Publications by authors named "Zheng-Lun Liang"

43 Publications

A cross-sectional seroepidemiology study of seven major enteroviruses causing HFMD in Guangdong, China.

J Infect 2021 Apr 16. Epub 2021 Apr 16.

National Institutes for Food and Drug Control, No.31, Huatuo Street, Beijing, P.R. China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2021.04.011DOI Listing
April 2021

Seroepidemiology of Coxsackievirus A10 infection in infants and children: A prospective cohort study in Jiangsu, China.

J Infect 2018 08 7;77(2):158-164. Epub 2018 May 7.

National Institutes for Food and Drug Control, Beijing 102629, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2018.04.005DOI Listing
August 2018

Seroepidemiology of enterovirus D68 infection in infants and children in Jiangsu, China.

J Infect 2018 06 8;76(6):563-569. Epub 2018 Feb 8.

National Institutes for Food and Drug Control, Beijing, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2018.02.003DOI Listing
June 2018

A phase 1 randomized open-label clinical study to evaluate the safety and tolerability of a novel recombinant hepatitis E vaccine.

Vaccine 2017 09 10;35(37):5073-5080. Epub 2017 Aug 10.

College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun 130062, Jilin, China; Key Laboratory for Zoonosis, Ministry of Education, and Institute for Zoonosis of Jilin University, Changchun 130062, Jilin, China. Electronic address:

Background: This study aimed to evaluate the safety and tolerability for variable dosages of a novel hepatitis E vaccine p179.

Methods: The randomized open-label parallel control phase 1 clinical trial enrolled 120 eligible participants aged 16-65years in Jiangsu Province, China. The experimental groups were randomized to receive different dosages of 20μg, 30μg, and 40μg Hepatitis E Virus (HEV) p179 vaccines, with the 30μgHEV vaccine p239 Hecolin as control, and vaccinated at 0, 1 and 6month intervals. Participants were observed for solicited local and systemic adverse reactions (ARs) occurring within 7days after each vaccination, and any serious adverse events (SAEs) occurring within 6months post-vaccination. Blood samples were collected from participants 3days before and after each injection, to determine the blood routine and serum biochemical indexes.

Results: The solicited local ARs incidence in experimental groups were significantly lower than that of the control group (P=0.027). The difference between solicited total and systemic ARs incidence of experimental groups and the control group were not significant (P>0.05). Similar patterns were observed when the analyses were performed on the group having ARs of varying grades and symptoms. All changes in blood biochemical indexes and routine blood tests before and after different vaccinations were mild (grade 1) or moderate (grade 2), and the difference in experimental groups and the control group were not statistically significant. No vaccine related SAEs occurred in any of the subjects during the study.

Conclusion: Three different dosages of HEV p179 vaccine were deemed safe and well tolerated. No vaccine-associated SAEs were identified, and the 30μg dosage formulation was selected for further investigation for efficacy. Clinical trials registration number: 2012L01657.
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http://dx.doi.org/10.1016/j.vaccine.2017.05.072DOI Listing
September 2017

The immunogenicity in healthy infants and efficiency to prevent mother to child transmission of Hepatitis B virus of a 10μg recombinant yeast-derived Hepatitis B vaccine (Hep-KSC).

Vaccine 2016 05 23;34(24):2656-62. Epub 2016 Apr 23.

Department of Microbiology and Infectious Diseases Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address:

Background And Aims: To evaluate immunogenicity and efficacy of a 10μg recombinant Saccharomyces cerevisiae-derived hepatitis B vaccine (Kangtai Biological Products Co. Ltd, Shenzhen, China) (Hep-KSC) in newborns.

Methods: Overall 1197 infants born to mothers negative for HBV markers (NM group) and 534 born to HBsAg-positive mothers (PM Group) were enrolled. Infants in NM group were given 10μg Hep-KSC, 10μg Engerix-B or 5μg Hep-KSC and those in PM group received 10μg Hep-KSC or 10μg Engerix-B at 0, 1 and 6 months, with an additional 200IU HBIG at birth for the latter.

Results: For NM Group, 10μg Hep-KSC paralleled 10μg Engerix-B but outperformed 5μg Hep-KSC regarding seroprotective rate (95.06% vs 94.83% vs 89.67%, p=0.0077) and anti-HBs geometric mean concentration (GMC) (798.87mIU/ml vs 790.16mIU/ml vs 242.04mIU/ml, p<0.0001) at 7 months. The proportion of infants with anti-HBs greater than 1000mIU/ml was higher in 10μg Hep-KSC than 5μg Hep-KSC group (45.77% vs 11.93%, p<0.0001) at 7 and 12 months. For PM Group, the HBsAg positivity rate in 10μg Hep-KSC and 10μg Engerix-B group was 1.60% and 4.27% at 7 months, respectively. In 10μg Hep-KSC group, 93.61% and 91.29% achieved seroprotection at 7 and 12 months, respectively, and correspondingly 90.24% and 86.96% in 10μg Engerix-B group. The anti-HBs GMC was comparable between 10μg Hep-KSC and 10μg Engerix-B group at 7 and 12 months (575.31mIU/ml vs 559.64mIU/ml; 265.79mIU/ml vs 264.48mIU/ml).

Conclusions: 10μg Hep-KSC might be appropriate for neonatal immunization with good immunogenicity and efficacy, especially for infants born to HBsAg-positive mothers.
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http://dx.doi.org/10.1016/j.vaccine.2016.04.042DOI Listing
May 2016

Short-Fragment DNA Residue from Vaccine Purification Processes Promotes Immune Response to the New Inactivated EV71 Vaccine by Upregulating TLR9 mRNA.

PLoS One 2016 15;11(4):e0153867. Epub 2016 Apr 15.

National Institutes for Food and Drug Control, Beijing, P.R. China.

To reduce potential oncogenic long genomic DNA in vaccines, nuclease treatment has been applied in the purification processes. However, this action increased the residue of short-fragment DNA and its effect on vaccine potency was still elusive. In this study, we found residual sf-DNA in an inactivated EV71 vaccine could enhance humoral immune response in mice. Ag stimulation in vitro and vaccine injection in vivo revealed that TLR9 transcription level was elevated, indicating that sf-DNA could activate TLR9. These new findings will help us to understand the molecular mechanism induced by vero-cell culture-derived vaccines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153867PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833324PMC
September 2016

Establishing the 1st Chinese National Standard for inactivated hepatitis A vaccine.

Biologicals 2016 Jul 8;44(4):198-205. Epub 2016 Apr 8.

National Institutes for Food and Drug Control, Beijing, PR China. Electronic address:

A reference standard calibrated in the International Units is needed for the quality control of hepatitis A vaccine. Thus, National Institutes for Food and Drug Control launched a project to establish a non-adsorbed inactivated hepatitis A vaccine reference as the working standard calibrated against the 1st International Standard (IS). Two national standard candidates (NSCs) were obtained from two manufacturers, and designated as NSC A (lyophilized form) and NSC B (liquid form). Six laboratories participated in the collaborative study and were asked to use their in-house validated enzyme-linked immunosorbent assay methods to detect hepatitis A vaccine antigen content. Although both exhibited good parallelism and linear relationship with IS, NSC B showed a better agreement among laboratories than NSC A. And based on suitability of the candidates, NSC B was selected. The accelerated degradation study showed that NSC B was stable at the storage temperature (≤-70 °C). Therefore NSC B was approved as the first Chinese national antigen standard for inactivated hepatitis A vaccine, with an assigned antigen content of 70 IU/ml.
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http://dx.doi.org/10.1016/j.biologicals.2016.02.002DOI Listing
July 2016

An epidemic of coxsackievirus B3 infection in infants and children in Jiangsu Province, China: a prospective cohort study.

Arch Virol 2016 Jul 28;161(7):1945-7. Epub 2016 Mar 28.

National Institutes for Food and Drug Control, No. 2, Tiantan Xili, Beijing, 100050, People's Republic of China.

To investigate the epidemiological data on coxsackievirus B3 (CVB3) infection and its incidence in infants and children, a prospective cohort study was carried out from 2012 to 2014 in Jiangsu Province, China. According to the results of seropositive rates and NTAb titers of CVB3, an epidemic of CVB3 infection was found, and a dynamic change in CVB3 neutralizing antibody was also observed. One case was recorded with CVB3-associated hand, foot and mouth disease (HFMD), and the isolates belonged to the CVB3 D2 subtype. Our data help us to better understand the epidemic characteristics of CVB3 infection in infants and children.
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http://dx.doi.org/10.1007/s00705-016-2842-7DOI Listing
July 2016

Enterovirus spectrum from the active surveillance of hand foot and mouth disease patients under the clinical trial of inactivated Enterovirus A71 vaccine in Jiangsu, China, 2012-2013.

J Med Virol 2015 Dec 9;87(12):2009-17. Epub 2015 Jun 9.

National Institute for Food and Drug Control, Beijing, China.

Epidemiological data from active surveillance on human enterovirus, which could cause hand, foot, and mouth disease, were limited. An active surveillance system was used to investigate the enterovirus spectrum and the incidence of different enteroviruses in infants aged 6-35 months in Jiangsu Province from 2012 to 2013. Fifty-nine infants were randomly selected from 522 non-EV-A71/CV-A16 HFMD patients. We collected 173 throat swabs and 174 rectal swabs from these infants. RT-PCR was used to amplify 5'-UTR and VP1 regions of enteroviruses and the serotypes were determined by the sequence comparison using BLAST. Twenty-one non-EV-A71/CA16 enterovirus serotypes were detected in those infants. E16, E18 were firstly reported in HFMD patients. The four top common non-EV-A71/CV-A enteroviruses among infants were CV-B3, CV-A10, CV-A6, and E9 with the HFMD incidence rates at 1.4%, 0.84%, 0.56%, and 0.47%, respectively. Over 20.8% patients were co-infected with multiple enteroviruses. Neither the course of sickness nor clinical symptoms of the co-infected patients was more severe than those infected with single enterovirus. Two patients were infected different enterovirus successively within 2 months. Several new enterovirus serotypes and multiple models of infection associated with HFMD were discovered through the active surveillance system. These data provide a better understanding of the viral etiology of HFMD.
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http://dx.doi.org/10.1002/jmv.24275DOI Listing
December 2015

Echovirus 7 associated with hand, foot, and mouth disease in mainland China has undergone a recombination event.

Arch Virol 2015 May 15;160(5):1291-5. Epub 2015 Feb 15.

National Institute for Food and Drug Control, No. 2 Tiantanxili, Beijing, 100050, China,

To investigate the evolution of echovirus 7 (Echo7) strains and the relationship between Echo7 strains and the prototype strain Wallace, phylogenetic analysis of Echo7 strains prevailing in mainland China was performed. The Echo7 strain, DH22G/JS/2012 was isolated from a 32-month-old boy who was clinically diagnosed with HFMD. The complete genome sequence of this isolate was determined after the virus was propagated in cell culture. Phylogenetic analysis showed that the subgroups B1 and C1 prevailed in mainland China from 1998 to 2012 and that the subgroup B2 began to circulate in mainland China in 2009. The result of Simplot analysis showed that the Echo7 strain DH22G/JS/2012 is a recombinant coxsackievirus B4 (CVB4) that circulated in mainland China in 2010.
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http://dx.doi.org/10.1007/s00705-015-2350-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412592PMC
May 2015

Complete Genome Sequence Analysis of Echovirus 24 Associated with Hand-Foot-and-Mouth Disease in China in 2012.

Genome Announc 2015 Feb 5;3(1). Epub 2015 Feb 5.

National Institutes for Food and Drug Control, Beijing, China

Echovirus 24 belongs to human enterovirus B species in the family Picornaviridae. Here, we report the whole-genome sequences of a novel complete genome sequence of a recombinant (echovirus 24) Echo 24 strain, PZ18/JS/2012, which was isolated from a patient with hand-foot-and-mouth disease in China.
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http://dx.doi.org/10.1128/genomeA.01456-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319619PMC
February 2015

Immune response to hepatitis B vaccine with high antigen content in non-responders after standard primary vaccination in Chinese adults.

Vaccine 2014 Jun 27;32(29):3706-12. Epub 2014 Mar 27.

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, Jiangsu, PR China. Electronic address:

Context: Alternative schedules are needed to provide greater immunogenicity in adults who fail to respond to the standard hepatitis B (HB) vaccine regimen.

Objective: To evaluate the immunogenicity and safety of high antigen content HB vaccine formulations administered to non-responders after routine primary vaccination.

Design Setting, And Participants: This was a phase III, double-blind, controlled clinical trial in China. We enrolled healthy participants (16-60 years old) seronegative for HB surface (HBs) antigen after primary vaccination, who had HBs antibody (anti-HBs) titres <10 mIU/ml at 28 days following routine vaccination with licensed HB vaccine containing 10 μg of antigen. Participants were randomised (2:2:1) to receive three booster doses of HB vaccine formulations containing 60 μg, 30 μg or 10 μg of antigen per dose 28 days apart. Blood samples were obtained pre-vaccination and 28 days after each dose to assess immunogenicity. Reactogenicity and safety were evaluated up to 28 days after each vaccine dose.

Results: Seroconversion rates were ≥ 92.1% and ≥ 87.1% as from the second dose of the 60 μg and 30 μg HB vaccine formulations, respectively, with geometric mean concentrations (GMCs) of ≥ 286.0 mIU/ml and ≥ 164.0 mIU/ml. In the 10 μg HB vaccine group the seroconversion rates were ≥ 83.0% and the GMCs ≥ 110.1 mIU/ml as from the second vaccine dose. All HB vaccine formulations were well tolerated: 352/1091 (32.3%) participants reported at least one injection-site or systemic adverse reaction (145/434 [33.4%] from the 60μg group; 138/435 [31.7%] from the 30 μg group and 69/222 [31.1%] from the 10 μg group). Most reactions were mild or moderate and resolved within 24h. No serious adverse events were reported.

Conclusion: Booster vaccination with a three-dose schedule of a high antigen content HB vaccine formulation was immunogenic and well tolerated in healthy adults. Clinicaltrialsgov Identifier: NCT01203319.
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http://dx.doi.org/10.1016/j.vaccine.2014.02.094DOI Listing
June 2014

Clinical evaluation for batch consistency of an inactivated enterovirus 71 vaccine in a large-scale phase 3 clinical trial.

Hum Vaccin Immunother 2014 14;10(5):1366-72. Epub 2014 Mar 14.

Beijing Vigoo Biological Co., Ltd; Beijing, PR China.

The demonstration of batch-to-batch consistency to confirm the reliability of the manufacturing process has become a mandatory step in vaccine development. This is a post-hoc analysis aimed to provide more solid evidence on the immunogenicity and consistency of 3 consecutive batches of a novel inactivated enterovirus 71 (EV71) vaccine. In total 10 245 healthy Chinese children aged 6-35 months had been recruited and randomized to receive one of 3 batches of EV71 vaccine or placebo according to a two-dose immunization schedule in a phase 3 clinical trial. Blood samples were taken just before and 28 days after vaccinations for serological tests of EV71 neutralizing antibody (NTAb) titer from the subjects. Among them, 7263 (70.9%) subjects with seronegative EV71 NTAb at baseline and the data of serological tests post-vaccination available were included for the analysis. The results showed that EV71 vaccine elicited high geometric mean titers (GMTs) of 407.0 U/mL (95% CI, 373.5-443.6) for batch 1, 468.1 U/mL (95% CI, 432.2-507.0) for batch 2, and 520.6 U/mL (95% CI, 481.2-563.3) for batch 3. The two-sided 95% confidence intervals (CIs) for the GMT ratios between each pair of vaccine batches were all within an interval of [0.67, 1.5]. Subjects who received EV71 vaccines demonstrated significant higher GMTs than those received placebos did (P<0.001). In terms of incidence of both local and general adverse reactions, no differences were found among 3 vaccine batches and placebos. EV71 vaccine was highly immunogenic in children, and the 3 consecutive batches were well consistent.
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http://dx.doi.org/10.4161/hv.28397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896521PMC
June 2015

Development of enterovirus 71 vaccines: from the lab bench to Phase III clinical trials.

Expert Rev Vaccines 2014 May 13;13(5):609-18. Epub 2014 Mar 13.

College of Pharmacy, Third Military Medical University and National Engineering Research Center for Immunological Products, Chongqing, PR China.

The widespread epidemics of enterovirus 71 (EV71) seriously affected the Western Pacific Region. Young children, especially those younger than 3 years are the most susceptible population to the EV71-associated diseases. Several Asian countries have begun to focus on the research and development of EV71 vaccines. Five inactivated whole-virus EV71 candidate vaccines (three were manufactured in mainland China based on a C4 genotype strain, one in Taiwan based on a B4 genotype strain and one in Singapore based on a B2 genotype strain) have been assessed in clinical trials. Three candidate vaccines developed in mainland China have already completed Phase III clinical trials recently. The tested EV71 vaccine could provide good efficacy, satisfactory safety, and high immunogenicity. Thus, inactivated EV71 vaccines are expected to become the first available vaccines against EV71 in the near future.
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http://dx.doi.org/10.1586/14760584.2014.897617DOI Listing
May 2014

How to understand the efficacy measurements for enterovirus type 71 vaccine?

Hum Vaccin Immunother 2014 26;10(3):623-7. Epub 2013 Nov 26.

Jiangsu Provincial Center for Disease Control and Prevention; Nanjing, PR China.

The choice of endpoint was most important for an efficacy vaccine trial. The objective of this paper is to gear toward answering questions about the rationality and scientificity of the primary endpoints choosing, case capturing and diagnosis strategy in our recently reported EV71 vaccine efficacy phase 3 trial. In order to obtain both high sensitivity and specificity in the case detecting, EV71-associated disease had been chosen as primary endpoint, a broad spectrum of clinical symptoms was surveyed, both the real-time RT-PCR and virus isolation were combined for the laboratory diagnosis, and serial specimens since disease onset were collected for assays. Though, the EV71 vaccine efficacy was well measured in the phase 3 trial, several potential factors could also have influences on the cases confirming. More evidence of EV71 vaccine efficacy will be demanded in post-marketing studies in the future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130280PMC
http://dx.doi.org/10.4161/hv.27253DOI Listing
March 2015

Immunogenicity, safety, and lot consistency of a novel inactivated enterovirus 71 vaccine in Chinese children aged 6 to 59 months.

Clin Vaccine Immunol 2013 Dec 9;20(12):1805-11. Epub 2013 Oct 9.

Jiang-Su Provincial Center for Disease Control and Prevention, Nanjing, China.

The determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children (n = 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between -0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered at ClinicalTrials.gov under registration no. NCT01636245.).
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http://dx.doi.org/10.1128/CVI.00491-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889509PMC
December 2013

Immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase II, Randomized, double-blind, placebo-controlled Trial.

J Infect Dis 2014 Jan 6;209(1):46-55. Epub 2013 Aug 6.

Center for Disease Control and Prevention of the Guangxi Zhuang Autonomous Region, Nanning.

Background: Vaccination is considered a top priority for the control of human enterovirus 71 (EV71) infection outbreaks.

Methods: On the basis of phase I trial results, we conducted a double-blind, randomized, controlled trial to evaluate the optimal dose, immunogenicity, safety and immune persistence of the vaccine. A total of 480 healthy infants were randomly assigned to receive 2 injections of 100 U of vaccine, 200 U of vaccine, 400 U of vaccine, or placebo. Solicited adverse events (AEs) within 7 days and unsolicited AEs within 28 days after each vaccination were collected for safety evaluation. Blood samples were collected for neutralizing antibody assay.

Results: EV71 vaccine was well tolerated, and no dose-related safety concerns were observed. Two doses of the vaccine yielded seropositivity frequencies of 92.3%, 95.9%, and 99.0% (with titers ≥1:8) in the 100 U, 200 U, and 400 U groups, respectively. Geometric mean titers measured by neutralizing antibody assay increased to 60.2 (95% confidence interval [CI], 41.9-86.4), 72.8 (95% CI, 50.8-104.3), and 252.1 (95% CI, 180.8-351.6) for the 100 U, 200 U, and 400 U groups, respectively. The dose-response relationship, with the 400 U dose showing higher immunogenicity than the 100 U and 200 U doses, remained until 13 months after the second vaccination, despite waning antibody levels.

Conclusions: The 400 U dose was recommended as the optimal dose for the phase III trial because of its good safety profile and higher immunogenicity.
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http://dx.doi.org/10.1093/infdis/jit429DOI Listing
January 2014

Progress on the research and development of inactivated EV71 whole-virus vaccines.

Hum Vaccin Immunother 2013 Aug 6;9(8):1701-5. Epub 2013 Jun 6.

National Institutes for Food and Drug Control; Beijing, P.R. China.

The prevalence of diseases caused by EV71 infection has become a serious public health problem in the Western Pacific region. Due to a lack of effective treatment options, controlling EV71 epidemics has mainly focused on the research and development (R&D) of EV71 vaccines. Thus far, five organizations have completed pre-clinical studies focused on the development of inactivated EV71 whole-virus vaccines, including vaccine strain screening, process optimization, safety and immunogenicity evaluation, and are in different stages of clinical trials. Among these organizations, three companies in Mainland China [Beijing Vigoo Biological Co., Ltd. (Vigoo), Sinovac Biotech Ltd. (Sinovac) and Institute of Medical Biology, Chinese Academy of Medical Science (CAMS)] have recently completed Phase III trials for the vaccines they developed. In addition, the other two vaccines, developed by National Health Research Institutes (NHRI) of Taiwan and Inviragen Pte., Ltd (Inviragen), of Singapore, have also completed Phase I clinical trials. Published clinical trial results indicate that the inactivated EV71 vaccines have good safety and immunogenicity in the target population (infants) and confer a relatively high rate of protection against EV71 infection-related diseases. The results of clinical trials suggest a promising future for the clinical use of EV71 vaccines. Here, we review and highlight the recent progress on the R&D of inactivated EV71 whole-virus vaccines.
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http://dx.doi.org/10.4161/hv.24949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906269PMC
August 2013

Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet 2013 Jun 29;381(9882):2024-32. Epub 2013 May 29.

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China.

Background: A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with infection. We assessed the efficacy, safety, immunogenicity, antibody persistence, and immunological correlates of an inactivated alum-adjuvant EV71 vaccine.

Methods: We did a randomised, double-blind, placebo-controlled, phase 3 trial. Healthy children aged 6-35 months from four centres in China were randomly assigned (1:1) to receive vaccine or alum-adjuvant placebo at day 0 and 28, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and participants and their guardians were masked to the assignment. Primary endpoints were EV71-associated hand, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01508247.

Findings: 10,245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71-associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90·0% (95% CI 67·1-96·9) against EV71-associated HFMD (p=0·0001) and 80·4% (95% CI 58·2-90·8) against EV71-associated disease (p<0·0001). Serious adverse events were reported by 62 of 5117 (1·2%) participants in the vaccine group versus 75 of 5123 (1·5%) in the placebo group (p=0·27). Adverse events occurred in 3644 (71·2%) versus 3603 (70·3%; p=0·33).

Interpretation: EV71 vaccine provides high efficacy, satisfactory safety, and sustained immunogenicity.

Funding: China's 12-5 National Major Infectious Disease Program, Beijing Vigoo Biological.
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http://dx.doi.org/10.1016/S0140-6736(13)61049-1DOI Listing
June 2013

Immunogenicity and safety of an enterovirus 71 vaccine in healthy Chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial.

Lancet 2013 Mar;381(9871):1037-45

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China.

Background: Enterovirus 71 (EV71) outbreaks are a socioeconomic burden, especially in the western Pacific region. Results of phase 1 clinical trials suggest an EV71 vaccine has a clinically acceptable safety profile and immunogenicity. We aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this EV71 vaccine in healthy Chinese children.

Methods: This randomised, double-blind, placebo-controlled, phase 2 trial was undertaken at one site in Donghai County, Jiangsu Province, China. Eligible participants were healthy boys or girls aged 6–36 months. Participants were randomly assigned (1:1:1:1:1) to receive either 160 U, 320 U, or 640 U alum-adjuvant EV71 vaccine, 640 U adjuvant-free EV71 vaccine, or a placebo (containing alum adjuvant only), according to a blocked randomisation list generated by SAS 9.1. Participants and investigators were masked to the assignment. The primary endpoint was anti-EV71 neutralising antibody geometric mean titres (GMTs) at day 56, analysed according to protocol. The study is registered with ClinicalTrials.gov, number NCT01399853.

Findings: We randomly assigned 1200 participants, 240 (120 aged 6–11 months [infants] and 120 aged 12–36 months [children]) of whom were assigned to each dose. 1106 participants completed the study and were included in the according-to-protocol analysis. The main reasons for dropout were withdrawal of consent and refusal to donate a blood sample. Infants who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (742·2 [95% CI 577·3–954·3]), followed by those who received the 320 U formulation (497·9 [383·1–647·0]). For children, those who received the 320 U formulation had the highest GMTs on day 56 (1383·2 [1037·3–1844·5]). Participants who received the vaccine had significantly higher GMTs than did who received placebo (p<0·0001). For the subgroup of participants who were seronegative at baseline, both infants and children who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (522·8 [403·9–676·6] in infants and 708·4 [524·1–957·6] in children), followed by those who received the 320 U adjuvant vaccine (358·2 [280·5–457·5] in infants and 498·0 [383·4–646·9] in children). 549 (45·8%) of 1200 participants (95 CI 42·9–48·6%) reported at least one injection-site or systemic adverse reaction, but the incidence of adverse reactions did not differ significantly between groups (p=0·36). The 640 U alum-adjuvant vaccine group had a significantly higher incidence of induration than did the 640 U adjuvant-free group (p=0·001).

Interpretation: Taking immunogenicity, safety, and production capacity into account, the 320 U alum-adjuvant formulation of the EV71 vaccine is probably the best possible formulation for phase 3 trials.

Funding: The National Science and Technology Major Project (2011ZX10004-902) of the Chinese Ministry of Science and Technology, China's 12–5 National Major Infectious Disease Program (2012ZX10002-001), and Beijing Vigoo Biological.
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http://dx.doi.org/10.1016/S0140-6736(12)61764-4DOI Listing
March 2013

Reactogenicity and immunogenicity of an enterovirus 71 vaccine in Chinese healthy children and infants.

Pediatr Infect Dis J 2012 Nov;31(11):1158-65

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, People's Republic of China.

Background: Enterovirus 71 (EV71) is highly contagious and can cause severe complications. A safe and effective vaccine is needed. We assessed the reactogenicity and immunogenicity of an inactivated, alum-adjuvanted EV71 vaccine in this study.

Methods: A randomized, double-blind, placebo-controlled clinical trial was undertaken in 360 healthy participants who were stratified into 2 age groups (6-12 and 13-60 months), and randomly allocated to receive placebo or the investigational vaccine containing 160 U, 320 U or 640 U antigen per dose by the ratio of 1:1:1:1 at days 0 and 28. Reactogenic data within 28 days after each vaccination were recorded. Blood samples were obtained on days 0, 28 and 56 for neutralizing antibody assay.

Results: Overall, 193 participants reported at least 1 injection-site or systemic adverse reaction with 53.3% and 54.4% participants receiving the study vaccine and placebo, respectively. Most of the reactions were mild or moderate. Three serious adverse events were observed, but none was related to vaccination. In the participants with seronegative baseline, after 2 doses all the participants receiving EV71 vaccines were seropositive and the seroconversion rates were more than 98.1%. In the participants with seropositive baseline, 1 dose induced good seroconversion rates of more than 64.3% in participants receiving EV71 vaccines.

Conclusions: This study found that the inactivated EV71 vaccine was well tolerated and had good immunogenicity in healthy children and infants. A single dose induced typical booster response in the participants with a seropositive baseline, and 2 doses were needed for the immunologically naive participants.
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http://dx.doi.org/10.1097/INF.0b013e31826eba74DOI Listing
November 2012

Retrospective study of the incidence of HFMD and seroepidemiology of antibodies against EV71 and CoxA16 in prenatal women and their infants.

PLoS One 2012 25;7(5):e37206. Epub 2012 May 25.

Acute Infectious Disease Control and Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, People's Republic of China.

Background: Hand, foot, and mouth disease (HFMD) has been emerging as an important public problem over the past few decades, especially in Asian and Pacific regions. A national program on EV71 vaccine development against HFMD was initiated in China, in 2008, which called for a need for seroepidemiological study for the target population.

Methodology/principal Findings: This was a retrospective study conducted in Jiangsu Province, in October, 2010. We measured the neutralizing antibodies against EV71 and CoxA16 in a cohort of infants aged of 2, 7, 12, and 27-38 months and their mothers just before delivery. Series sera samples from 975 infants and 555 mothers were collected and analyzed. Questionnaires on the history of HFMD were completed in the survey. A total of 143 HFMD cases were collected, but only 11.2% were reported to the National Infectious Disease Information Management System. The level of maternal antibody titers decreased dramatically during the first 7 month and remained at a relatively low level thereafter. But it increased significantly from month 12 to months 27-38. The accumulate incidence density of HFMD demonstrated a significant increase after 14 months of age, resulting in a accumulate incidence density of 50.8/1000 person-years in survey period. Seropositivity of EV71 antibody in infants at the age of 2 months seems to demonstrate a protective effect against HFMD.

Conclusions And Significance: High seropositive rate of EV71 and CoxA16 antibody was found in prenatal women in mainland China, and there is a need to enhance the HFMD case management and the current surveillance system. We suggest that infants aged between 6 to 14 months should have the first priority to receive EV71 vaccine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360679PMC
December 2012

Tolerability and immunogenicity of an inactivated enterovirus 71 vaccine in Chinese healthy adults and children: an open label, phase 1 clinical trial.

Hum Vaccin Immunother 2012 May 1;8(5):668-74. Epub 2012 May 1.

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, PR China.

In this open labeled phase 1 clinical trial with enterovirus 71 (EV71) vaccine (ClinicalTrials.gov number: NCT01267903) performed in Donghai County, Jiangsu Province, China, in January 2011. A total of 100 healthy participants, stratified by age (40 adults aged 16-22 y and 60 children aged 6-15 y), were enrolled from volunteers and sequentially received EV71 vaccines of 160U (only for children), 320U, or 640U on day 0 and 28, in a manner of dose escalation. All the participants were followed for 28 d after each shot. During the study period, 37 participants reported at least one injection-site or systemic adverse reaction. No case of grade 3 adverse reaction or serious adverse event (SAE) was observed. Also no dose-related increase in reaction rate was noticed. Pain at injection-site and fever were the most frequently reported local and systematic reaction, respectively. The studied EV71 vaccines demonstrated acceptable tolerability and no anti-nuclear antibody (ANA) seropositive was detected pre or post vaccinations in participants. Also, no clinically significant abnormal change for the liver or kidney function indexes was found. In the according-to-protocol cohort for immunogenicity, it was observed one dose of EV71 vaccine elicited good immune response in the participants, especially for the ones with sero-positive baseline. No obvious dose-response relationship for immunogenicity was found.
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http://dx.doi.org/10.4161/hv.19521DOI Listing
May 2012

Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, Phase I clinical trial.

Vaccine 2012 May 15;30(22):3295-303. Epub 2012 Mar 15.

The Center for Disease Control and Prevention of the Guangxi Zhuang Autonomous Region, China.

Unlabelled: There is an urgent need for a novel vaccine that is effective against human Enterovirus 71 (EV71) outbreaks. A double-blind, randomized controlled study was to evaluate the safety and immunogenicity of a human EV71 vaccine in healthy adults, children and infants. The vaccine dosages were 200 U and 400 U for children and adults, and 100 U, 200 U and 400 U for infants. Subjects were randomized to receive different dosages of the vaccine or placebo. Adults received intramuscular injection on Days 0, 14 and 28. Children and Infants received on Days 0, 28 and 56. The novel human EV71 inactivated vaccine was well tolerated and highly immunogenic in healthy volunteers, especially in infant populations. For immune response, the seropositive rates (with titers ≥≥1:8) of neutralizing antibody [NTAb] increased to 100% for all dosage groups after the second vaccination. For NTAb seronegative infants before vaccination, after one dose, the NTAb GMTs were 29.7 (95% CI, 13.1-67.2), 10.1 (95% CI, 6.6-15.3), and 27.4 (95% CI, 14.3-52.2) in the 100 U, 200 U, and 400 U vaccine groups, respectively; after two doses, the GMTs were 114.1 (95% CI, 44.5-292.4), 159.5 (95% CI, 49.3-515.3), and 509.0 (95% CI, 181.3-1429.1), respectively.

Trial Registration: ClinicalTrial.gov identifier: NCT01273246 and NCT01273233.
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http://dx.doi.org/10.1016/j.vaccine.2012.03.010DOI Listing
May 2012

Enterovirus 71 viral capsid protein linear epitopes: identification and characterization.

Virol J 2012 Jan 20;9:26. Epub 2012 Jan 20.

National Institutes for Food and Drug Control, Beijing, China.

Background: To characterize the human humoral immune response against enterovirus 71 (EV71) infection and map human epitopes on the viral capsid proteins.

Methods: A series of 256 peptides spanning the capsid proteins (VP1, VP2, VP3) of BJ08 strain (genomic C4) were synthesized. An indirect enzyme-linked immunosorbent assay (ELISA) was carried out to detect anti-EV71 IgM and IgG in sera of infected children in acute or recovery phase. The partially overlapped peptides contained 12 amino acids and were coated in the plate as antigen (0.1 μg/μl). Sera from rabbits immunized with inactivated BJ08 virus were also used to screen the peptide panel.

Results: A total of 10 human anti-EV71 IgM epitopes (vp1-14 in VP1; vp2-6, 21, 40 and 50 in VP2 and vp3-10, 12, 15, 24 and 75 in VP3) were identified in acute phase sera. In contrast, only one anti-EV71 IgG epitope in VP1 (vp1-15) was identified in sera of recovery stage. Four rabbit anti-EV71 IgG epitopes (vp1-14, 31, 54 and 71) were identified and mapped to VP1.

Conclusion: These data suggested that human IgM epitopes were mainly mapped to VP2 and VP3 with multi-epitope responses occurred at acute infection, while the only IgG epitope located on protein VP1 was activated in recovery phase sera. The dynamic changes of humoral immune response at different stages of infection may have public health significance in evaluation of EV71 vaccine immunogenicity and the clinical application of diagnostic reagents.
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http://dx.doi.org/10.1186/1743-422X-9-26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292509PMC
January 2012

Dynamic change of mother-source neutralizing antibodies against enterovirus 71 and coxsackievirus A16 in infants.

Chin Med J (Engl) 2010 Jul;123(13):1679-84

2nd Division of Viral Vaccines, National Institute for Control of Pharmaceutical and Biological Products, Beijing 100050, China.

Background: Enterovirus 71 (EV71) and coxsackievirus A16 (Cox A16) are major causative agents for hand, foot and mouth disease (HFMD). Studies indicate that the frequent HFMD outbreaks result in a few hundreds children's death in China in recent years. The vaccine and other research for HFMD need to be developed urgently.

The Aims Of Our Study Were: to explore dynamic development of mother-source neutralizing antibodies against EV71 and Cox A16 in infants from Jiangsu Province, China, and to provide the fundamental data for further establishing of corresponding immunization course.

Methods: Peripheral blood samples were collected from 133 of parturient women once immediately before delivery and their infants at two and seven months of age. Method of micro-dose cytopathogenic effect was used to measure neutralizing antibodies against EV71 and Cox A16, respectively.

Results: Seropositive rates of anti-EV71 and anti-Cox A16 in prenatal women were 79.7% (106/133) and 92.5% (123/133), respectively; geometric mean titers (GMTs) were 29.0 and 61.9; 75.9% (101/133) prenatal women were both positive in anti-EV71 and anti-Cox A16; seropositive rates of anti-EV71 and anti-Cox A16 were 25.6% (34/133) and 38.3% (51/133) in infants at two months of age; GMTs were 12.3 and 18.0, respectively. GMTs of anti-EV71 were significantly higher for infants at seven months (82.6) compared with that at two months (P < 0.05), showing infants had inapparently infected by EV71 during two to seven months. Although only one offspring (0.75%) at seven months was found having anti-Cox A16 transfered from maternal, this observation suggested no maternal antibody may remain in infants at seven months.

Conclusions: The prevalence of EV71 and Cox A16 were relatively high in Jiangsu Province. Bivalent vaccine against both EV71 and Cox A16 should be developed, and the ideal time point for prime immunization for infants is around 2-5 months of age.
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July 2010

[Epidemiology of hepatitis E in clinical patients in Dongtai, Jiangsu province].

Zhonghua Liu Xing Bing Xue Za Zhi 2010 May;31(5):594

Second Division of Viral, National Institute for the Control of Pharmaceutical and Biological Products, Beijing 100050, China.

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May 2010

[Evaluation on the analytical sensitivity of 31 HBsAg enzyme immunoassay kits].

Zhonghua Liu Xing Bing Xue Za Zhi 2009 Aug;30(8):841-4

National Institute for the Control of Pharmaceutical and Biological Products, Beijing 100050, China.

Objective: To study the analytical sensitivity on 31 HBsAg enzyme immunoassy (EIA) test kits.

Methods: Thirty one HBsAg EIA kits produced by domestic or overseas manufactories and applied for approval during May 2007 to May 2008, were evaluated using the national reference panels. The hyperbolic curve of the log A value and log concentration for the national sensitivity standards was established. The cut-off value of each kit was substituted into the curvilinear equation to determine the analytical sensitivity which was compared between different HBsAg EIA kits.

Results: Twenty seven (351 lots) domestic and 4 (27 lots) overseas kits were compared. Among 378 lots of the 31 HBsAg EIA kits, only 2 lots of the domestic kits had a lower sensitivity when tested with the national HBsAg reference panels, with an average approvalr ate of 99.43% (349/351). The mean analytical sensitivity of the domestic kits for adr, adw, ay serotypes were 0.307, 0.419, 0.513 ng/ml, respectively. There was a significant difference between serotypes (F = 97.30, P < 0.01). The mean analytical sensitivity of the overseas kits for adr, adw, ay serotypes were 0.054, 0.066, 0.050 ng/ml respectively, with no significant difference between serotypes (F = 0.65, P > 0.05). The analytical sensitivity of the overseas kits for all the three serotypes was higher than that of the domestic kits (P < 0.01). There was no significant difference found between the analytical sensitivities of the kits produced by the same manufactory using 30- or 60-minute incubation of detection (P > 0.05). In contrast, there was significant difference noticed between the analytical sensitivities of the kits produced by the same manufactory when tested for 10 or 15-minute coloration of the results (P < 0.01).

Conclusion: Analytical sensitivity of the HBsAg EIA domestic kits should be further improved, especially for detecting adw and ay serotypes.
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August 2009

[Genetic characterization of enterovirus 71 complete genome isolated in Beijing, 2008].

Zhonghua Liu Xing Bing Xue Za Zhi 2009 Jul;30(7):729-32

National Institute for Control of Pharmaceutical and Biological Products, Beijing, China.

Objective: To investigate the characterization of the complete genome of EV71 in Beijing, 2008 and to provide basis for selecting appropriate virus strain to develop vaccine.

Methods: 12 throat swab samples were collected from children with hand-foot-mouth disease (HFMD). One sample named 08YM-3 was cultured and isolated in vero cells. Viral RNA was extracted and carried out by RT-PCR and 5', 3' rapid amplification of cDNA ends (RACE) to obtain the sequence from 08YM-3. PCR products were cloned and analyzed. Nucleotide identity between sequences was calculated and sequence alignments were made to generate phylogenetic trees using MegAlign in DNAStar.

Results: 3 clones were constructed that covered EV71 complete genome. Data from sequences analysis showed that this viral strain named BJ08 shared 95.6%-96.7%, 88.3%-96.1%, 78.1%-94.0%, 90.8%-94.6%, 85.9%-94.1% and 90.9%-93.9% in 5' UTR, P1, P2, P3, 3' UTR region and complete genome with C4 subtype, respectively. BJ08 showed low nucleotides identity (<90%) with other subtypes. Phylogenetic trees established from alignment of the complete genome and VP1 region indicated that BJ08 belonged to C4 subtype. BJ08 and C4 subtype strains shared the same amino acids in 6 sites in VP1 region, which were associated with EV71 subtype. There was no mutation in VP1 antigen epitope (92-107aa).

Conclusion: This BJ08 strain belonged to C4 subtype. Further study on EV71 complete genome would have great significance for vaccine research.
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July 2009