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(WP)CDS(S)/ICP/CDS/Oll
14 March 1988 ENGLISH ONLY
REPORT ~RKING
GROUP ON HEPATITIS B
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Convened by the REGIONAL OFFICE FOR THE WESTERN PACIFIC OF THE WORLD HEALTH ORGANIZATION Seoul, Republic of Korea 24-26 August 1987
Not for sale Printed and distributed by the Regional Office for the Western Pacific of the World Health Organization Manila, Philippines March 1988 WHO/\"P!-UI LU\HAK's' \t1:ilii::1. t 'I~iiipplnes
II NOTE The views expressed in this report are those of the members of the Working Group on Hepatitis B and do not necessarily reflect the policies of the World Health Organization.
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This report has been prepared by the Regional Office for the Western Pacific of the World Health Organization for governments of Member States in the Region and for those who participated in the Working Group on Hepatitis B which was held in Seoul, Republic of Korea, from 24 to 26 August 1987.
CONTENTS
1.
INTRODUCTION OBJECTIVES
1
2. 3.
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1 1
INCREASED AVAILABILITY OF HB VACCINE DECREASED COST OF HB VACCINE REVISION OF WHO GUIDELINES FOR PRODUCTION OF HB VACCINE ALTERNATIVE APPROACHES TO THE PRODUCTION OF HB VACCINE OTHER ISSUES CONCERNED WITH VACCINE PRODUCTION DELIVERY OF HB VACCINE 8.1 8.2 Il\UIIunization schedules ••••••••••••••••••••••••••••••••••• Delivery systems .. ... ... . ........................ ...... . .
4. 5.
2 2
6.
3 4 4 4 5 5
7. 8.
9.
RECOMMENDATIONS
ANNEX 1 - AGENDA ANNEX 2 - FINAL LIST OF MEMBERS, OBSERVERS, CONSULTANTS AND SECRETARIAT • • • • • • • • • • • • • • • . . • . • • • • • • • • . • • • • • • • • •
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1.
INTRODUCTION
A meeting of the Working Group on Hepatitis was convened in Seoul, Republic of Korea, from 24 to 26 August 1987. The members were welcomed by Dr H. Nakajima, Regional Director, WHO Regional Office for the Western Pacific. Dr When Kook Chung was elected Chairman, Dr E.O. Domingo, Vice-Chairman and Dr I. Gust, Rapporteur.
2.
OBJECTIVES
The objectives of the Working Group were: (1) to review the status of the large-scale local production of hepatitis B vaccine and the role of international collaboration in improving HB vaccine supply and distribution; (2) to consolidate hepatitis B immunization strategies in order to facilitate their integration into the activities of the expanded programme on immunization; and (3) vaccine. to review progress In the development of recombinant DNA/HB
3.
INCREASED AVAILABILITY OF HB VACCINE
In the past four years, increased quantities of hepatitis B vaccine have become available in the Region. In collaboration with WHO and Japan, a technical cooperation scheme for the local production of plasma-derived hepatitis B vaccine in four production centres was developed in China. About 9 million doses were produced in 1986 and 18 million in 1987. In the South Pacific, WHO, in collaboration with Japan, has established a collection system for high titre HBsAg plasma. The plasma is sent to Japan for processing into HB vaccine and the vaccine is returned to the countries. The efforts of local vaccine manufacturers have also resulted In increased production of HB vaccine. Currently in the Western Pacific Region, plasma-derived vaccines are being produced by four laboratories in China (Beijing, Shanghai, Langzhou and Changchun), three in Japan (Japanese Green Cross, Kitasato Institute, Chemo-serotherapeutic Institute) and two in the Republic of Korea (Korean Green Cross, Cheil Sugar Company). In addition, Singapore produces vaccine locally under licence. Fiji, Samoa and Tonga are included under the WHO and Japan collaborative scheme for the collection and eventual processing of high titre HBsAg plasma into HB vaccine. At global level, other manufacturers located in Europe and the United States of America are producing plasma-derived hepatitis vaccine.
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There is no reason to believe that the expansion of production facilities is complete as at least eight other groups are currently working towards the development and licensing of hepatitis B vaccines produced by recombinant DNA technology in the world. Although some of these are likely to drop out along the way, the Working Group is convinced that with adequate planning, the Western Pacific Region could be self-sufficient in HB vaccine by 1995.
4.
DECREASED COST OF HB VACCINE
Perhaps the most significant advance in this field in the last year has been the reduction in cost of the vaccine, particularly when large orders are placed (for public sector programmes) and purchasing involves competitive tendering. At least, two companies are currently planning to supply HB vaccine to the public sector at about US$2.00 a dose ($1.00 per dose for newborn babies).
5.
REVISION OF WHO GUIDELINES FOR PRODUCTION OF HB VACCINE
In May 1987, WHO organized a meeting at the National Institute for Biological Standardization in London to review the existing guidelines for production of HB vaccine and determine whether the original criteria should be modified to take into account new knowledge and the excellent safety record of all currently licensed vaccines. The Group noted that plasma-derived hepatitis B vaCClnes are safe and that no serious side effects have been noted. In particular, no cases of AIDS have been attributed to the vaccine. There are now over 12 licensed manufacturers of plasma-derived hepatitis B vaccines globally. These vaccines have been manufactured, utilizing a variety of biochemical and biophysical procedures for purification and inactivation; but, regardless of procedures utilized, these vaccines have been shown to be highly immunogenic and efficacious. The Group recommended revisions of the current WHO requirements in regard to several important items. (1) Purity
The Group noted that plasma-derived vaccines should be pure enough to be safe, and that arbitrary specification of degree of purity was no longer appropriate. (2) Inactivation
The Group noted that the inactivation procedure or procedures utilized should be capable of inactivating agents found in human blood and that arbitrary specification of the nature or number of procedures to be utilized is no longer required.
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(3)
Chimpanzee safety test
The Group recommended that, after a chimpanzee safety test has been performed on five consecutive lots of a newly developed vaccine, additional chimpanzee safety tests on additional lots are no longer required. (4) HIV testing
The Group recommended that plasma used as starting material for vaccine production be free of HIV, as determined by an appropriate serological test. A draft of these revised requirements is now being reviewed, in anticipation of applied adoption by the WHO Expert Committee on Biological Standardization in December· 1987.
6.
ALTERNATIVE APPROACHES TO THE PRODUCTION OF HB VACCINE
Initial shortages in the supply of HB vaccines and the high cost of the early vaccines, together with concerns about the safety of products derived from human plasma, has led a number of manufacturers to develop HB vaccines using recombinant DNA technology. HBsAg has been expressed in a number of systems, the most widely used being yeast (5. cerevisiae) and mammalian cells (Chinese hamster ovary) and insect cells.- At least two such vaccines (produced in yeast cells) have now been licensed for use in man. In practice, these vaccines contain a product HBsAg, which is closely related but not identical to the HBsAg particles produced as a result of natural infection. Despite minor biochemical differences, the particles appear to be immunologically indistinguishable and have comparable antigenicity and efficacy to standard plasma-derived vaccines. Although much attention has been placed on the importance of pre-S proteins in induction of immunity, there is no convincing evidence that vaccines containing this protein are more effective than those that do not have. Although DNA vaccines were originally considered to offer significant advantages in yield (and, hence, in price), this has not proved to be the case. Expressed HBsAg is found within the transformed cells and associated with cell membranes and can only be recovered after the cells are lyzed and subjected to lengthy and expensive purification procedures. At the moment, recombinant DNA HB vaccines offer no significant advantages over plasma-derived vaccines. Public health providers should not hesitate to utilize plasma-derived vaccines. All the currently licensed vaccines are safe, antigenic and of proven efficacy.
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7.
OTHER ISSUES CONCERNED WITH VACCINE PRODUCTION
While there has been marked improvement in the quality of vaccines produced in the Region, some countries require assistance to ensure that their vaccines are produced by internationally accepted codes of good manufacturing practice and to ensure that internal and external quality control programme and licensing practices are strengthened. WHO can playa useful role in this process by the provision of consultants and by developing institutional linkages. In some countries, the production of the vaccine is considerably less than the capacity of the existing plant. WHO should work with national health authorities to define the limiting factors and make the production process more efficient.
8.
DELIVERY OF HB VACCINE
8.1
Immunization schedules
Many different schedules have been studied in the Region. The results of these studies are difficult to compare since they involve vaccines produced by different processes (with varying degrees of purity and content of HBsAg) evaluated under a variety of conditions. A few studies have been undertaken, in which several vaccines are evaluated for antigenicity and efficacy in the same population. Notwithstanding these limitations, it seems that the most important factor, which determines the efficacy of HB vaccines in preventing transmission of infection from carrier mothers to their newborn babies, IS the timing of the first and second doses of the vaccine. There is considerable evidence to show that the best results are obtained when the first dose of vaccine is given within 24 hours of birth, and the second about a month later. Considerable latitude exists in the timing of the third dose (with some recommending that it be given one month later, others five months later), so that immunization schedules can be adapted to fit in with local delivery systems. Currently, much work is being undertaken to devise ways in which the HB vaccine can be integrated into the expanded programme on immunization without the need for additional contacts with the child. Further work needs to be done to determine whether it is possible to combine several vaccines (e.g., DPT, hepatitis B), in a single vial, thus reducing the number of injections needed to deliver each vaccine. To promote acceptance of the value of immunization, particularly by women who have no formal education, practical health education measures designed to change their behaviour need be devised.
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8.2
Delivery systems
The Working Group considered that, in the near fllture, access to low-priced HBV vaccine may no longer be the major factor limiting the development of hepatitis 'B control programmes in the Region, and that Member States should begin to focus their attention on developing adequate delivery systems. They noted that, while a few countries are now producing several million doses of the vaccine per year, distribution is not being undertaken on the basis of the greatest need. The Group urged Member States to review their policies covering the distribution of the vaccine and to ensure that, whe're supplies are limited, the vaccine is used where it will be of greatest benefit. The Group believes that the major challenge for WHO and its Member States is to develop efficient systems of vaccine delivery, and, Ln particular, to integrate them with the expanded programme on immunization. It is important to address such issues as stability of HS vaccine under field conditions or to work with manufacturers to develop and field test vaccines which will withstand extremes of temperature. It is important to address such issues as the stability of the HS vaccine, particularly its ability to withstand extremes of temperature under field conditions. It is also essential to work with local health workers and vaccinators not only to develop more effective ways of vaccine delivery but also to improve their performance in this regard. The Group suggested that these issues can best be addressed by model immunization projects in selected sites, such as in the southern provinces of China, where HB infection is hyperendemic and the incidence of long-term sequelae is well documented.
9.
RECOMMENDATIONS
The Group made the following recommendat ions; (1) WIIO should encourage Member States to review the use of HB vaccine in their countries to ensure that it is consistent with their own policies and the WHO strategy for control of hepatitis B.
(2) In most countries the most cost-effective manner of reducing HB infection is immunization of net4born babies; immunization should be extended to older children where appropriate. (3) WHO should support Member States to define the problems which limit current production processes. In order to overcome these barriers: (a) Studies shollld continue to determine the optimal dose and schedule of immunization, the stability of vaccines and duration of immunity under field conditions.
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(b) Greater emphasis should be placed on establishing efficient delivery systems and integrating hepatitis B vaccine into the expanded programme on immunization (EPI). In particular, pilot vaccination projects should be undertaken in several countries to evaluate alternative systems for efficient vaccine delivery in both rural and urban populations. These studies should include populations in which the majority of children are born at home. (c) Only one sterile syringe and needle should be used for each injection. Sate storage should be made available and instructions provided in the proper disposal of needles and injection equipment. (d) Screening ot blood donors of HBsAg (and anti-HB) should be encouraged a~ blood transfusion is an important means of transmission of infection in some endemic areas. (e) Some latitude may exist in the timing of the second and subsequent doses provided the first dose is administered as soon as possible after birth. (f) The schedule used in any country should be based on experience with the particular vaccine and in general should be the least costly regimen which induces acceptable levels of anti-HBs in the target population. (4) Member States are urged to strengthen efforts to educate policy-makers, the medical profession and the public on the importance of HB infection, its mode of transmission and the opportunity for control, stressing in particular, the importance of immunization in infancy.
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ANNEX 1
AGENDA
1. 2. 3. 4. 5. 6. 7. 8. 9.
Registration Opening Ceremony Large-scale local production of hepatitis B vaCC1ne 1n China Immunization against hepatitis B in Long Ahn County High-titre HBsAg plasma collection in Fiji and Tonga Hepatitis immunization strategies Overview of the development of recombinant DNA/HB vaccine Drafting of recommendations Finalization of recommendations Closing Ceremony
10.
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ANNEX 2
FINAL LIST OF MEMBERS, OBSERVERS, CONSULTANTS AND SECRETARIAT
1. AUSTRALIA Dr Ian D. Gust Director Virus Laboratory Fairfield Hospital Yarra Bend Road Fairfield Victoria 3078
MEMBERS
CHINA
Professor Zhang Quanyi Director Changchun Institute of Biological Products Changchun Dr Guo Shengq i Director Department of Hepatitis Shanghai Institute of Biological Products Shanghai Professor Yin Suiya Director Lanzhou Institute of Biological Products Lanzhou Professor Zhao Kai Beijing Institute of Biological Products Beijing Professor Li Hemin Honorary Director National Institute for the Control of Pharmaceutical and Biological Products Beijing Dr Liu Lihua sichuan Provincial Epidemic Prevention Station Chengdu
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Annex 2
FIJI
Dr Laijia Matadradra Seruvatu Consultant Pathologist Colonial War Memorial Hospital Suva Dr Pierre Coursaget Laboratoire de Microbiologie Faculte de Pharmacie 2 bis, boulevard Tonnelle 37042 Tours Cedex Dr Michitami Yano Director Department of Clinical Research Nagasaki Chuo National Hospital 1001-1 Kubara 2-chome Omura City Nagasaki 856 Dr Takashi Takahashi Vice Director Research Centre for Liver Disease The Kitasato Institute 5-9-1 Shirokane, Minato-ku Tokyo 108 Dr Tatsuo Miyamura National Institute of Health 10-35 Kamiosaki, 2-chome Sh inagawa-ku Tokyo
FRANCE
JAPAN
NEW ZEALAND
Mr Alexander Milne Director Hepatitis Research Unit Whakatane Hospital P.o. Box 241 Whakatane Dr Ernesto o. Domingo Associate Dean College of Medicine Team Leader, Liver Study Group University of the Philippines System Health Sciences Center 547 Pedro Gil Manila 2801
PHILIPPINES
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Annex 2
REPUBLIC OF KOREA
Dr Moon-Shik Kim Director Division of Preventive Medicine Ministry of Health and Social Affairs Seoul Mr Hak-Kyoon Shin Chief Division of Enteric Virus Department of Virology National Institute of Health Seoul
SINGAPORE
Dr Goh Kee Tai Head Quarantine and Epidemiology Department Ministry of the Environment 40 Scotts Road, 22nd Storey Environment Building Singapore 0922 Dr Sioeli Tilitili Puloka Chief Medical Officer-In-Charge Public Health Division Ministry of Health c/o Vaiola Hospital P.O. Box 59 Nuku'alofa Dr P. Beasley University of Texas Health Science Center Houston Texas Dr J.E. Maynard Assistant Director Medical Science, DVD Centers for Disease Control Atlanta, Georgia 30333
TONGA
UNITED STATES OF AMERICA
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Annex 2
2. JAPAN
OBSERVERS
Mr Hideo Fukushima Senior Manager Pharmaceuticals Development Department Mitsubishi Chemical Industries Tokyo Dr Kyong-Ho Kim Director Mogam Bio-Technology Research Institute 729 So cho Dong Kangnam Ku ~ Mr Byong-Hoon Park Technical Manager Pharmaceutical Division Cheil Sugar Co., Ltd. 24-6 Moonbae Dong Yongsan Ku Seoul
REPUBLIC OF KOREA
THAILAND
Professor T. Chainuvati, M.D. Division of Gastroenterology Siriraj Hospital Mahidol University Bangkoknoi Bangkok 10700 Dr Seung-Il Shin President Eugene Tech International, Inc. 4 Pearl Court, Allendale New Jersev , 07401
UNITED STATES OF AMERICA
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Annex 2
3.
CONSULTANTS
Dr Kusuya Nishioka Vice Director The Japanese Red Cross Central Blood Centre 1-31, Hiroo 4-chome, Shibuya-Ku Tokyo 150 Japan Dr Whan Kook Chung Department of Internal Medicine St Mary's Hospital Catholic University Medical College No. 62 Yoido-dong Youngdeungpo-ku Seoul ~lic of Korea
4.
SECRETARIAT
Dr Y. Ghendon Medical Officer Microbiology and Immunology Support Services WHO Headquarters Geneva Dr Sujarti Jatanasen Acting Regional Adviser in Communicable Diseases WHO Regional Office for South-East Asia New Delhi Dr Takusei Umenai Director Disease Prevention and Control WHO Regional Office for the Western Pacific United Nations Avenue Manila Philippines Mr Bo Simonsson EPI Consultant WHO Regional Office for the Western Pacific United Nations Avenue Manila Philippines