A Phase I, Prospective, Randomized, Open-labeled Study to Evaluate the Safety, Tolerability, and Immunogenicity of Booster Dose with MVC-COV1901 or MVC-COV1901(Beta) SARS-CoV-2 Vaccine in Adults

BackgroundThe use of variant-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as a booster is being evaluated to overcome reduced neutralisation of variants induced by the original SARS-CoV-2 vaccine and waning protection over time. MethodsThis is a phase one, prospective, randomized, and open-labeled trial to study the safety and immunogenicity of a booster dose consisting of a subunit vaccine based on the stabilized prefusion SARS-CoV-2 spike protein, MVC-COV1901 or its Beta version, MVC-COV1901-Beta. One-hundred and seven participants aged [≥]18 and <55 years, who received two or three prior doses of MVC-COV1901 vaccines, were enrolled and were to receive a booster dose of either 15 mcg of MVC-COV1901, 15 mcg or 25 mcg of MVC-COV1901-Beta in 1:1:1 ratio. The primary endpoints were the incidences of adverse events and immunogenicity of the booster dose from Visit 2 (the day of the booster) to Visit 5 (four weeks after the booster). Cellular immunity was also investigated with memory B cell (MBC) and T cell assays. FindingsAdverse reactions after either MVC-COV1901 or MVC-COV1901-Beta booster doses after two or three doses of MVC-COV1901 were comparable and mostly mild and transient. At four weeks after the booster dose, participants with two prior doses of MVC-COV1901 exhibited numerically higher levels of neutralising antibodies against SARS-CoV-2 or Beta variant than participants with three prior doses of MVC-COV1901 regardless of the type of booster used. However, compared to 15 mcg of MVC-COV1901, 25 mcg of MVC-COV1901-Beta significantly improved neutralising antibody titre against Beta variant and BA.4/BA.5 Omicron variant pseudoviruses. The booster dose also significantly increased the proportion of spike-specific MBCs, including those of Beta and Omicron variants. InterpretationMVC-COV1901-Beta can be effectively used as a booster dose against SARS-CoV-2, including the circulating BA.4/BA.5 Omicron variant. FundingMedigen Vaccine Biologics Corporation

Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine

The widespread SARS-CoV-2 in humans results in the continuous emergence of new variants. Recently emerged Omicron variant with multiple spike mutations sharply increases the risk of breakthrough infection or reinfection, highlighting the urgent need for new vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x), which showed high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine comprised of STFK and STFK1628x elicited high titers of broad-spectrum antibodies to neutralize all 14 circulating SARS-CoV-2 variants, including Omicron; and fully protected vaccinees from intranasal SARS-CoV-2 challenges of either the ancestral strain or immune-evasive Beta variant. Strikingly, the vaccination of hamsters with the bivalent vaccine completely blocked the within-cage virus transmission to unvaccinated sentinels, for either the ancestral SARS-CoV-2 or Beta variant. Thus, our study provides new insights and antigen candidates for developing next-generation COVID-19 vaccines.

Expression and significance of HERG protein in Cajal interstitial cells of gallbladder tissue in patients with gallbladder stones / 中华肝胆外科杂志

Objective:To investigate the expression and significance of human ether-a-go-go related gene (HERG) protein in interstitial cells of Cajal (ICC) in patients with gallbladder stones.Methods:The gallbladder tissues of 60 patients with gallbladder diseases who underwent cholecystectomy from January 2018 to December 2020 in the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital were collected, including 36 males and 24 females, aged (46.0±14.0) years. They were divided into two groups according to whether there were gallstones: gallstone group and control group (patients with gallbladder polyps and gallbladder adenomyosis), with 30 cases in each group. Color ultrasound was used to detect and calculate the gallbladder contraction rate. The neck, body and bottom tissues of the gallbladder were excised and sectioned. The expression of HERG protein and CD117 ( marker of ICC) was detected by immunofluorescence staining, immunohistochemistry and Western blot.Results:The gallbladder contraction rate in the gallstone group was (65.8±4.1)%, lower than that in the control group (73.8±5.3)%, with a statistically significant difference ( t=4.14, P<0.001). Immunohistochemistry showed that HERG protein was mainly distributed in the mucosal layer of gallbladder tissue, which was pale brown. The relative expression of HERG protein at the bottom of gallbladder in the gallstone group was (0.293±0.102), lower than that in the control group (0.694±0.059), with a statistically significant difference ( t=3.38, P=0.027). Immunofluorescence staining showed that HERG protein was mainly distributed in ICC of gallbladder epithelium. HERG protein expression in ICC at the bottom of gallbladder in gallstone group was lower than that in control group, while HERG protein expression at the neck and body of gallbladder had no significant difference. Conclusion:There are ICC and HERG protein in gallbladder tissue of patients with gallstone. The decrease of gallbladder contraction rate may be related to the decrease of HERG protein expression in ICC in gallbladder bottom tissue.

Safety and Immunogenicity of SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901 in People Living with HIV

ObjectivesTo provide data on the immune response to COVID-19 vaccines in people living with HIV (PWH), MVC-COV1901, a recombinant protein vaccine containing S-2P protein adjuvanted with CpG 1018 and aluminium hydroxide, was assessed. MethodsA total of 57 PWH of [≥] 20 years of age who are on stable antiretroviral therapy and with CD4+ T cell [≥] 350 cells/mm3 and HIV viral load < 103 copies/ml were compared with 882 HIV-negative participants. Participants received 2 doses of MVC-COV1901 28 days apart. Safety and the immunogenicity were evaluated. ResultsNo vaccine-related serious adverse events (SAEs) were recorded. Seroconversion rates (SCRs) of 100% and 99.8% were achieved in people living with HIV (PWH) and comparators, respectively, 28 days after second dose. The geometric mean titers (GMTs) (95% confidence interval [CI]) against wild type SARS-CoV-2 virus were 136.62 IU/mL (WHO Standardized International Unit) (95% CI 114.3-163.3) and 440.41 IU/mL (95% CI 421.3-460.4), for PWH and control groups, respectively, after adjusting for sex, age, BMI category, and comorbidity, and the adjusted GMT ratio of comparator/PWH was 3.22 (95% CI 2.6-4.1). A higher CD4/CD8 ratio was associated with a higher GMT (R=0.27, p=0.039). ConclusionsMVC-COV1901 has shown robust safety but weaker immunogenicity responses in PWH. As a result, a third dose or booster doses of MVC-COV1901 may be appropriate for PWH.

Safety and Immunogenicity of CpG 1018 and Aluminium Hydroxide-Adjuvanted SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901: A Large-Scale Double-Blinded, Randomised, Placebo-Controlled Phase 2 Trial

BackgroundWe have assessed the safety and immunogenicity of the COVID-19 vaccine MVC-COV1901, a recombinant protein vaccine containing prefusion-stabilized spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide. MethodsThis is a phase 2, prospective, randomised, double-blind, placebo-controlled, and multi-centre study to evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 vaccine candidate MVC-COV1901. The study comprised 3,844 participants of [≥] 20 years who were generally healthy or with stable pre-existing medical conditions. The study participants were randomly assigned in a 6:1 ratio to receive either MVC-COV1901 containing 15 g of S-2P protein or placebo containing saline. Participants received two doses of MVC-COV1901 or placebo, administered 28 days apart via intramuscular injection. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from Day 1 (the day of first vaccination) to Day 57 (28 days after the second dose). Immunogenicity of MVC-COV1901 was assessed through geometric mean titres (GMT) and seroconversion rates (SCR) of neutralising antibody and antigen-specific immunoglobulin. This clinical trial is registered at ClinicalTrials.gov: NCT04695652. FindingsFrom the start of this phase 2 trial to the time of interim analysis, no vaccine-related Serious Adverse Events (SAEs) were recorded. The most common solicited adverse events across all study participants were pain at the injection site (64%), and malaise/fatigue (35%). Fever was rarely reported (<1%). For all participants in the MVC-COV1901 group, at 28 days after the second dose against wild type SARS-CoV-2 virus, the GMT was 662{middle dot}3 (408 IU/mL), the GMT ratio was 163{middle dot}2, and the seroconversion rate was 99{middle dot}8%. InterpretationMVC-COV1901 shows good safety profiles and promising immunogenicity responses. The current data supports MVC-COV1901 to enter phase 3 efficacy trials and could enable regulatory considerations for Emergency Use Authorisation (EUA). FundingMedigen Vaccine Biologics Corporation and Taiwan Centres for Disease Control.

Sequential transcatheter arterial chemoembolization and selective portal vein embolization before major hepatectomy for large hepatocellular carcinoma: a pilot study / 中华肝胆外科杂志

Objective:To preliminarily study the feasibility, safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with selective portal vein embolization (SPVE) before surgical resection in the treatment of large liver cancer.Methods:A retrospective study was conducted on the clinical data of 17 patients with large liver cancer treated with TACE combined with SPVE from January 2016 to December 2019 at the Department of Hepatobiliary Surgery, the Sixth Medical Center of PLA General Hospital. The study included 15 males and 2 females, aged (59.17±10.30) years. The levels of alanine aminotransferase, tumor changes and patient survival were analyzed before operation, after TACE, and after SPVE.Results:Among the 17 patients, the levels of alanine aminotransferase on the 1st and 3rd day after SPVE was significantly higher than those after TACE [191.4 (30.5-1966.4) IU/L vs 125.3 (35.7-846.2) IU/L on the first day, and 298.5 (24.6-1334.2) IU/L vs 208.6 (21.6-775.6) IU/L on the 3rd day], all P<0.05. One month after the two combined embolism, among the 6 patients with a tumor diameter of 5-10 cm, 2 patients (33.3%) had complete remission, 3 patients (50.0%) had partial remission, and 1 patients (16.6%) had stable disease. For the tumor’s longest diameter, among the 11 patients with tumors >10 cm, 1 patient had complete remission (9.1%), 4 patients had partial remission (36.4%), 5 patients had stable diseases (45.5%), and 1 patient had disease progression (9.1%). Eventually, 11 patients underwent surgical exploration. The median residual liver volume before treatment was 329.5 (284.9-365.7) ml, and after the combined procedure 415.6 (354.7-718.8) ml. The median hyperplasia ratio was 28.1% (14.1%-51.3%). Eight patients finally underwent surgical resection. There was no death in the perioperative periods. The median tumor-free survival time was 17 (7-42) months, and the median survival time was 27 (7-42) months. Conclusion:For patients with large liver cancer with insufficient remnant liver volume, preoperative TACE+ SPVE has certain value in controlling tumor progression, promoting remnant liver hyperplasia, increasing surgical resection rate and improving prognosis.

Clinical efficacy of end-inside anastomosis for keeping biliary mucosal integrity / 中华肝胆外科杂志

Objective To compare the effect of two procedures,named "mucosa to mucosal "and "end-inside" anastomosis for cholangiojejunostomy,and analyze its applicable scope.Methods A retrospective analysis was performed on the clinical data of 340 patients who underwent choledochojejunostomy from May 2012 to May 2017 in the Navy General Hospital.These patients were divided into two groups according to the procedure they received,including " mucosa to mucosal" anastomosis (n =249) and " end-inside"anastomosis (n =91).Two anastomotic methods of intraoperative state and postoperative complications were compared respectively under normal bile duct condition and cholangiectasis condition.Results When the common bile duct was not dilated,time spent for anastomoting in "end-inside" anastomosis was significantly shorten than that in "mucosa to mucosal" anastomosis (12.7 ± 1.2) min vs.(25.2 ± 5.8) min,and incidences of anastomotic leakage,bile duct infection,liver abscess,blie duct stricture postoperation (1.6％ vs.9.7％) in "end-inside" anastomosis were significantly lower than those in "mucosa to mucosal" anastomosis (P ＜ 0.05).Whether the common bile duct was dilated or not,the shrinking extents of stoma in " end-inside" anastomosis were lower than those in " mucosa to mucosal" anastomosis (1.4 ± 0.4) mm vs.(3.6 ± 1.2),(2.9 ± 0.6) mm vs.(4.2 ± 1.2) mm with statistical significances (P ＜ 0.05).There was no significant differences between two procedures when common bile duct was dilated.Conclusion Compared to the mucosa to mucosal anastomosis,the end-inside anastomosis had the advantage of easy operating and low postoperative complications when the bile duct was not dilated.

Analysis on the clinical therapeutic effects of arterial first approach pancreatoduodenectomy in the treatment of borderline resectable pancreatic adenocarcinoma / 中华外科杂志

Objective@#To compare the clinical therapeutic effects of arterial first approach pancreaticoduodenectomy(AFA-PD) with standard approach pancreaticoduodenectomy(SPD) in the treatment of borderline resectable pancreatic cancer (BRPC).@*Methods@#A retrospective analysis of the clinical data of 113 cases of pancreatic cancer patients from January 2014 to August 2015 at Department of Hepato-Biliary-Pancreatic Surgery, Changhai Hospital, the Second Military Medical University, including 43 cases in AFA-PD group and 70 cases in SPD group.Every patient had gone high-resolusion computed tomography before the surgery, when BRPC was definitely diagnosed by both experienced radiologist and pancreatic surgeon.There were 24 males and 19 females in the AFA-PD group, with average age of (61.6±10.2)years.And in the SPD group, there were 47 males and 23 females, with average age of (62.7±9.4)years.@*Results@#The operation time was (210.7±31.5)minutes in AFA-PD group, (187.9±27.4)minutes in SPD group, and peroperative bleeding volume was (1 007.1±566.3)ml in AFA-PD group, (700.0±390.0)ml in the other group.Those two indicators of AFA-PD group, compared with SPD group, were relatively higher, the difference was statistically significant(all P<0.01). And with regard to postoperative diarrhea(9.3% vs.5.7%), postoperative 1, 3 days of white blood cells(postoperative 1 day: (13.3±1.1)×109/L vs.(12.4±2.4)×109/L; postoperative 3 days: (12.7±1.6)×109/L vs.(11.7±2.5)×109/L), postoperative 1, 3, 5 days of peritoneal drainage fluid volume(postoperative 1 day: (184±42)ml vs.(156±54)ml; postoperative 3 days: (155±48)ml vs.(133±35)ml; postoperative 5 days: (66±20)ml vs.(47±31)ml), the differences between the two groups were statistically significant (all P<0.05). One patient in the SPD group was treated with unplanned secondary surgery for postoperative intraperitoneal hemorrhage, and the patient was cured and discharged.There was no death in the two groups within 30 days after surgical operation and no patient with positive gastric margin, duodenal margin, or anterior margin.The resection rate of superiormesenteric artery(SMA) margin R0 in AFA-PD group was higher than that in SPD group (P=0.019). The two groups were followed up for 14 to 30 months.As for AFA-PD group, the average survival time, progression free survival time and median survival time was respectively (20.4±1.2)months, (21.5±1.4)months and 20 months.There were 3 cases(7.0%) with local recurrence and 8 cases(18.6%) with liver metastasis or distant metastasis.In the SPD group, the average survival time, progression free survival time and median survival time was (17.1±1.1)months, (16.4±1.3)months and 16 months, respectively.There were 13 cases(18.6%) with local recurrence and 25 cases(35.7%) with liver metastasis or distant metastasis.As a result, the AFA-PD group had longer survival time(P=0.001)and progression free survival time(P=0.002). However, the lower local recurrence and distant metastasis rate in AFA-PD group did not reach statistical standard (P>0.05).@*Conclusion@#The arterial first approach pancreaticoduodenectomy is safe and effective in the treatment of borderline resectable pancreatic cancer, which can improve the resection rate of SMA margin R0, and prolong patient survival time.

Transgenic mice over-expressing GABA(B)R1a receptors acquire an atypical absence epilepsy-like phenotype.

In this study, we tested whether over-expressing the GABA(B) receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3-6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABA(B)R1a receptor subtype in the etiology of atypical absence epilepsy.