Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

Baseline HBsAg predicts response to pegylated interferon-α2b in HBeAg-positive chronic hepatitis B patients.

AIM: To evaluate the predictive effect of baseline hepatitis B surface antigen (HBsAg) on response to pegylated interferon (PEG-IFN)-α2b in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. METHODS: This retrospective analysis compared the treatment efficacy of PEG-IFN-α2b alone in 55 HBeAg-positive CHB patients with different baseline HBsAg levels. Serum HBV DNA load was measured at baseline, and at 12, 24 and 48 wk of therapy. Virological response was defined as HBV DNA < 1000 IU/mL. Serum HBsAg titers were quantitatively assayed at baseline, and at 12 and 24 wk. RESULTS: Eighteen patients had baseline HBsAg > 20 000 IU/mL, 26 patients had 1500-20000 IU/mL, and 11 patients had < 1500 IU/mL. Three (16.7%), 11 (42.3%) and seven (63.6%) patients in each group achieved a virological response at week 48, with a significant difference between groups with baseline HBsAg levels > 20000 or < 20000 IU/mL (P = 0.02). Thirteen patients had an HBsAg decline > 0.5 log10 and 30 patients < 0.5 log10 at week 12; and 6 (46.2%) and 10 (33.3%) in each group achieved virological response at week 48, with no significant difference between the two groups (P = 0.502). Eighteen patients had an HBsAg decline > 1.0 log10 and 30 patients < 1.0 log10 at week 24, and 8 (44.4%) and 11 (36.7%) achieved a virological response at week 48, with no significant difference between the two groups (P = 0.762). None of the 16 patients with HBsAg > 20000 IU/mL at week 24 achieved a virological response at week 48. CONCLUSION: Baseline HBsAg level in combination with HBV DNA may become an effective predictor for guiding optimal therapy with PEG-IFN-α2b against HBeAg-positive CHB.

Non-alcoholic fatty liver disease (NAFLD) fibrosis score predicts 6.6-year overall mortality of Chinese patients with NAFLD.

The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has emerged as a useful predictor of long-term outcome in NAFLD patients. We evaluated the predictive performance of the NFS for overall mortality in a Chinese population with NAFLD. All NAFLD patients diagnosed ultrasonographically at Xixi Hospital of Hangzhou between 1996 and 2011 were retrospectively recruited to the study. Outcome was determined by interview and causes of death were confirmed by medical records. The area under the receiver operating characteristic curve (AUCROC ) was used to determine the predictive accuracy of the NFS, BARD (body mass index, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, diabetes) score, FIB-4 index and the AST/platelet ratio index (APRI) for mortality. Data from a total of 180 eligible patients (median age 39 years; 96 men) were analysed, with 12 deaths over a median follow-up period of 6.6 years (range 0.5-14.8 years). Using Cox model analysis, the NFS as a continuous variable was identified as the only predictor for all-cause mortality (hazard ratio 2.743, 95% confidence interval (CI) 1.670-4.504). The NFS yielded the highest AUCROC of 0.828 (95% CI 0.728-0.928, P < 0.05), followed by the FIB-4 index, APRI and BARD score (AUCROC 0.806 (P < 0.05), 0.732 (P < 0.05) and 0.632, respectively). The data indicated that the NFS is a useful predictor of 6.6-year all-cause mortality for Chinese patients with NAFLD.

[The relationship between serum HBsAg levels and liver inflammation and fibrosis in patients with chronic hepatitis B].

OBJECTIVE: To investigate the relation of hepatitis B surface antigen (HBsAg) level with chronic hepatitis B (CHB) and liver inflammation and fibrosis. METHODS: A total of 301 patients who diagnosed CHB and underwent liver biopsy were enrolled into the study. Meantimes, the biochemical markers, ferritin (FERR), serum HBsAg and HBV DNA quantitation were detected. The relation between HBsAg level and liver pathology were determined by spearman rank correlation analysis. The receiver operating characteristic curve was used to evaluate the accuracy of HBsAg level for liver inflammation and fibrosis. RESULTS: The body mass index (BMI), age, gender, genotype and family history had no effective on liver inflammation and fibrosis (P < 0.05). With the progressing of inflammation and fibrosis, the serum AST and ALT raise obviously (chi2 = 71.193, 96.344, 47.847, 63.981; P = 0.000, 0.000, 0.000, 0.000). When fibrosis reached to S4, the level of HBV DNA decreased obviously (chi2 = 33. 322; P = 0.000). With the aggravation of inflammation and fibrosis, the serum HBsAg gradually descended (chi2 = 68.173,15.719; P = 0.000, 0.000). The areas under operating characteristics curves of HBsAg predicted < or = G3 and < or = S3 were 0.732 and 0.793, and the specificity were 0.778, 0.891, and sensitivity were 0.685, and 0.633, respectively. CONCLUSION: The level of HBsAg of Chinese CHB patients descended gradually with the aggravation of liver inflammation and fibrosis. The serum HBsAg had a higher specificity to predict < or = G3 and < or = S3 of CHB patients. But there had superiority of predicting fibrosis than inflammation.

[The studies on clinical value of AFP-L3 detected by microspincolum method for judgment of treatment response in patients with HCC undergoing TACE].

OBJECTIVE: To explore the clinical value of Lens culinaris agglutinin-reactive alpha-fetoprotein detected by microspincolum method for judgment of treatment response in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization. METHODS: Twenty eight patients with HCC undergoing TACE follow-up in hospital were recruited. AFP and AFP-L3 were measured in all the patients before and after TACE, and correlations were analyzed between AFP-L3% and response to treatment. RESULTS: Among the twenty eight patients with HCC undergoing TACE, 8 out 11 case in AFP-L3% descent group had well treatment response, 5 out 17 case in AFP-L3% elevated group had well treatment response(Chi2 = 4. 858, P < 0. 05). CONCLUSIONS: The detection of AFP-L3 by microspincolum method is useful to judgment of treatment response in patients with HCC undergoing TACE.

[Genotypes and evolution characteristics of three patients with poor response to initial treatment of Lamivudine and Adefovir dipivoxil for hepatitis].

OBJECTIVE: To understand the genotype characteristics and its evolution of patients with poor response to initial combined treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B. METHODS: We detected the HBV genotypes of three patients-S1, S2, S3, who with poor response to initial treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B over 12 months by the application of cloning and sequencing method at the time point of baseline,4 weeks after treatment, 12 weeks, 24 weeks, 48 weeks, 60 weeks. 25 clones were randomly selected to identify and sequence at each time point. RESULTS: The total number of clones from 3 patients with poor response to initial combined treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B at each time point was 398. About patient S1 at baseline, genotype C accounting for 8.3%, genotype B, for 91.7%, so genotype B was in dominant (22/24). But genotype C has gradually developed to 100% after treatment for 60 weeks. About patient S2 and S3, genotype B was the only type at baseline. However type B has gradually "drift" to type C during treatment. When treatment for 60 weeks, type C has taken the absolute advantage 75% for S2, and 100% for S3. CONCLUSIONS: The cloning and sequencing can represent the overall genotype level better. HBV genotype has performed the evolution trend that genotype has drifted from B to C during long-term drug pressure, which is the main reason for poor response to initial combined treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B.

[Three-year efficacy and side effect of adefovir dipivoxil for the treatment of the old patients with chronic hepatitis B virus infection].

OBJECTIVE: To investigate 3-year antiviral efficacy and side effect of adefovir dipivoxil (ADV) on the old patients with hepatitis B chronic infection. METHODS: 31 HBeAg-negative chronic hepatitis B virus infected old patients (include 8 patients with chronic hepatitis B and 23 patients with liver cirrhosis) with serum HBV DNA levels > 1000 copies/ml, and ALT > 2 times the upper limit of normal, without company with other liver diseases, cancer, renal dysfunction, and autoimmune disease. All the patients were treated with ADV orally (10 mg once daily) for 36 months. HBV DNA and biochemical and blood routine indexes were checked after treated. RESULT: Serum total bilirubin, direct bilirubin, alamine aminotransferase, aspartate aminotransferase and load of HBV DNA decrease significantly after therapy (P < 0. 001). Other biochemical indexs and blood routine are no significant changes (P > 0.05). CONCLUSION: The way to treat with ADV is safe and effective for old patients with chronic hepatitis B virus infection.