ICP/CIlS/003
ENGLISH ONLY
~OND
TASK FORCE MEETING ON HEPATITIS B
Convened by the REGIONAL OFFICE FOR THE WESTERN PACIFIC OF
THE
WORLD HEALTH ORGANIZATION
Sendai, Japan 27-30 August 1984
WHOIWPR1fLIBRARY '\1;\ l\'TLA.
T'Hn .n'T'TNES
Not for sale Printed and distributed by the Re~ional
Office for the Western Pacific of the World Health Or~anization Manila, Philippines February 1985
NOTE
The views expressed in this report are those of the Members of the Task Force and do not necessarily reflect the policies of the Organization.
This report has been prepared bV the Regional Office for the Western Pacific of the World Health Or~anization for ~overnments of Member States in the Region and for those who participated in the Second Task Force Meeting on Hepatitis B, which was held in Sendai, Japan, from 27 to 30 August 1984.
CONTENTS
1• 2. 3.
INTRODUCT ION •••••••••••••••••••••.•.•••........•... BACKGROUND AND OBJECTIVES ••••••••••••••...•••.••••. SUMMARY OF PROCEEDINGS ••••••••••••••••••••.•••••.•. 3.1 3.2 3.3 3.4 3.5 Progress on the development of vaccines ••••••• Licensing of vaccines ••••••••••••••••••••••••• Prevention of HRV infection by immunological methods •••••••••••••••••••••••.• Diagnostic reagents ..••••••••••••..••....•..•• Control of hepatitis B virus infection •••.••••• 2.
2 4 4 5
5 6
4.
RECOMMENDATIONS
Annex 1 - AGENDA ,. ••• ,.,. •••••••. ,. •••••••• ,.,..,..,. .• ,..",.
9
Annex 2 - LIST OF MEMBERS, CONSULTANTS, OBSERVERS AND SECRETARIAT •••••••..•••••..
13
1.
INTRODUCTION
Re~ion.
Hepatitis B virus infection is widespread in the Western Pacific In most countries, between 5 and 15% of the population are persistent carriers of the virus, and the long-term sequelae - cirrhosis, chronic active hepatitis and primary hepatocellular carcinoma - are common. It has been estimated that of the 160 million carriers in the Region, approximately 40% of the males and 15% of the females are likely to die of one of the long-term complications of their infection. In recent years, a number of safe effective vaccines have become available and some of these are now licensed for use in man. WHO has developed a set of guidelines and requirements for manufacturers and is providing support for studies on the production and distribution of these vaccines and the development of control programmes.
2.
BACKGROUND AND OBJECTIVES
A Scientific Group on Hepatitis B Virus and Its Related Liver Diseases met in Nagasaki, Japan, from 29 September to 2 October 1982. Among other things, the Group recommended that a small regional task force consisting of representatives of institutions with special expertise in the field of viral hepatitis be convened. Pursuant to this recommendation, the WHO Re~ional Office for the Western Pacific established a Task Force on Hepatitis B with the following objectives: To act as a coordinatin~
body for WHO's regional programme by
collecting and analysing data; defining areas requiring further research and assisting in the development of collaborative research proposals; closelv reviewing progress in vaccine development and its application in the Region, especially in preventing maternal/ infant transmission; coordinating research in the Region; encouraging the sharing of data and effective use of resources. The first meeting of the Task Force took place in Manila, Philippines on 8 - 11 November 1983. The Task Force recommended that WHO should place particular emphasis on developing and distributing diagnostic reagents, assisting local vaccine production and control, developing appropriate
2
immunization strate~ies and encouraging technical cooperation between countries in the Region.~/ It suggested that a further meeting be held in one year to review progress. The Second Meeting of the Task Force took place in Sendai, Japan on 27-30 August 1984. The objectives of this meeting were: (i) to review progress in the production and distribution of HBV vaccines and diagnostic reagents and to identify problems;
(ii) to formulate a plan of work relevant to the above objective. The Agenda and list of participants are found in Annexes 1 and 2 respectively.
3.
SUMMARY OF PROCEEDINGS
The meetine was opened by the Regional Director, Dr H. Nakajima. Dr Nishioka was nominated as Chairman, Dr Chung as Vice-Chairman and Dr Gust as Rapporteur. 3.1 Progress on the development of vaccines (a) Plasma-derived particle vaccines The Task Force was encouraged to note the increasing number of hepatitis vaccines being produced and tested in the Region. In addition to studies that have been carried out with American, Dutch and French hepatitis B vaccines, vaccines are now being produced in the People's Republic of China (Beijing, Shanghai, Lanzhou, Changchun), Japan (Kitasato Institute, Green Cross Corporation, ChemoSero-Therapeutic Institute) and the Republic of Korea (Korea Green Cross Corporation) while an institute in Taiwan (province of the People's Republic of China) has plans to produce the French vaccine under licence. It is expected that within the next two or three years, China, Japan, the Republic of Korea and Singapore will be able to produce sufficient plasma-derived vaccine to satisfy their own demands, after which excess production may be available for other countries in the Region. In addition, some manufacturers may be prepared to process plasma collected in countries that have no vaccine-producing capacity and return the finished vaccine.
l/Report of the Meeting of the Task Force on Hepatitis B, Manila, Philippines, 8-11 November 1983, WHO Regional Office for the Western Pacific document, published March 1984.
3
The cost of locally produced vaccines is expected to be cheaper than those that are currently available. The estimated price of the Japanese and lorean vaccines is of the order of $7-12 per dose. Of the vaccines currently produced in the Re~ion, the Japanese vaccines produced by the Green Cross Corporation and the Kitasato Institute will be licensed in September 1984. Both these vaccines meet current WHO requirements. The third Japanese vaccine is expected to be licensed in 1985. The Korean Green Cross Corporation vaccine meets the requirements of the national licensing authority and was released for local use in August 1983. The Task Force noted the need for WHO to support some Member States in developing means to improve production and quality control of vaccines by providing appropriate consultants and expert advice and training the staff of vaccine licensing authorities. (b) Vaccines produced by recombinant DNA technology
The Task Force discussed the data now available on expression of hepatitis B surface antigen (HBsAg) in E. coli, yeast and mammalian cells. It was noted that a yeast-derived ~ine produced by Merck Sharpe and Dohme (MSD) has been shown to be safe, antigenic and protective in chimpanzees. Because the antigenic polypeptides produced in this system lack several components found in the HBsAg of the plasma vaccine, it was felt that control authorities would require formal proof of efficacy before licensing the yeast vaccine for use in man. Such studies are currently under way and, if successful, should lead to licensing of the MSD vaccine in 1985. Plans are also in hand to produce this vaccine in Sin~apore under licence. In addition, work is well advanced for the production of yeast-derived vaccines in Japan by the Chemo-Sero-Therapeutic Institute and the Green Cross Corporation. The first batches of these vaccines are likely to be ready for testing in March/April 1985. Plans to produce yeast vaccines are also being formulated in China and the Republic of Korea. Current estimates suggest that yeast-derived vaccine could be produced for as little as $2 per dose. (c) Other approaches
A variety of other techniques may be utilized to produce hepatitis B vaccines. These include expression of HBsAg in mammalian cells, production of synthetic polypeptides which contain epitopes present on the surface antigen, the use of hybrid viruses, and the use of idiotype antiidiotype preparations. Of these perhaps the most promising at present is the production of in transformed Chinese hamster ovary cells. Unlike the yeast vaccine, HBsAg produced in hamster ovary cells is biochemically indistinguishable from naturally produced antigen and can be produced in vast quantities. If tests can be devised to establish that vaccines produced in transformed cells are free from potentially oncogenic material, this vaccine could be produced for a few cents per dose. HBsA~
4
While synthetic polypeptide vaccines are an alternative possibility, it may be necessary to use mixtures of polypeptides possessing several epitopes to obtain adequate immunity and better adjuvants or immunomodulators will be needed to stimulate long lasting high titre antibody. The Task Force noted with interest work on insertion of the gene for HBsAg into vaccinia virus and use of the resultant hybrid to produce immunity to hepatitis B virus. While aware of the incidence of side effects during mass vaccination campaigns, the Task Force was reluctant to disregard this approach because rapid advances in molecular biology might make it possible to develop a totally safe parental strain, and use of hybrid vaccinia viruses offers the possibility of immunizing against several diseases with a single dose of vaccine. In view of the importance of this work it suggested that one or more representatives from the Region should be invited to attend the forthcoming meeting on the use of hybrid vaccines to he held at the National Institute of Health, Maryland, later this year.l/ 3.2 Licensing of vaccines
In addition to strengthening the capability of local licensing authorities, the Task Force noted the need for WHO to develop requirements for the next generation of HB vaccines before they are ready for use in man. As several producers are located in the Western Pacific Region (which will also be the major consumer of the vaccine), the Task Force stressed the need for local scientists and control authorities to work closely with academic institutions and research institutes in their respective countries to develop relevant skills. 3.3 Prevention of HBV infection by immunological methods
Further data were presented on prevention of perinatal transmission of HBV by active immunization or combined active passive immunization. The results of studies carried out in China, Hong Kong, Japan and the Republic of Korea up until the beginning of 1984 were presented. In summary the prevalence of transmission of hepatitis B virus from HBsAg HBeAg positive mothers to their babies in this Region ranged from 73-100% with a mean of 84%. Five studies on the effect of HB vaccine in reducing perinatal transmission have been carried out. In each case the first dose of vaccine was administered within 48 hours of birth followed by a further two or three doses over the next six months. In three studies using different vaccines, the protective efficacy of vaccination ranged from 70-75%. In the remaining two studies, both of which were small, the
~/The use of vaccinia virus as a carrier for hybrid vaccines, Joint WHO/USA PHS/NIBSC meeting to be held at NIH, Bethesda, Maryland, 12-15 November 1984.
)
5
protective efficacy was of the order of 90%. It is of interest that in these studies the vaccines were inactivated by formalin or by heat and formalin only. Several studies on combined passive/active immunization were reported, each of which showed a protective efficacy in excess of 90%. The highest degree of protection was obtained with a re~imen in which HBI~ was administered intravenously at birth and was followed by several doses of HBIg and vaccine. The Task Force believes that each country will have to determine its own strategy for the prevention of perinatal infection in the light of its resources and the availability of vaccine and HBI~. It believes that in most countries of the Re~ion the simplest and most effective programme would be to immunize all newborn babies with HB vaccine alone. 3.4 Diagnostic reagents
The Task Force endorsed the recommendations of its first meetin~ and noted with pleasure that many had been implemented. A wide range of diagnostic reagents are now bein~ produced in several centres in China and these have been evaluated both internally and in collaboration with WHO collaborating centres in Tokyo and Melbourne. Although originating from research laboratories, the potential now exists to mass produce some or all of these reagents. A range of reagents are also being produced in the Republic of Korea and are under development in the Philippines. The Task Force noted that two countries, Malaysia and the Philippines, may need additional help in the production and standardization of reagents and recommended that the Regional Director should investigate means of providing technical cooperation, perhaps by arrangin~ a visit of staff from one or more collaborating centres in the Region, or arranging future meetings of the Task Force in these countries, or both. It further noted that, while well trained staff exist in some laboratories in the Region, they are often unable to embark upon a programme of work because of lack of resources, lack of support of their director or lack of interest from the Ministry of Health. The Task Force recommended that the Regional Director should continue to stress the importance of control of hepatitis B virus infections with relevant government officials in the Region. 3.5 Control of hepatitis B virus infection
The Task Force expressed the view that sufficient information and sufficient quantities of vaccine would soon be available to allow countries in the Region to begin pro~rammes to control and eventually eliminate this disease. It believes that strate~ies will vary from country to country but that many the simplest strategy will be immunization of all newborn babies. In countries in which the prevalence of chronic carriers of HBsAg is relatively low or confined to certain groups, vaccination is likely to be restricted to those at high risk of infection. . ~n
6
As in many countries, the cost is likely to limit the extent of immunization programmes, further research needs to be carried out on the most cost-effective and practical way of immunizing newborn babies. WHO should help countries to devise and evaluate different immunization strategies and to train people who will be involved in the control programme. The Task Force noted that every hepatitis B vaccine that has been tested has been demonstrated to reduce the frequency of transmission of hepatitis R virus by carrier mothers to their babies. It believes that future studies of vaccine efficacy can only proceed on the expectation that the vaccine under test will be as good as or better than those currently available, and that the use of placebo or unimmunized controls is unethical. The Task Force suggests that the Regional Office should support demonstration projects in communities in which hepatitis R is hyperendemic. These projects will serve to improve understanding of the disease in the countries in which they are performed and identify and train key personnel who will have the responsibility for implementing national control programmes. These projects should be evaluated in the short term by reduction in the number of chronic carriers, in the medium term by the persistence of antibody, and in the long term by the reduction of sequelae.
4.
RECOMMENDATIONS
The Task Force endorsed the recommendations of the First Meeting and made the following additional recommendations: 4.1 The WHO Regional Office for the Western Pacific should encourage Member States to identify suitable institutions as national centres for the study of viral hepatitis. After designation by Member States and approval by WHO, these laboratories and the existing collaborating centres will provide a two-tiered network of laboratories. The WHO collaborating centres will serve as regional laboratories and be responsible for the following: development, evaluation and distribution of reference reagents; development of standard procedures for the production of reagents; transfer of skills to national laboratories; development of training programmes and training manuals; development of regional quality control programmes;
7/8
\
National centres will be ultimately responsible for the development of training, production of workin~ reagents and a quality control programme on a national basis. 4.2 The WHO Regional Office for the Western Pacific should continue to cooperate in organizing bi-re~ional/intercountry courses with the objective of trainin~ key laboratory personnel to be assi~ned to the national centres in methods of detection of viral hepatitis markers with standardized diagnostic reagents and in the production of reagents. 4.3 The WHO Regional Office for the Western Pacific should publish regional guidelines with information on the production of dia~nostic reagents, standardized laboratory procedures for detectin~ hepatitis markers, and ~uidelines for control programmes and vaccination strategies. 4.4 The WHO Regional Office should consult with ~overnments of Member States about national control programmes and appropriate vaccination strategies. An appropriate starting point might be to encourage the establishment of national hepatitis advisory committees to advise each Ministry of Health. 4.5 WHO should collaborate with Member States to strengthen national vaccine control authorities. 4.6 WHO should develop reference preparations of hepatitis B vaccines and make these available to competent manufacturers in the Region. 4.7 WHO should support operational studies to establish the most appropriate means of carrying out lar~e-scale immunization programmes. Such studies should include evaluation of the cost, delivery systems, methods of monitoring and degree of acceptance. 4.8 WHO collaborating centres in the Re~ion should be encoura~ed to produce and distribute proficiency test panels and to supply them to individual laboratories on request.
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9
ANNEX 1
AGENDA Monday, 27 0800 0830
Au~ust
Registration Opening Production of in China Shanghai Changchun Langzhou Beijing General Comments dia~nostic
0900
reagents Dr Tao Yi-Xun Dr Zhang Quan-vi
J)r Zhao Kai Dr I.i Ho-min
1200 1400
Lunch break Pro~ress in the development of diagnostic reagents and vaccine
Philippines South Pacific Singapore Republic of Korea Japan Dr H. Shimojo
nr E. Domingo Dr 1.D. Gust Professor Oon Dr K.H. Kim
Tuesday, 28 August 0900
Prevention of HBV infection by immunological methods Japan Republic of Korea China Dr M. Yano
Dr W.K. Chung
10 Annex 1 II
II
General comments 1015 1030 Coffee break Development of new vaccines Japan China General comments 1200 1400 Lunch break Review of training programme on HBV Japan Australia Wednesdav. 29 August 0900 Standardization of diagnostic reagents Global view National view Japan Australia China Republic of Korea 1015 1030 1200 1400 Coffee break Consultation meeting on China project Lunch break Draftin~
Dr K. Nishioka Dr J. Maynard
II
I,
"
" Dr F. Assaad
Dr K. Nishioka Dr 1. D. Gust
Dr F. Assaad
Dr K. Nishioka Dr 1.D. Gust
Dr Li Ho-min Dr K.H. Kim
of recommendations
11/12
Annex 1
Thursday, 30 August 0900 1200 Finalization of recommendations Closing ceremony
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ANNEX 2
LIST OF MEMBERS, CONSULTANTS, OBSERVERS AND SECRETARIAT
1.
MEMBERS
Dr Whan Kook Chun~ Director St Mary's Hospital Catholic Medical School Seoul Republic of Korea Dr Ding Zhen~rong Epidemic Prevention Station Guan~xi
Zhuang Autonomous Region People's Republic of China Dr Ernesto Domingo Associate Dean and Chairman of Medicine College of Medicine University of the Philippines Pedro Gil Street Manila Philippines Dr Ian D. Gust Director Virus Laboratory Fairfield Hospital Yarra Bend Road Fairfield, Victoria 3078 Australia Dr He Baoguan~ Shanghai Institute of Biological Products Shanghai People's Republic of China
14 Annex 2
Dr Kyonll Ho Kim Director Korea Green Cross Research Institute 729, Seocho-Donll, KangNam-Ku Seoul T-135 Republic of Korea Dr Li He-min National Institute for the Control of Biological and Pharmaceutical Products Beijin~
People s Republic of China Dr James E. Maynard Assistant Director for Medical Science, DVD Centers for Disease Control Atlanta, Georgia 30333 United States of America Dr Kusuya Nishioka Vice-President Tokyo Metropolitan Institute of Medical Sciences 3-18 Honkoma~ome Bunkyo-ku Tokyo 113 Japan Professor Oon Chong Jin Associate Professor of Medicine and Consultant Physician National Centre for Reference and Research on Hepatitis and Related Diseases University Department of Medicine 1 National University of Singapore Sin~apore General Hospital Singapore 0316 Republic of Singapore Dr Hiroto Shimojo Director Department of Enteroviruses National Institute of Health Kamiosaki, Shinagawa-ku Tokyo 141 Japan
15 Annex 2
Dr Tao Yixun Shanghai Medical Laboratory 3/120 Tai An Road Shanghai 200031 People's Republic of China Dr Michitami Yano Director Institute of Clinical Research Na~asaki Chuo National Hospital Nasasaki Japan Dr Zhang Quanvi Chan~chun Institute of Biological Products Changchun People's Republic of China Dr Zhao Kai National Vaccine and Serum Institute Beijing People's Republic of China Dr Zheng Lijun Department of Hygiene and Epidemic Prevention Ministry of Public Health Beijing People's Republic of China
2.
CONSULTANTS
Dr Nakao Ishida Professor and Chairman Department of Bacteriology Tohoku University School of Medicine 2-1 Seiryomachi Sendai 980 Japan
16 Annex 2
Dr Toshitsu~u Oda Director National Medical Center, Japan 1-21-1 Toyama, Shinjuku-ku Tokyo 162 Japan
3.
OBSERVERS
Dr Fukusaburo Hamada The Chemo-Sero-Therapeutic Research Institute 668 Okubo Shimizu Kumamoto 860 Japan Dr M. Nishida Managing Director Central Research Laboratories The Green Cross Corporation 1-15-1 Imabashi, Higashi-ku Osaka 542 Japan Dr Hideo Matsuzawa Ministry of Health and Welfare 1-2-2, Kasumigaseki Chiyoda-ku Tokyo 100 Japan Dr Takashi Takahashi Head of Hepatitis Research Unit The Kitasato Institute 5-9-1 Shirokane, Minato-ku Tokyo 108 Japan
17
Annex 2
4.
SECRETARIAT
Dr Fakhry Assaad Director Division of Communicable Diseases WHO Headquarters Geneva Dr Yun~ Han Paik Chief Research Promotion and Development WHO Re~ional Office for the Western Pacific Manila Dr Otakar Sobeslavsky Medical Officer Virus Diseases Unit WHO Headquarters Geneva Dr Takusei Umenai Re~ional Adviser in Communicable Dis.eases WHO Regional Office , for the Western Pacific Manila