Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.

BACKGROUND: Heterologous boosting is suggested to be of use in populations who have received inactivated COVID-19 vaccines. We aimed to assess the safety and immunogenicity of a heterologous vaccination with the mRNA vaccine CS-2034 versus the inactivated BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 omicron (BA.5) variant. METHODS: This trial contains a randomised, double-blind, parallel-controlled study in healthy participants aged 18 years or older (group A) and an open-label cohort in participants 60 years and older (group B), who had received three doses of inactivated whole-virion vaccines at least 6 months before enrolment. Pregnant women and people with major chronic illnesses or a history of allergies were excluded. Eligible participants in group A were stratified by age (18-59 years and ≥60 years) and then randomised by SAS 9.4 in a ratio of 3:1 to receive a dose of the mRNA vaccine (CS-2034, CanSino, Shanghai, China) or inactivated vaccine (BBIBP-CorV, Sinopharm, Beijing, China). Safety and immunogenicity against omicron variants of the fourth dose were evaluated in group A. Participants 60 years and older were involved in group B for safety observations. The primary outcome was geometric mean titres (GMTs) of the neutralising antibodies against omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. The intention-to-treat group was involved in the safety analysis, while all patients in group A who had blood samples taken before and after the booster were involved in the immunogenicity analysis. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575). FINDINGS: Between Oct 13, and Nov 22, 2022, 320 participants were enrolled in group A (240 in the CS-2034 group and 80 in the BBIBP-CorV group) and 113 in group B. Adverse reactions after vaccination were more frequent in CS-2034 recipients (158 [44·8%]) than BBIBP-CorV recipients (17 [21·3%], p<0·0001). However, most adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by eight (2%) of 353 participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14·4-fold (GMT 229·3, 95% CI 202·7-259·4 vs 15·9, 13·1-19·4) higher concentration of neutralising antibodies to SARS-CoV-2 omicron variant BA.5 than did homologous boosting with BBIBP-CorV. The seroconversion rates of SARS-CoV-2-specific neutralising antibody responses were much higher in the mRNA heterologous booster regimen compared with BBIBP-CorV homologous booster regimen (original strain 47 [100%] of 47 vs three [18·8%] of 16; BA.1 45 [95·8%] of 48 vs two [12·5%] 16; and BA.5 233 [98·3%] of 240 vs 15 [18·8%] of 80 by day 28). INTERPRETATION: Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 omicron infections compared with homologous boosting, which could support the emergency use authorisation of CS-2034 in adults. FUNDING: Science and Technology Commission of Shanghai, National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Effects of exogenous melatonin on photosynthesis and physiological characteristics of chry-santhemum seedlings under high temperature stress.

We examined the effects of exogenous melatonin (MT) on the resistance of Chrysanthemum morifolium 'Jinba' to high temperature stress. Chrysanthemum leaves were sprayed with 200 µmol·L-1MT, and then subjected to high temperature stress at 40 ℃ (day)/ 35 ℃ (night). The ultrastructure of chloroplast and thylakoid of chrysanthemum leaves were observed, and the photosynthetic and physiological indices were measured. The results showed that the chloroplast and thyla-koid structures of chrysanthemum were damaged under high temperature stress. The chlorophyll contents and maximum fluorescence (Fm) were significantly reduced, while the OJIP curve changed with the fluorescence of K and J points increased. The net photosynthetic rate (Pn), transpiration rate (Tr) and stomatal conductance (gs) were significantly decreased, while the internal CO2 concentration (Ci) was significantly increased. The relative conductivity (REC), malondialdehyde (MDA), reactive oxygen species (ROS), osmotic adjustment substances content and antioxidant enzyme activity all increased significantly. Spraying exogenous MT onto leaves could maintain the integrity of chloroplast and thylakoid structure under high temperature in chrysanthemum and significantly decrease the increment in the K and J points of OJIP curve. Exogenous application of MT alleviated the inhibition of high temperature stress on photosynthesis and fluorescence of chrysanthemum, as indicated by significantly higher Fm, Pn, gs, Tr and photosynthetic pigment contents and lower Ci. Exogenous MT also significantly reduced the REC, MDA and ROS contents of chrysanthemum under high temperature stress, and enhanced the osmotic adjustment substances content and antioxidant enzyme activity in chrysanthemum leaves. It suggested that exogenous MT could protect the integrity of chloroplast structure of chrysanthemum leaves, enhance photosynthesis, inhibit the excessive production of ROS in the plants under high temperature stress, improve the activity of antioxidant enzyme system, reduce the level of membrane peroxidation and keep the integrity of lipid membrane, and thus improve the ability of chrysanthemum plants to resist high temperature stress.

[Associativity between differentiation potential and VEGF secretory capability of immortalized human mesenchymal stem cells].

OBJECTIVE: To investigate the multi-differentiation potential and VEGF secretory volume of monoclonal immortalized human mesenchymal stem cells (hMSC-TERT) and to determine the relationship between them. METHODS: Monoclonal hMSC-TERT were isolated using limiting dilution. The growth curves of them were detected by method of MTT. ELISA was used to detect the concentration of VEGF in the supernatant of those monoclonal hMSC-TERT. Their adipocytic, osteogenic, neuronal differentiation potential in vitro were determined by Oil Red O staining, Von Kossa staining and immunocytochemistry for Tubulin-ßIII antibody. Those Monoclonal hMSC-TERT were transplanted into the subcutaneously of severe combined immunodeficiency (SCID) mice. The grafts of those cells were removed and analyzed by immunohistochemistry for pathologic tissue markers to discover the multi-differentiation potential of those monoclonal hMSC-TERT in vivo. RESULTS: There was statistically significant difference between different monoclonal hMSC-TERT in mult differentiation potential and the decreased concentration of VEGF in the supernatant of those monoclonal hMSC-TERT from the 3(rd) day to the 5(th) day. The positive rates of CK in grafts formed by those monoclonal hMSC-TERT in SCID mice were direct correlation with the decreased concentration of VEGF in the supernatant of those cells. CONCLUSION: The secretory capability of VEGF of those monoclonal hMSC-TERT may direct correlation with the epithelial differentiation potential of those cells.

[Effect of monoclonal or different cell seeding densities on the differentiation potential of immortalized human mesenchymal stem cells in vitro and in vivo].

OBJECTIVE: To determine whether monoclonality or different cell seeding densities could influence the differentiation potential of immortalized human mesenchymal stem cells (hMSC-TERT) and to find an effective cultural method of hMSC-TERT in vitro. METHODS: From the parental hMSC-TERT cell line, we derived 30 monoclonal cell lines and two independent cell lines based on different plating densities during expansion in culture. Their adipocytic, osteogenic, neuronal differentiation potential in vitro and multidirectional differentiation potential in vivo were analyzed by immunohistochemistry for pathologic tissue markers. RESULTS: Monoclonal cell lines and the cell line derived at low seeding density had a lower differentiation potential in vitro than the cell line derived at higher cell seeding density. The differentiation potential of monoclonal hMSC-TERT cells were dissimilar. Some of monoclonal hMSC-TERT lines expressed epithelial differentiation potential in vivo while the parental hMSC-TERT cells line did not. CONCLUSION: Multiclonal hMSC-TERT cells cultured in high seeding density can keep the differentiation potential, cloning the hMSC-TERT cells before transplantation to find the special clones for special purpose of transplantation.