immunity in recovered patients to maintain high levels of anti-receptor-binding domain (RBD) and anti-nucleocapsid protein (NP) antibody titers within 9 months, and high neutralizing activity against the prototype, Delta, and Omicron strains was observed. Nevertheless, the antibody response decreased over time, and the Omicron variant exhibited more pronounced resistance to neutralization than the prototype and Delta strains. Moreover, the intensity of the SARS-CoV-2-specific CD4+ T cell response was also increased in recovered patients who received COVID-19 vaccines. Overall, the repeated antigen exposure provided by inactivated COVID-19 vaccination greatly boosted both the potency and breadth of the humoral and cellular immune responses against SARS-CoV-2, effectively protecting recovered individuals from reinfection by circulating SARS-CoV-2 and its variants.

A novel cervix carcinoma biomarker: Pathological-epigenomics, integrated analysis of MethylMix algorithm and pathology for predicting response to cancer immunotherapy.

Herein, A non-invasive pathomics approach was developed to reveal the methylation status in patients with cervical squamous cell carcinoma and predict clinical outcomes and treatment response. Using the MethylMix algorithm, 14 methylation-driven genes were selected for further analysis. We confirmed that methylation-driven genes were differentially expressed in immune, stromal, and tumor cells. In addition, we constructed a methylation-driven model and explored the alterations in immunocyte infiltration between the different models. The methylation-driven subtypes identified in our investigation could effectively predict the clinical outcomes of cervical cancer. To further evaluate the level of methylation-driven patterns, we constructed a risk model with four genes. Significant correlations were observed between the score and immune response markers, including PD1 and CTLA4. Multiple immune infiltration algorithms evaluated the level of immunocyte infiltration between the high- and low-risk groups, while the components of anti-tumor immunocytes in the low-risk group were significantly increased. Subsequently, a total of 205 acquired whole-slide imaging (WSI) images were processed to capture image signatures, and the pathological algorithm was employed to construct an image prediction model based on the risk score classification. The model achieved an area under the curve (AUC) of 0.737 and 0.582 for the training and test datasets, respectively. Moreover, we conducted vitro assays for validation of hub risk gene. The proposed prediction model is a non-invasive method that combines pathomics features and genomic profiles and shows satisfactory performance in predicting patient survival and treatment response. More interdisciplinary fields combining medicine and electronics should be explored in the future.

Predictive Efficacy of a Radiomics Random Forest Model for Identifying Pathological Subtypes of Lung Adenocarcinoma Presenting as Ground-Glass Nodules.

Purpose: To establish and verify the ability of a radiomics prediction model to distinguish invasive adenocarcinoma (IAC) and minimal invasive adenocarcinoma (MIA) presenting as ground-glass nodules (GGNs). Methods: We retrospectively analyzed 118 lung GGN images and clinical data from 106 patients in our hospital from March 2016 to April 2019. All pathological classifications of lung GGN were confirmed as IAC or MIA by two pathologists. R language software (version 3.5.1) was used for the statistical analysis of the general clinical data. ITK-SNAP (version 3.6) and A.K. software (Analysis Kit, American GE Company) were used to manually outline the regions of interest of lung GGNs and collect three-dimensional radiomics features. Patients were randomly divided into training and verification groups (ratio, 7:3). Random forest combined with hyperparameter tuning was used for feature selection and prediction modeling. The receiver operating characteristic curve and the area under the curve (AUC) were used to evaluate model prediction efficacy. The calibration curve was used to evaluate the calibration effect. Results: There was no significant difference between IAC and MIA in terms of age, gender, smoking history, tumor history, and lung GGN location in both the training and verification groups (P>0.05). For each lung GGN, the collected data included 396 three-dimensional radiomics features in six categories. Based on the training cohort, nine optimal radiomics features in three categories were finally screened out, and a prediction model was established. We found that the training group had a high diagnostic efficacy [accuracy, sensitivity, specificity, and AUC of the training group were 0.89 (95%CI, 0.73 - 0.99), 0.98 (95%CI, 0.78 - 1.00), 0.81 (95%CI, 0.59 - 1.00), and 0.97 (95%CI, 0.92-1.00), respectively; those of the validation group were 0.80 (95%CI, 0.58 - 0.93), 0.82 (95%CI, 0.55 - 1.00), 0.78 (95%CI, 0.57 - 1.00), and 0.92 (95%CI, 0.83 - 1.00), respectively]. The model calibration curve showed good consistency between the predicted and actual probabilities. Conclusions: The radiomics prediction model established by combining random forest with hyperparameter tuning effectively distinguished IAC from MIA presenting as GGNs and represents a noninvasive, low-cost, rapid, and reproducible preoperative prediction method for clinical application.

Immunogenicity and safety of NVSI-06-07 as a heterologous booster after priming with BBIBP-CorV: a phase 2 trial.

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1-3 months, 4-6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01-63.85 folds on day 28 after vaccination, whereas only 4.20-16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron.

Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients in a randomized phase 2 trial.

NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluate the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in BBIBP-CorV recipients in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who have administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, are randomized 1:1 to receive either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The incidence of adverse reactions is low, and the overall safety profile is quite similar between two booster regimens. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster are significantly higher than those by BBIBP-CorV booster against not only SARS-CoV-2 prototype strain but also multiple variants of concerns (VOCs). Especially, the neutralizing antibody GMT against Omicron variant induced by heterologous NVSI-06-08 booster reaches 367.67, which is substantially greater than that boosted by BBIBP-CorV (GMT: 45.03). In summary, NVSI-06-08 is safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which is immunogenically superior to the homologous boost with another dose of BBIBP-CorV.

Potent Anti-SARS-CoV-2 Efficacy of COVID-19 Hyperimmune Globulin from Vaccine-Immunized Plasma.

Coronavirus disease 2019 (COVID-19) remains a global public health threat. Hence, more effective and specific antivirals are urgently needed. Here, COVID-19 hyperimmune globulin (COVID-HIG), a passive immunotherapy, is prepared from the plasma of healthy donors vaccinated with BBIBP-CorV (Sinopharm COVID-19 vaccine). COVID-HIG shows high-affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein, the receptor-binding domain (RBD), the N-terminal domain of the S protein, and the nucleocapsid protein; and blocks RBD binding to human angiotensin-converting enzyme 2 (hACE2). Pseudotyped and authentic virus-based assays show that COVID-HIG displays broad-spectrum neutralization effects on a wide variety of SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529) in vitro. However, a significant reduction in the neutralization titer is detected against Beta, Delta, and Omicron variants. Additionally, assessments of the prophylactic and treatment efficacy of COVID-HIG in an Adv5-hACE2-transduced IFNAR-/- mouse model of SARS-CoV-2 infection show significantly reduced weight loss, lung viral loads, and lung pathological injury. Moreover, COVID-HIG exhibits neutralization potency similar to that of anti-SARS-CoV-2 hyperimmune globulin from pooled convalescent plasma. Overall, the results demonstrate the potential of COVID-HIG against SARS-CoV-2 infection and provide reference for subsequent clinical trials.

Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN-γ Signaling.

Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn-/- HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn-/- HSPCs are enriched for gene sets related to interferon gamma (IFN-γ) signaling. Hemgn-/- HSPCs show enhanced responses to IFN-γ treatment and increased aging over time. Blocking IFN-γ signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn-/- HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-γ-treated Hemgn-/- mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-γ signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation.