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Huang H.,Centers for Disease Control and Prevention | Zhu T.,Tianjin University of Science and Technology | Gao C.,Tianjin CanSino Biotechnology Inc. | Gao Z.,Centers for Disease Control and Prevention | And 9 more authors.
Epidemiology and Infection | Year: 2015

Active symptom surveillance was applied to three selected communities ( 160 147 persons) in Tianjin from 2010 to 2012. We examined 1089 individuals showing pertussis-like symptoms, of which 1022 nasopharyngeal specimens were tested for pertussis by polymerase chain reaction and 802 sera for anti-pertussis toxin antibodies. Of the total cases tested, 113 were confirmed, and their demographic, clinical, and vaccination-related data were collected. The annual incidence was 23·52 cases/100 000 persons among communities, which was 16·22 times that obtained via hospital reports for the same period (P < 0·001). The actual incidence in the 15-69 years age group was most significantly underestimated by hospitals, given that it was 43·08 times that of the reported hospital rate. Among the cases aged <15 years, 84·5% were individuals who had been fully vaccinated. The misdiagnosis rate was as high as 94·69%, and only 5·31% of the confirmed pertussis cases were properly diagnosed as pertussis at their first medical visit. Pertussis incidence in China has been severely underestimated and this was in part due to a high misdiagnosis rate. Adolescents and adults have become new high-risk populations. Future work should focus on reinforcing immunization programmes, especially among adolescents and adults. Copyright © Cambridge University Press 2014. Source

Zhu F.-C.,U.S. Center for Disease Control and Prevention | Hou L.-H.,Beijing Institute of Biotechnology | Li J.-X.,U.S. Center for Disease Control and Prevention | Wu S.-P.,Beijing Institute of Biotechnology | And 16 more authors.
The Lancet | Year: 2015

Background Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. Methods We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. Findings Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; p<0·0001) and day 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2], respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0-1202·5) in participants in the low-dose group and 765·0 cells (400·0-1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. Interpretation Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. Funding China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. © 2015 Elsevier Ltd. Source

Dai F.,Tianjin University of Science and Technology | Shi J.-M.,Tianjin CanSino Biotechnology Inc. | Zhu T.,Tianjin University of Science and Technology | Zhu T.,Tianjin CanSino Biotechnology Inc.
Chinese Journal of New Drugs | Year: 2016

Objective: To develop and optimize animal-component-free medium for culturing Clostridium tetani and explore a tetanus toxin purification process. Methods: Animal component materials in the culuture medium was replaced by soytone or yeast extract as nitrogen source. Cell density and the production of toxin meseaured in Lf·mL-1 were compared in a 2L fermenter. Toxin was recovered by centrifugation and TFF operation, and was purified by column chromatography. Yields of toxin at different elution conditions were compared. Results: Soytone as nitrogen source supported good growth of tetanus but toxin formation was low; yeast extract as nitrogen source supported less tetanus growth but had higher toxin yield. The maximum concentration of toxin in the fermenter was 52 Lf·mL-1. Purification of tetanus toxin by DEAE chromatography resulted in a toxin yield of 80% with higher purity. Conclusion: Animal-component-free medium produces a larger amount of toxin; DEAE can be adopted as a method for tetanus toxin purification. © 2016, Chinese Journal of New Drugs Co. Ltd. All right reserved. Source

Shen C.F.,National Research Council Canada | Jacob D.,National Research Council Canada | Zhu T.,Tianjin University of Science and Technology | Bernier A.,National Research Council Canada | And 6 more authors.
Vaccine | Year: 2016

Tuberculosis (TB) is the second leading cause of death by infectious disease worldwide. The only available TB vaccine is the Bacille Calmette–Guerin (BCG). However, parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. AdAg85A, an adenoviral vector expressing the mycobacterial protein Ag85A, is a new tuberculosis vaccine candidate, and has shown promising results in pre-clinical studies and phase I trial. This adenovirus vectored vaccine is produced using HEK 293 cell culture. Here we report on the optimization of cell culture conditions, scale-up of production and purification of the AdAg85A at different scales. Four commercial serum-free media were evaluated under various conditions for supporting the growth of HEK293 cell and production of AdAg85A. A culturing strategy was employed to take advantages of two culture media with respective strengths in supporting the cell growth and virus production, which enabled to maintain virus productivity at higher cell densities and resulted in more than two folds of increases in culture titer. The production of AdAg85A was successfully scaled up and validated at 60 L bioreactor under the optimal conditions. The AdAg85A generated from the 3 L and 60 L bioreactor runs was purified through several purification steps. More than 98% of total cellular proteins was removed, over 60% of viral particles was recovered after the purification process, and purity of AdAg85A was similar to that of the ATCC VR-1516 Ad5 standard. Vaccination of mice with the purified AdAg85A demonstrated a very good level of Ag85A-specific antibody responses. The optimized production and purification conditions were transferred to a GMP facility for manufacturing of AdAg85A for generation of clinical grade material to support clinical trials. © 2016 Source

Miao D.-Q.,Tianjin University of Science and Technology | Li J.-Q.,Tianjin CanSino Biotechnology Inc. | Yang M.-M.,Tianjin CanSino Biotechnology Inc. | Shao Z.-Q.,Tianjin CanSino Biotechnology Inc. | Zhu T.,Tianjin University of Science and Technology
Chinese Journal of New Drugs | Year: 2016

Objective: To evaluate the feasibility of the fusion protein (Hin47-HiD) as a new carrier protein for the preparation of the Haemophilus influenzae type b (Hib) conjugate vaccine. Methods: A DNA fragment coding for the Hin47-HiD fusion protein was constructed by overlap PCR and cloned into pET-9a vector for expression in the E.coli host cell BL21 (DE3). The fusion protein was purified by column chromatography and used for the preparation of the Hib polysaccharide conjugate vaccine. BALB/c mice were immunized with the Hib-Hin47-HiD conjugate, and antibody titers in mouse sera against the Hib polysaccharide as well as the carrier protein were analyzed using indirect ELISA. Results: The Haemophilus influenzae type b conjugate vaccine prepared using the fusion protein was highly immunogenic, producing high antibody levels in mouse sera against the Hib polysaccharide following two injections. In addition, the Hib-Hin47-HiD conjugate also generated good antibody responses against both Hin47 and HiD. Conclusion: The Hin47-HiD fusion protein can effectively improve the immunogenicity of the Hib polysaccharide, and may be used as an alternative carrier protein for the preparation of the conjugate vaccine. © 2016, Chinese Journal of New Drugs Co. Ltd. All right reserved. Source

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