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Xu D.-Z.,Capital Medical University | Wang X.-Y.,Fudan University | Shen X.-L.,National Vaccine and Serum Institute | Gong G.-Z.,Central South University | And 25 more authors.
Journal of Hepatology | Year: 2013

Background & Aims Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. Methods Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24 weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. Results In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p >0.05). Conclusions Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation. © 2013 European Association for the Study of the Liver.


PubMed | Centers for Disease Control and Prevention, Wenzhou University, First Municipal Hospital of Hangzhou, Hangzhou Sixth Peoples Hospital and Zhejiang University
Type: Journal Article | Journal: PloS one | Year: 2015

Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs.


Xu F.,Centers for Disease Control and Prevention | Yao P.-P.,Centers for Disease Control and Prevention | Xia Y.,Centers for Disease Control and Prevention | Qian L.,Centers for Disease Control and Prevention | And 20 more authors.
PLoS ONE | Year: 2015

Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs. © 2015 Xu et al.


Yao P.-P.,Centers for Disease Control and Prevention | Qian L.,Centers for Disease Control and Prevention | Xia Y.,Centers for Disease Control and Prevention | Xu F.,Centers for Disease Control and Prevention | And 7 more authors.
PLoS ONE | Year: 2012

A reliable disease model mimicking Enterovirus 71 (EV71) infection in humans is essential for understanding pathogenesis and for developing a safe and effective vaccine. Commonly used rodent models including mouse or rat models are not suitable for vaccine evaluation because the rodents are resistant to EV71 infection after they reach the age of 6 days. In this study, 21-day-old gerbils inoculated intraperitoneally (IP) with a non mouse-adapted EV71 strain developed neurological lesion-related signs including hind limb paralysis, slowness, ataxia and lethargy similar to those of central nervous system (CNS) infection of EV71 in humans. The infected gerbils eventually died of the neurological lesions and EV71 could be isolated from lung, liver, spleen, kidney, heart, spinal cord, brain cortex, brainstem and skeletal muscle. Significantly high virus replication was detected in spinal cord, brainstem and skeletal muscle by cellular analysis, real-time quantitative PCR (RT-PCR) and immunohistochemical staining. Histopathologic changes such as neuronal degeneration, neuronal loss and neuronophagia were observed in spinal cord, brain cortex, brainstem, and skeletal muscle along with necrotizing myositis and splenic atrophy. Gerbils that received two doses of inactive whole-virus vaccine showed no EV71-specific symptoms after challenged with EV71. In contrast, gerbils that received mock vaccination died of EV71-induced neuropathology after challenged with EV71. The result indicates that gerbils can serve as a reliable disease model for evaluating safety and efficacy of EV71 vaccine. © 2012 Yao et al.


Huang W.,Hangzhou First Peoples Hospital | Zhu G.,Hangzhou Sixth Peoples Hospital | Huang M.,Hangzhou First Peoples Hospital | Lou G.,Hangzhou Sixth Peoples Hospital | And 2 more authors.
Clinica Chimica Acta | Year: 2010

Background: The association between OPN level and the histological severity of hepatic fibrosis and inflammation in hepatitis C virus (HCV) induced liver fibrosis remains unknown. Methods: 120 chronic HCV-infected subjects and 75 controls were enrolled in this study. Assessment of liver histology was performed based on liver biopsy. Plasma OPN levels were determined. Results: Significant differences were noted in the mean plasma OPN levels between subjects with extensive fibrosis and those with mild fibrosis (4.29 ± 1.01. ng/ml vs. 2.15 ± 0.63. ng/ml, respectively; p<0.001). Similarly, the subjects with higher histological activity index (HAI) score had elevated OPN levels than those with mild HAI score (4.41 ± 1.11. ng/ml vs. 2.25 ± 0.94. ng/ml, respectively; p<0.001). The correlation between the plasma OPN levels and the severity of liver fibrosis degree and HAI score were noted (r=0.945, and r=0.788, respectively both p<0.001). Logistic regression analysis showed that serum OPN was an independent risk factor contributing to extensive liver fibrosis and inflammation (p=0.0018 and p<0.001, respectively) in patients with HCV subjects. Conclusion: The plasma OPN level is correlated with the severity of liver fibrosis and inflammation, suggesting OPN could be used as a biomarker to evaluate the severity of liver damages in HCV subjects. © 2010 Elsevier B.V.


Zhuang R.X.,Hangzhou Sixth Peoples Hospital
Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology | Year: 2012

To study the effects of acetylcysteine magnesium on the vasoactive substances and hepatic fibrosis indexes in liver cirrhosis and portal hypertension of rats. The rat liver cirrhosis model was made with 12 microg/kg dimethylnitrosamines. Then acetylcysteine magnesium was injected respectively with 25, 50, and 100 mg x kg(-1) dose daily into abdominal cavity. After 8 weeks treatment, pathological section, TGF-beta1, NO, TNOS and iNOS of hepatic tissue were detected to assess the effect of acetylcysteine magnesium against cirrhosis portal hypertension. After the DMNA modeling was completed, the HE and Sweet reticulocyte staining of liver pathological section showed that cirrhosis of the liver was in the III-IV phase, the infiltration of lymphocytes and formation of pseudolobuli in liver were alleviated in three acetylcysteine magnesium treatment groups (low, medium, and high dose), and the degree of liver fiber sclerosis in three groups was significantly lower than control group. Compared with control group, TGF-beta1, NO, TNOS and iNOS were significantly reduced in all treatment groups (P < 0.05). Acetylcysteine magnesium is probably a distinctive antioxidant which can remove various free radical in body and modulate ligand-dependent signal transduction and the growth of cell. It also have protection in the liver cirrhosis and portal hypertension of rats induced by dimethylnitrosamine.


Liu S.R.,Hangzhou Sixth Peoples Hospital
Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology | Year: 2011

To investigate the influence of the individual genotype differences of DC-SIGN and DC-SIGNR on the mother-to-neonate intrauterine infection of HBV. The genotypes of the gene DC-SIGN and DC-SIGNR in the pregnant women with HBV positive were detected by PCR and agarose gel electrophoresis. The significant difference of gene diversity of DC-SIGN and DC-SIGNR was analyzed by chi-square test. (1) All of 29 cases in intrauterine infection group were 7/7 DC-SIGN genotype. In the non-intrauterine infection group, 7/5 genotype were observed in 2 of 54 cases, and the other 52 cases were 7/7 genotype. The two groups was no significant difference (P = 0.54). (2) 29 cases of intrauterine infection group was observed 4 genotypes of DC-SIGNR such as 7/7, 7/5, 9/7 and 6/5, the genotype frequencies were 0.3793, 0.3448, 0.2414 and 0.0345 respectively. 54 cases of non-intrauterine infection group was found 6 genotypes such as 7/7, 7/5, 9/5, 9/7, 7/6 and 6/5, genotype frequencies were 0.5186, 0.1481, 0.0926, 0.1852, 0.0370 and 0.0185 respectively. The distribution of 7/5 genotype in the intrauterine infection group (29 cases) and the non-intrauterine infection group (54 cases) was statistically significant (P = 0.038) , and no significant difference was found in other genotypes between the two groups (P > 0.05). The gene DC-SIGN showed relatively little variation in the pregnant women infected with HBV. On the countrary, there were multiple genotypes of the gene DC-SIGNR in these women, and the genotype "7/5" of DC-SIGNR might be one of the susceptibility genes associated with intrauterine infection.

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