Lecture Video: 2018 Workshop on Regulation of Enterovirus Vaccines in Taiwan and Vietnam

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Date: March 6, 2018

Location: Taipei, Taiwan

20180306

Time Opening Remark
09:00-09:05 Dr. Tzou-Yien Lin Chair person, Board of Directors, NHRI, Taiwan
I. Taiwan Regulation Section
Topic Speaker Moderator
09:05-09:30 Development of Enterovirus71 (EV71) Vaccines in Taiwan Dr. Min-Shi Lee
NHRI, Taiwan
Dr. Mei-Shang Ho
Academia SINICA, Taiwan
09:30-10:00 Clinical Perspective on EV 71 Vaccines Regulation in Taiwan Dr. Ya-Lei Wang
CDE, Taiwan
10:00-10:30 CMC Perspective on EV 71 Vaccines Regulation in Taiwan Dr. Yu-Ping Ho
CDE, Taiwan
10:45-11:15 Lot Release System for Vaccines in Taiwan Dr. Yi-Chen Yang
FDA, MOHW, Taiwan
11:15-11:40 Current Status and Future Plans for Clinical Trial of EV 71 Vaccines (Enimmune) Dr. Chin-Fen Yang
Enimmune, Taiwan
11:45-12:15 Current Status and Future Plans for Clinical Trial of EV 71 Vaccines (Medigen) Dr. Kathy Tai
Medigen Vaccines, Taiwan
II. Vietnam Regulation Section
13:30-14:00 Review on IND of Human Vaccines in Vietnam Dr. Nguyen Ngo Quang
ASTT, MOH,
Vietnam
Prof. Oliver Yoa-Pu Hu
Taipei Medical University, Taiwan
14:00-14:30 Regulati on on Surveillance of Adverse Event Following Immunization Dr. Nguyen Minh Hang
GDPM, MOH,
Vietnam
14:30-15:00 Implementation of Vaccine Trials in Vietnam, Experiences from the Pasteur Institute Ho Chi Minh City Dr. Nguyen Vu Thuong
Paster Institute-HCMC,
Vietnam
15:15-15:45 Experiences Sharingon Multi-national Clinical Trials of Pediatric Vaccines in Vietnam Dr. Nguyen Trong Toan
Paster Institute-HCMC,
Vietnam
Dr. Min-Shi Lee
NHRI, Taiwan
15:45-16:15 Cost of Illness of HFMD in Vietnam Dr. Le Nguyen Thanh Nhan
Children’s Hospital 1,
HCMC, Vietnam
16:15-16:45 Experiences sharing on clinical trials of pediatric vaccines in Vietnam Dr. Do Tuan Dat
VABIOTECH Vaccine,
Vietnam

Lecture Video: 2017 International Workshop on Enterovirus Surveillance and Vaccine Development

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Enteroviruses : Frequently Asked Questions?

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Data from Division of Acute Infectious Diseases, CDC, Taiwan

FAQ

  1. What are enteroviruses?

Enterovirus is a general term of a group of small RNA viruses which accounts for more than 70 viruses, including Coxsackieviruses A, Coxsackieviruses B, polioviruses, echoviruses, and enteroviruses.

  1. Can these enteroviruses only be found in Taiwan?

What are the epidemic seasons?

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Enterovirus / Enterovirus Infection with Severe Complications in Taiwan

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Data from Division of Acute Infectious Diseases, CDC, Taiwan

Background

Enterovirus belongs to a group of small RNA viruses, including polioviruses, Coxsackie A viruses, Coxsackie B viruses, echoviruses, and other enteroviruses (EVD68~). EVA71 has a significantly higher pathogenicity compared to other known enteroviruses, especially regarding neurological complications. Enteroviruses are found in the gastrointestinal tract (the stool of infected persons, mouth) and respiratory tract (such as saliva, sputum, or nasal mucus). Infections can be produced by direct contact with the secretions of infected persons or with contaminated surfaces or objects. Humans appear to be the only known host and source for enteroviruses transmission. The patient is contagious before their onset, and the infectivity will last for weeks after the patient is recovered. There are currently no preventive vaccines for non-polio enteroviruses in Taiwan and no known highly efficacious medicine to eliminate the virus once it is inside the human body. Therefore, enteroviruses will continue to pose a threat to human health for the foreseeable future.

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Public urged to pay attention to health of children as Taiwan CDC confirms 5 new cases of enterovirus infection with severe complications ( 2017-12-26 )

Data from Division of Planning and Coordination, CDC, Taiwan

During December 17 and 23, 2017, the Taiwan Centers for Disease Control (Taiwan CDC) confirmed 5 new cases of enterovirus infection with severe complications. In light of the increasing number of cases of enterovirus infection with severe complications reported and the majority of these new cases are infected with enterovirus D68, Taiwan CDC invited the Pediatric Neurology professor from the Fu Jen Catholic University College of Medicine who is also Taiwan CDC’s Acute Flaccid Paralysis Surveillance Expert Northern Region Convener to discuss the symptoms induced by enterovirus D68, including acute flaccid paralysis and numbness, and urge parents to pay attention to the health of the children in their households and take the children to hospitals immediately when suspected symptoms develop.

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Parents urged to pay attention to health of children as Taiwan CDC confirmed 3 new cases of enterovirus D68 infection with severe complications last week ( 2018-01-09 )

Data from Division of Planning and Coordination, CDC, Taiwan

During December 31, 2017 and January 6, 2018, the Taiwan Centers for Disease Control (Taiwan CDC) confirmed 3 new cases of enterovirus D68 infection with severe complications. Unlike the common symptoms of enterovirus infection such as hand, foot and mouth disease (HFMD) and herpangina, the primary symptoms of enterovirus D68 infection include the symptoms of the upper respiratory tract infection such as fever, runny nose, and cough. Hence, Taiwan CDC reminds the public to pay attention to the health of the children in their household if suspected symptoms such as acute flaccid paralysis and numbness develop in a child, please take the child to seek medical attention immediately.

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Parents and child care providers urged to stay vigilant for enterovirus infection as Taiwan CDC confirms 2 new cases of enterovirus D68 infection with severe complications ( 2017-12-12 )

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  • Last modified at 2017-12-12
  • Data from Division of Planning and Coordination, Taiwan CDC

Although the enterovirus epidemic has passed its peak, the number of enterovirus D68 infection cases has continued to increase and the majority of the infected individuals are children aged below 5. Moreover, the primary symptoms of enterovirus D68 infection are fever, runny nose and cough and infected individuals rarely develop typical symptoms of enterovirus infection such as herpangina and hand, foot, and mouth disease. Therefore, the public is urged to remain vigilant of the health of the children and infants in their family and ensure a child receives immediate medical attention if he/she develops symptoms such as acute limb weakness.

Last week, the Taiwan Centers for Disease Control (Taiwan CDC) confirmed 2 new cases of enterovirus D68 infection with severe complications respectively in a 4-year-old boy and a 9-year-old girl who reside in central Taiwan. Both of them developed symptoms, including fever, runny nose, fever, and upper/lower limb weakness on one side of the body in late November. Infection with enterovirus D68 was confirmed in both cases by the Taiwan CDC laboratory. As of now, the cases are still hospitalized for treatment. A cumulative total of 15 cases of enterovirus D68 infection have been confirmed in Taiwan thus far this year. Among them, 4 were found to be cases of enterovirus infection with severe complications after case review. In light of the recent increase in the number of cases of enterovirus D68 infection, Taiwan CDC would be convening an expert meeting on December 13 to discuss relevant control strategies and response measures that reinforce surveillance in order to reduce the risk of transmission among children.

Thus far this year, 13 cases of enterovirus infection with severe complications, including 1 death, respectively caused by enterovirus D68 (4 cases), CA 6 (3 cases), CB3 (2 cases), echovirus 5 (2 cases), CA 2 (1 case), and enterovirus 71 (1 case) have been confirmed.

In terms of international outbreaks, a nationwide outbreak of enterovrisu D68 infection occurred in the United States during August 2014 and January 2015 and a cumulative total of 1,153 cases of cases with a significant number of severe cases were confirmed during that outbreak. Canada and Argentina respectively isolated enterovirus D68 in 2014 and 2016, and only a few sporadic cases developed severe complications. Over 15 countries in Europe isolated enterovirus D68 during 2010 and 2016. Among those countries, Germany, the United Kingdom, France, Italy, the Netherlands, Portugal, Norway and Sweden reported sporadic cases that developed severe complications. Countries in Southeast Asia observed an increase in the number of acute respiratory infection cases caused by enterovirus 68 during 2005 and 2014 and all of them were mild cases. Japan confirmed 258 mild cases of enterovirus D68 infection and 9 severe cases in 2015.

Enterovirus D68 infection is transmitted through the fecal-oral route, respiratory droplets and direct contact. The primary symptoms include, fever, runny nose, and cough. A few infected individuals may develop complications such as pneumonia, encephalitis and limb weakness. Currently, there is no effective vaccine to prevent or drug to treat the infection. Hence, the public is urged to practice good personal hygiene, wash hands with soap and water properly and frequently. If a child in the family develops limb weakness, please ensure the child receive medical assistance as soon as possible.

The most effective ways to ward off enterovirus D68 and other enteroviruses are to practice good hand hygiene and cough etiquette, avoid visiting crowded public places, and rest at home when sick. For more information, please visit the Taiwan CDC website at http://www.cdc.gov.tw or call the toll-free Communicable Disease Reporting and Consultation Hotline, 1922 (or 0800-001922). 

https://www.cdc.gov.tw/english/info.aspx?treeid=bc2d4e89b154059b&nowtreeid=ee0a2987cfba3222&tid=C25228DF92C1D3A4

As Taiwan CDC confirms 1 new case of enterovirus D68 infection with severe complications, parents urged to stay vigilant as enterovirus activity continues to peak ( 2017-11-07 )

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  • Last modified at 2017-12-20
  • Data from Division of Planning and Coordination, Taiwan CDC)

On November 7, 2017, the Taiwan Centers for Disease Control (Taiwan CDC) announced 1 new case of enterovirus D68 infection with severe complications in a five-year-old girl who resides in southern Taiwan. During mid-October, the case sought medical attention after developing symptoms, including high fever, runny nose, cough and vertigo. Subsequently, she developed neurological complications, including leg weakness, and her conditions worsened. When she sought further medical attention, she was hospitalized. After the case was reported to the health authority as a suspected case by the hospital, infection with enterovirus D68 was confirmed in the case by the Taiwan CDC laboratory. As of now, the case is still being treated in the hospital for her leg weakness and none of the contacts residing in the same household has developed any suspected symptoms.

According to the epidemiological investigation, none of the case and the case’s family members who reside in the same household has recently traveled domestically or internationally. The kindergarten class the case attends was suspended in early October due to enterovirus infection confirmed among the students. At the moment, none of the students in the same class has developed suspected symptoms. Therefore, the possibility that the case became infected by an asymptomatic carrier cannot be ruled out. The local health authority will continue to follow up on the case and the health of the contacts. In addition, the local health authority has provided the case’s family with relevant health education and the proper ways to disinfect the environment.

According to the surveillance data compiled by Taiwan CDC, during October 29 and November 4, 2017, the number of visits to outpatient services and ER for enterovirus infection in the nation was 12,214, which has been on a declining trend since four weeks ago though entoervirus activity remains at its peak. Thus far this year, 11 cases of enterovirus infection with severe complications, including 1 death, respectively caused by CA 6 (3 cases), CB3 (2 cases), echovirus 5 (2 cases), enterovirus D68 (2 cases), CA 2 (1 case), and enterovirus 71 (1 case) have been confirmed. Currently, most reported cases experience mild symptoms and coxsackie A virus is the dominant strain circulating in the community. Further, so far, 40 cases of infection with EV71 have been confirmed this year, indicating enterovirus 71 continues to circulate in the community.


Taiwan CDC once again reminds that enterovirus is highly contagious, especially in crowded places such as households and child care facilities. The public is also urged to clean and disinfect the environment and toys and objects children play with regularly, educate children the importance of washing hands frequently with soap and water in maintaining health and resting at home when sick, reinforce case reporting and follow the protocol for class suspension in order to effectively prevent disease transmission.
  When a child in a household is diagnosed with enterovirus infection, parents and child caregivers are urged to refrain the sick child from close contact with other children to prevent further spread of the disease and watch for the development of prodromal symptoms of complications in the sick child such as drowsiness, disturbed consciousness, inactivity, flaccid paralysis, myoclonic jerk, continuous vomiting, tachypnea, and tachycardia to ensure timely treatment at a hospital. For more information, please visit the Taiwan CDC website at http://www.cdc.gov.tw or call the toll-free Communicable Disease Reporting and Consultation Hotline, 1922 (or 0800-001922).

https://www.cdc.gov.tw/english/info.aspx?treeid=bc2d4e89b154059b&nowtreeid=ee0a2987cfba3222&tid=0AD41E71148075AA

Assay Development for Quantification of Enterovirus 71 Vaccine Antigens

Dr. Min-Shi Lee (李敏西)
Investigator, Coordinator of Emerging Virus Program,
National Institute of Infectious Diseases and Vaccinology (NIIDV),
National Health Research Institutes (NHRI), Taiwan

ABSTRACT

Enterovirus 71 (EV71) and polioviruses both belong to enterovirus genus and could cause neurological infections. Based on phylogenetic analysis of VP1 genes, EV71 could be classified into three major genogroups (A, B and C), including eleven genotypes (A, B1~B5, and C1~C5). Since 1997, different EV71 genotypes have caused life-threatening epidemics in Asian countries, including Malaysia, Taiwan, Singapore, Brunei, Vietnam, Cambodia and China. Therefore, development of EV71 vaccines is a national priority in these countries. Currently, five vaccine candidates have been evaluated in clinical trials in China (3 genotype C4 candidates), Singapore (1 genotype B2 candidate), and Taiwan (1 genotype B4 candidate) and the three C4 candidates was recently approved for marketing in China. However, these five vaccine candidates have the following limitations to be improved, including low-growth efficiency (~107 TCID50/ml) and the shortage of standard assays for quantifying vaccine antigens. In this study, we have adapted high-growth genotype B5 vaccine virus which could grow to ~108 TCID50/ml in microcarrier-based and BelloCell-based Vero cell culture systems and induce cross-reactive neutralizing antibody responses against the three EV71 major genogroups in rabbits. In addition, we generated rabbit antisera and mouse monoclonal antibody with high neutralizing antibody titers to develop an enzyme-linked immunosorbent assay (ELISA) which could quantify protective vaccine antigens and predict immunogenicity of vaccine bulks in rabbits. Therefore. this ELISA could be potentially used as in vitro potency assay for product release and in-process control assay for monitoring EV71 vaccine production.

The content is authorized by Dr. Min-Shi Lee on October 30, 2017.

Development of Standard Reagents for Harmonization of EV 71 Vaccines

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Dr. Javier Martin
Principal Scientist
Division of Virology,
National Institute for Biological Standards and Control (NIBSC),
United Kingdom

ABSTRACT

Enterovirus A71 (EV71) is the major causative agent of severe and fatal hand, foot and mouth (HFMD) disease. Since EV71 was first isolated from patients in California in 1969, it has been associated with sporadic cases and outbreaks of a wide spectrum of diseases, including HFMD, herpangina, aseptic meningitis, encephalitis, cerebellar ataxia and poliomyelitis-like syndrome. From the late 1990s, outbreaks and epidemics caused by EV71, particularly in the Asia-Pacific region, have occurred more frequently with the incidence of severe HFMD cases and mortalities. Vaccine development is the best way to prevent and control infectious diseases and vaccines against EV71 are already available or under development. Three EV71 vaccine products have been approved by the China Food and Drug Administration (CFDA) since December 2015, having shown good immunogenicity and more than 90% protective efficacy in more than 30,000 infants and children.

Projects to establish WHO International Standards for anti-EV71 serum (Human) and EV71 vaccine antigen were endorsed by ECBS, WHO, in 2012.  The 1st WHO International Standard (IS) for anti-EV71 serum (Human) was established in 2015 following a collaborative study led by the National Institute for Biological Standards and Control (NIBSC, UK) and the National Institutes for Food and Drug Control (NIFDC, China). The study showed that between laboratory variations in neutralization titres were significantly reduced when values were expressed relative to those of the IS. The use of this IS will ensure that methods used to measure the serum neutralizing activity or antibody levels against EV71 are accurate, sensitive and reproducible, which will contribute to the standardized assessment of the quality and efficacy of vaccines used in immunization programs globally.

The project to establish an IS for EV-71 vaccine antigen has been initiated with an aim to harmonize methods for the measurement of the antigen content of EV71 products. Different immunochemistry assays are in use for this purpose that employ different antibody reagents and references, which results in difficulties in comparing different EV71 vaccines and in interpreting research results on virus antigenic and immunogenic properties. Being able to establish an IS with an assigned potency should facilitate comparing both EV71 vaccine products and antigen assays. We also aim at establishing both in vitro and in vivo potency assays for EV71 vaccines with good correlation between them.  In addition, it will be important to study the relative contribution of full and empty virus particles to the antigenic and immunogenic properties of the different EV-71 products including their ability to induce antibodies against EV71 isolates from different genogroups. Preliminary results on this project and the different steps required to conduct this collaborative study will be discusse.

The content is authorized by Dr. Javier Martin on October 30, 2017.