WHO/V&B/02.02 ORIGINAL: ENGLISH. Vaccines, Immunization and Biologicals: Strategy. Vaccines and Biologicals. World Health Organization WHO

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1 Document1 17/3/03 12:04 pm Page 2 WHO/V&B/02.02 ORIGINAL: ENGLISH Vaccines, Immunization and Biologicals: Strategy Vaccines and Biologicals World Health Organization WHO

2 WHO/V&B/02.02 ORIGINAL: ENGLISH Vaccines, Immunization and Biologicals Strategy WHO Vaccines and Biologicals World Health Organization

3 The Department of Vaccines and Biologicals thanks the donors partners whose unspecified financial support during has made the production of this publication possible. Ordering code: WHO/V&B/02.02 Printed: March 2003 This publication is available on the Internet at: Copies may be requested from: World Health Organization Department of Vaccines and Biologicals CH-1211 Geneva 27, Switzerland Fax: vaccines@who.int World Health Organization 2002 All rights reserved. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: ; fax: ; bookorders@who.int). Requests for permission to reproduce or translate WHO publications whether for sale or for noncommercial distribution should be addressed to Publications, at the above address (fax: ; permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitat-ion of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. Cover Photos: top-philippe Blanc, bottom-irene R Lengui/L IV Design & Layout by L IV Com Sàrl, Morges, Switzerland ii

4 CONTENTS ABBREVIATIONS INTRODUCTION 1 V&B approach 1 V&B objectives 1 V&B structure 3 V&B role in GAVI 4 TARGET ONE 5 Preclinically evaluate new vaccines and delivery systems and prepare their clinical evaluation Improved tuberculosis vaccine New parenteral and oral Shigella vaccines A safe and effective dengue vaccine Vaccines against acute respiratory infections Novel vaccine delivery systems 8 TARGET TWO 10 Clinically evaluate vaccines for use in developing countries Pneumococcal vaccines Meningococcal vaccines against serogroups A,C,Y,W Serogroup B meningococcal vaccines Vaccine against enterotoxigenic Escherichia coli (ETEC) Cholera and typhoid vaccines Second-generation Japanese encephalitis vaccine Human papillomavirus vaccine Rotavirus vaccine HIV/AIDS vaccines 18 v VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY TARGET THREE 20 Accelerate the introduction of licensed new and underutilized vaccines A high-quality global supply of new vaccines Technology development initiatives to increase access to new vaccines Strategies to decrease financial barriers to the introduction of new vaccines Tools, materials and methods to support decision-making on immunization Technical support for new vaccine introduction Adequate demand forecasting to ensure appropriate production capacity for priority vaccines Combination vaccines 25 TARGET FOUR 27 Assess, apply and promote relevant new technologies and methods for the standardization and control of biologicals Coordination of regulatory research through the Expert Committee on Biological Standardization New and updated recommendations for the production and control of biological products International reference materials for biological substances used in medicines 29 iii

5 CONTENTS TARGET FIVE 30 Assure adequate supply and quality of all vaccines delivered by national immunization services up to and including the time of administration Effective and sustainable logistics systems for vaccine distribution High-quality, global supply of vaccines used in routine immunization services Promote an effective vaccine regulation system 33 TARGET SIX 35 Establish a comprehensive system to ensure the safety of all immunizations given by national immunization services Assurance of vaccine safety through quality control procedures and quality specifications Tools to ensure vaccine quality and safety up to vaccine administration Safe and efficient vaccine administration and disposal technologies Mechanisms to monitor and respond to adverse events following immunization 39 TARGET SEVEN 40 Strengthening key immunization functions and public health managerial capacity at national and district levels Improve efficiency and access to immunization services, particularly by building on the experiences of polio eradication Strengthen human and institutional resources through management and technical training Global, national and regional monitoring and assessment systems Enhance advocacy, information, and social mobilization for immunization 43 TARGET EIGHT 44 Certify all WHO regions as polio-free in Polio eradication: Global coordination and strategic planning Polio eradication: Strategy implementation Polio eradication: Optimizing the impact on health systems Post-certification: Polio immunization policies Polio eradication: Resource mobilization, advocacy, communications Polio eradication: Effective administration 54 TARGET NINE 56 Define and implement control and elimination strategies for priority diseases and conditions that are vaccine preventable Reduce measles mortality and achieve regional elimination goals Accelerated control and elimination of maternal and neonatal tetanus Improve control of yellow fever and other diseases of regional significance Accelerated control and elimination of vitamin A deficiency Adequate demand and capacity data for vaccines used in accelerated immunization strategies and epidemic control 62 iv

6 ABBREVIATIONS AD auto-disable (syringes) AEFI adverse events following immunization AFP acute flaccid paralysis CDC Centers for Disease Control and Prevention (USA) CRS congenital rubella syndrome DT diphtheria tetanus (vaccine) DTwP diphtheria tetanus, whole cell pertussis DOMI diseases of the most impoverished (countries) DTP3 third dose of the diphtheria tetanus pertussis combined vaccine ETEC enterotoxigenic Escherichia coli GAS group A streptococcus GAVI Global Alliance for Vaccines and Immunization GTN Global Training Network HepB hepatitis B vaccine Hib Haemophilus influenzae type b Hib3 third dose of Hib vaccine HPV human papillomavirus HVI HIV Vaccine Initiative (WHO) HVTN HIV Vaccine Trial Network IAVI International AIDS Vaccine Initiative ICC interagency coordinating committee ICG interagency coordinating group IPV inactivated polio vaccine IVI International Vaccines Institute IVR Initiative for Vaccine Research (WHO) JE Japanese encephalitis MMR measles mumps rubella (vaccine) MNT maternal and neonatal tetanus NRA national regulatory authority NID national immunization day OPV oral polio vaccine PATH Program for Appropriate Technology in Health PEI Global Polio Eradication Initiative RAT rapid assessment tool R&D research and development RSV respiratory synctial virus SAGE Strategic Advisory Group of Experts SIA supplementary immunization activities SIGN Safe Injections Global Network TB tuberculosis TCG Global Technical Consultative Group TT tetanus toxoid (vaccine) VAD vitamin A deficiency V&B Department of Vaccines and Biologicals (WHO) VDPV vaccine-derived polioviruses VVM vaccine vial monitor YF yellow fever VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY v

7 INTRODUCTION INTRODUCTION V&B Mission: A world in which all people at risk are protected against vaccine-preventable diseases The Vaccines, Immunization and Biologicals Strategy describes the current work and future direction of the Department of Vaccines and Biologicals (V&B). The strategy is grouped into nine targets, each associated with an indicator against which progress is measured. Under each of the nine main targets, a number of products are identified for achievement. All activities of V&B are directed towards fulfilling these products and ultimately, the nine targets. Over the plan s timeframe, significant progress will be marked by the milestones that are accomplished, charting the success of V&B s implementation. This structure links directly to WHO s principal financial planning tool the Programme Budget which reflects the same objectives and expected results on a biennial basis, and illustrates the agreed allocation of WHO s financial resources by geographical area. Centers for Disease Control and Prevention (CDC), and the Joint United Nations Programme on HIV/AIDS (UNAIDS), and of course the Global Alliance for Vaccines and Immunization (GAVI). V&B objectives Over 36 million children born every year still do not have access to immunization services. Millions of children have no access to vaccines that are routinely given to children in the industrialized world, and a lack of financial resources continues to impede the introduction of new vaccines to low-income countries. Figure 1: 36 million children not immunized (DTP3), Best estimate to reach 100% coverage Western Pacific (5.2) African (11.9) The Strategy follows on from previous plans, adapting individual products to the changing trends in global public health priorities, but broadly maintaining the directions mapped out in the previous strategy for The Strategy is an essential planning and communications tool for the department. An updated version of the Strategy will be produced at the end of 2004 for the period South-East Asian (12.5) Americas (1.6) V&B approach Due to the magnitude of global health challenges and the resources needed in fulfilling V&B s mission, WHO can achieve very little as a single entity. Partnership is an essential aspect of almost every area of V&B s work. Global health partners come from many different spheres of action, and the relationships take many different forms. Critical major partners in the bilateral and multinational arena are development agencies and international organizations such as UNICEF, the World Bank, USAID, the Program for Appropriate Technology in Health, the Red Cross and Red Crescent Societies, the Children s Vaccine Program at PATH, the Vaccine Fund, the United Nations Foundation, the Rockefeller Foundation, Rotary International, the Source: WHO/UNICEF, September 2002 European (0.6) Eastern Mediterranean (4.4) While great strides have been made in strengthening immunization services worldwide and decreasing the detrimental impact of vaccine-preventable diseases as demonstrated by the enormous progress made in polio eradication over the past biennium significant problems remain to be tackled. To address these challenges, V&B has organized its activities to cover objectives in three broad areas: innovation, immunization systems, and accelerated disease control. Of the nine targets encompassed under these objectives, extra emphasis is placed upon three cross-cutting targets, termed Priority Projects: Accelerated Vaccine Introduction, Safety of Immunization, and Polio 1 Available from the Department of Vaccines and Biologicals on request. 1

8 Eradication. All teams within V&B contribute to the activities of these priority projects. Innovation Activities in this area target the research, development and introduction of new vaccines, biologicals or immunization-related strategies and technologies that reduce the burden of diseases of public health importance. The Initiative for Vaccine Research (IVR) is the new embodiment of the vaccine research and development (R&D) efforts at WHO, including the Special Programme for Research and Training in Tropical Diseases (TDR) and UNAIDS. Its mandate is to provide a centralized source of leadership, vision, priority setting, and coordination with (or coordination of) worldwide vaccine R&D efforts. IVR will be the key body responsible for drawing together the necessary expertise and efforts to address both worldwide priorities and gaps. The R&D activities of IVR span the vaccine pipeline from preclinical to clinical, to post-licensing issues. The disease focus is likewise broad, including platform technologies (such as improved delivery systems), global targets (HIV, malaria, TB, rotavirus), diseases selected as priorities by the GAVI partners (pneumococcal pneumonia, meningococcus meningitis, rotavirus diarrhoea), and diseases receiving lower priority, for example leishmaniasis, schistosomiasis, dengue, shigellosis and cervical cancer associated with HPV infection. IVR s role is not primary research but prioritization, coordination, and guidance. Disease burden studies, capacity building, and clinical trial facilitation are three areas that will profit from links forged through IVR. Priority target Accelerated vaccine introduction This project focuses on accelerating the introduction of new and underused vaccines, with prominence placed upon the introduction of vaccines against hepatitis B and Haemophilus influenzae type B (Hib). V&B s activities are targeted at critical junctures of the vaccine continuum. This includes evaluation of vaccine efficacy, development of guidelines and standard-setting for immunological and biochemical assays, disease burden and cost-effectiveness studies, vaccine supply and financing issues, and monitoring and surveillance activities. Ongoing technical support is provided for effective and sustainable vaccine introduction into immunization services. By 2002, hepatitis B vaccine was used routinely in 152 countries and Hib vaccine in 94 countries, as compared to 116 and 63 respectively, in The success of the project has been boosted with the 2000 launch of GAVI and the Vaccine Fund. Immunization systems National immunization services have been established in all countries around the globe, but many are stagnating in their performance. The greatest challenge for V&B is to build upon the successes established under polio eradication and to capitalize on the opportunity of GAVI to rejuvenate the national infrastructures required to deliver vaccines. V&B efforts strive toward ensuring that immunization systems are strengthened to reach all children in a manner that is technically sound, safe and sustainable. Priority target Immunization safety This priority project targets an important challenge for immunization services: ensuring and monitoring the safety of all aspects of immunization including vaccine quality, vaccine administration and the disposal of sharps and encouraging an overall culture of safety. Despite the increasing number of countries reporting use of auto-disable (AD) syringes for immunizations, unsafe immunization injections remain a significant problem, especially in non-developed countries (i.e. least-developed countries, developing countries and economies in transition). As at December 2001, 18 countries had undertaken an injection safety assessment using a standard tool. Only 20% of non-developed countries are estimated to have sterile immunization injection practices, however, for the majority (80%) the status is unknown. Accelerated disease control Vaccine-preventable diseases are the cause of over 2 million infant deaths per year, the majority of which occur in the poorest countries. Approximately deaths are still due to measles alone, despite the existence of a very effective, low-cost vaccine which has been available for decades. Globally, million children under five years of age are deficient in vitamin A, thereby facing an increased risk of death from measles and diarrhoea. Through a range of activities, V&B works to reduce the harmful impact of vaccinepreventable diseases. In certain instances, its efforts are more intensely concentrated on supplementing routine immunization services with additional activities to achieve control, elimination or eradication goals. Priority target Polio eradication The Global Polio Eradication Initiative has made remarkable advances in recent years. After intensive activities to immunize every child, the incidence of polio fell from over 7000 cases in 1999 to only 480 in Three WHO regions are now certified as poliofree (Region of the Americas, Europe and Western Pacific) and circulation of indigenous poliovirus is limited to ten countries. While the disease is now on the brink of eradication, even more VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 2

9 INTRODUCTION rigorous efforts are now demanded to reach the goal of certifying the world as polio-free in 2005.The global approach must be wellcoordinated, with careful strategic planning and implementation, and must be supported by adequate resources. The monumental efforts required to complete the polio end-game of containment, certification and cessation of oral polio vaccine are not to be underestimated. V&B comprises five functional groups, each of which focuses on a particular aspect of the vaccine continuum. Every group is headed by a coordinator, or a director in the case of IVR, and supports the overall objectives of the Department. In the case of the priority projects, teams work collaboratively to achieve the ultimate target, drawing on the whole skill-base of the group. V&B structure Vaccines and Biologicals (V&B) is a component of the Health Technology and Pharmaceuticals cluster (HTP). Norms and Standards: Quality Assurance and Safety of Biologicals (QSB) Team mission: to ensure the quality and safety of vaccines and other biological medicines through the development and establishment of global norms and standards. Figure 2: The Department of Vaccines and Biologicals (V&B) VACCINES AND BIOLOGICALS (V&B) FUNCTIONAL GROUPS Norms and Standards Research and Development Assessment and Monitoring Technologies and Financing (All the above groups contribute to the nine targets below) Immunization Strategies OBJECTIVES INNOVATION IMMUNIZATION SYSTEMS ACCELERATED DISEASE CONTROL TARGET ONE: TARGET TWO: Preclinically evaluate new vaccines and delivery systems and prepare their clinical evaluation Clinically evaluate vaccines for use in developing countries project! TARGET THREE: Accelerate the introduction of licensed new and underutilized vaccines Priority TARGET FOUR: Assess, apply and promote relevant new technologies and methods for the standardization and control of biologicals TARGET FIVE: Assure adequate supply and quality of all vaccines delivered by national immunization services up to and including the time of administration project! TARGET SIX: Establish a comprehensive system to ensure the safety of all immunizations given Priority by national immunization services TARGET SEVEN: Strengthening key immunization functions and public health managerial capacity at national and district levels project! TARGET EIGHT: Certify all WHO regions as polio-free in 2005 Priority TARGET NINE: Define and implement control and elimination strategies for priority diseases and conditions that are vaccine preventable WHO 3

10 Research and Development: Initiative for Vaccine Research (IVR) The mission of the Initiative for Vaccine Research and its three teams dealing with research and development of viral, bacterial and parasitic vaccines is: to coordinate and facilitate the research and development of new vaccines and immunization-related technologies. Assessment and Monitoring: Vaccine Assessment and Monitoring (VAM) Team mission: to assess the strategies and activities for reducing morbidity and mortality of vaccinepreventable diseases. Technologies and Financing: Access to Technologies (ATT) Team mission: to reduce financial and technical barriers to the introduction of new and existing vaccines and immunization-related technologies. Immunization Strategies: Expanded Programme on Immunization (EPI) Team mission: to develop policies and strategies for maximizing the use of vaccines of public health importance and their delivery; to support regions and countries in acquiring the necessary skills, competence and infrastructure to implement these policies and strategies and achieve disease control/elimination and eradication objectives. V&B role in GAVI Launched in January 2000, GAVI has revitalized international commitment toward securing the right of every child to a healthy start, via immunization. Two years after its inception, GAVI partners through the Vaccine Fund have made tremendous progress in strengthening immunization systems and supporting the introduction of new and underutilized vaccines in a number of the world s poorest countries. V&B is WHO s operating arm in GAVI. The Department contributes directly to GAVI objectives, which aim to: improve access to sustainable immunization services; expand the use of existing safe and cost-effective vaccines; accelerate the development and introduction of new vaccines; accelerate research and development efforts for vaccines and related products specifically needed by developing countries, particularly vaccines against HIV/AIDS, malaria and tuberculosis; and make immunization coverage a centrepiece in the design and assessment of international development efforts, including deep debt relief. By the end of 2001, 88 applications had been approved from 52 countries for new vaccines, strengthening immunization systems or immunization safety. The total five-year financial commitment exceeds US$ 800 million. The secretariats for the GAVI Task Force on Research and Development and Implementation Task Force are both housed under and co-chaired by V&B. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 4

11 TARGET ONE 1 TARGET ONE Preclinically evaluate new vaccines and delivery systems and prepare their clinical evaluation Critical indicator: Number of targeted vaccine candidates and vaccine delivery systems of public health importance that advance to phase I clinical trials Globally, the development of new vaccines is a complex and expensive process that involves many partners in both the public and private sectors. In budgetary terms, WHO is only a minor player in vaccine R&D, as compared to classical research funding agencies, philanthropic organizations and the vaccine industry. Nevertheless, in a field that is largely driven by expectations of significant economic returns on the one hand and by academia on the other, WHO has an important role to play: assuring that at least a significant part of the vaccine R&D effort is directed towards the development of safe, effective and affordable vaccines for the poor countries of the South. The reasons why progress with some of these products has been slow are manifold and include scientific challenges, unclear epidemiology, or lack of commercial incentives. In accordance with the different nature of these hurdles, WHO has developed, together with international partners, a specific R&D agenda, tailor-made for each pathogen in order to remove obstacles and thus accelerate the availability of the final products. These global agendas clearly identify areas of WHO s comparative advantage. Examples in the preclinical area include in particular filling knowledge gaps through targeted research projects, the establishment of networks for preclinical evaluation of vaccine candidates under standard conditions, the preparation of guidelines, and the provision of reference reagents and clinical isolates. Table 1 represents, in broad terms, the global state of development of each vaccine type, and indicates the predominant area of activities for each product. The research and development of vaccines can include various candidates for the same product in different development phases at any given time. The table reflects the primary targets of V&B s activities. Table 1: of V&B's activities for the preclinical evaluation of new vaccines TARGET ONE P1 Product/vaccine against: Tuberculosis: Global state of development V&B activities Epidemiological studies Early preclinical studies Predominant area of activities Late preclinical studies Phase I Phase II Phase III Phase IV post-licensure P2 Sigella: Global state of development V&B activities P3 Dengue: Global state of development V&B activities P4 Acute respiratory infections Respiratory syncytial virus: Global state of development V&B activities P5 Novel vaccine delivery systems: Global state of development V&B activities 5

12 Improved tuberculosis vaccine To accelerate the development of an improved vaccine against tuberculosis. Despite substantial international efforts to treat active cases chemotherapeutically and to immunize against the disease using the BCG vaccine, tuberculosis (TB) continues to create an overwhelming disease burden in many global communities. It causes about 8 million new cases every year and is one of the leading infectious causes of death worldwide. One-third of the world s population is infected with Mycobacterium tuberculosis rising to two-thirds in certain geographic areas, such as Africa, where 25% to 75% of people infected with the TB bacillus are also HIV-positive, this being the single most important risk factor for infection to develop into clinical disease. Tuberculosis not only affects public health in these communities but also has a major impact on society and on the economy, especially of developing nations. The BCG vaccine, although it is efficacious against extra-pulmonary complications of TB in children, is highly variable in its protective efficacy against pulmonary disease, the main problem in adolescents and adults. Substantial progress in genomics and proteomics, immunology and the vaccinology of tuberculosis has been made in the last years. This has resulted in the development of prospective TB vaccine candidates including live, adjuvanted subunit, DNA, rationally attenuated M. tuberculosis and improved BCG that have shown promise in preclinical studies. A few of these candidates are likely to be investigated in human clinical studies in the near future with WHO providing support through site identification/characterization, and capacity building for infrastructure/research. By 2002: A standardized reference control vaccine and a standardized challenge strain of M. tuberculosis are available. Product profiles for new TB vaccines are defined. By 2003: 1.1 Two trial sites are selected and upgraded to be able to perform a phase III clinical trial of a TB vaccine candidate. Two primate facilities are validated for testing of tuberculosis vaccine candidates. Results of a study are published modelling the health economic parameters of a new TB vaccine, in particular its cost-effectiveness. Molecular characterization is completed of BCG seeds and vaccines. By 2004: At least one immunological indicator of vaccinemediated protection against tuberculosis is standardized. 1 Two phase I/II clinical trials of a tuberculosis vaccine are completed. By 2005: Two clinical sites are ready to start phase III efficacy testing of a new tuberculosis vaccine candidate. 1.2 New parenteral and oral Shigella vaccines To accelerate development of a vaccine against Shigella infection. It has been estimated that more than 163 million episodes of endemic shigellosis occur each year in developing countries. Approximately 1.1 million of these cases are fatal. In developing countries, the major burden of Shigella infection is among children less than five years of age. There is room for optimism, however, as advances in biotechnology have enabled research institutions in the public sector to develop a new generation of candidate vaccines that show great promise for the prevention of shigellosis. However, no manufacturer is currently developing a vaccine against this pathogen. The public sector needs to give special attention to this orphan vaccine, establishing some sort of partnership to accelerate its availability and introduction in developing countries. There are two principal approaches in the development of vaccines against shigellosis: (i) subunit vaccines based on either conjugates containing the O-specific polysaccharide of Shigella lypopolysaccharide (LPS) or ribosomes extracted from atoxic lipid A Shigella strains, in collaboration with the programme against diseases of the most impoverished (DOMI); and (ii) live bacteria with genetically engineered mutations in a virulence gene and/or a synthetic pathway gene. For example, an oral live attenuated candidate (SC602) has already been VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 2 The aim of these studies is to define a true surrogate of protection, but the scientific feasibility is uncertain for all diseases where protection strongly depends on T-cell immune responses, as is the case for tuberculosis. 6

13 TARGET ONE evaluated in phase I and II trials with volunteers in North America and in Bangladesh and a phase III trial will be undertaken in a developing country setting, monitored by WHO through participation in the data safety and monitoring board. By 2002: An immunological correlate of protection against shigellosis is defined. Vaccine testing sites are selected in different developing countries for phase III trials. By 2003: Ribosomal vaccine is prepared using standard good manufacturing practices from atoxic lipid A Shigella strains. An analysis is completed of private-public partnerships for accelerated vaccine introduction in developing countries. By 2004: A phase III trial of an oral live attenuated candidate vaccine (SC602) is completed in a developing country setting. A phase I/II trial is completed with ribosomal vaccine in a developing country. By 2005: A phase III trial will be ongoing in a developing country with ribosomal vaccine. 1.3 A safe and effective dengue vaccine To promote the development of a vaccine against all four dengue serotypes to reduce the risk of acquiring dengue haemorrhagic fever. Every year, 50 million people throughout the world are affected by dengue fever or the more serious dengue haemorrhagic fever (to which children are especially vulnerable), which can lead to shock syndrome and death. Each year, more than half a million people are hospitalized and approximately die from this disease. As there is no drug to cure dengue, and the prevention of human disease by vector control is impractical, immunization is a key control measure. An immense array of possibilities for vaccine development opened up with the sequencing of the flavivirus genome during the 1980s along with the identification of the genes encoding the proteins relevant for eliciting an immune response. Dengue vaccine development has focused on two main approaches. The first is the serial passaging of a virus in tissue culture (or animal tissues) and examination of viral properties at specific passage levels. The second approach uses different biotechnological techniques including recombinant and subunit vaccines, DNA and infectious clone technologies. Over the period of the Plan, WHO will support phase I clinical trials of dengue and yellow fever vaccines with scientific advice, in 2004 adding monitoring of the clinical trials of the dengue vaccine candidates. By 2002: Neutralizing antibody responses to candidate dengue vaccines are standardized. Phase I clinical trials of chimeric vaccines (dengue/ yellow fever) are completed. By 2003: A preclinical study in monkeys to evaluate the efficacy against all four serotypes of a selected tetravalent vaccine is completed. Immunological correlates of protection are defined. An analysis is completed of public-private partnerships for accelerated vaccine introduction in developing countries. By 2004: A phase II clinical trial of tetravalent live attenuated dengue vaccine is completed in a developing country setting. A phase I/II clinical trial of chimeric dengue candidate vaccine is completed in a developing country setting. Studies on the mechanism of immune enhancement and neutralization escape are completed. By 2005: A tetravalent live attenuated vaccine is submitted to phase III clinical trials. 7

14 1.4 Vaccines against acute respiratory infections To accelerate the development and evaluation of candidate vaccines against respiratory syncytial virus (RSV) and group A streptococcus (GAS) in developing countries. RSV is the most important viral agent causing acute respiratory infection in children worldwide. Almost all children are infected within the first two years of life. In developed countries, about 1 3% of infections require hospitalization; mortality is uncommon except in children with underlying cardiac or respiratory disease. Dual infection with RSV and bacterial pathogens is common in developing countries and often results in more severe disease. An effective vaccine against RSV would potentially prevent considerable child mortality and morbidity. In the 1970s, trials were conducted with a candidate RSV vaccine containing formalin-inactivated virions. However, the vaccine actually brought about severe disease on exposure to wild RSV and some vaccinated infants died. The result was a complete cessation in RSV vaccine development for some years. More recent vaccine development has proceeded very cautiously. Currently two vaccines are undergoing phase I trials. A subunit vaccine is being evaluated in high-risk seropositive children and in the elderly; it is unlikely that the vaccine will be used in seronegative infants for fear of enhanced disease. A live attenuated vaccine was shown to be immunogenic in seronegative infants, but produced unacceptable nasal congestion in the youngest infants. Further attenuated vaccine strains are in development. There is considerable support within industry for RSV vaccine development. WHO s role would be to ensure that the disease burden in developing countries is understood and evaluation of suitable candidates in developing countries occurs in parallel with those in developed countries. WHO has sponsored a series of studies to assess the disease burden due to RSV in Indonesia, Mozambique, Nigeria and South Africa using a generic protocol. Another group in Guinea Bissau has received support to analyse data from RSV field studies conducted previously. Meetings of the WHO RSV Study Group have also reviewed the status of RSV vaccine development. By 2002: A joint paper is published from the WHO-funded RSV studies in Indonesia, Mozambique, Nigeria and South Africa. By 2003: Methods are developed and data extracted from the literature for estimating the economic and disease burden of RSV. By 2005: An expert review and national consultations are completed for economic and burden estimates related to RSV; estimates are documented and published. 1.5 Novel vaccine delivery systems To prioritize and coordinate the development of novel vaccine delivery systems and formulations that are safer and more effective than the existing ones. The scale of immunization services is expected to rise dramatically in the coming decade, partly due to the increasing number of vaccines used. Inadequate logistics, including cold-chain failures and poor geographical access have historically hampered immunization coverage in developing countries. Rendering vaccines insensitive against exposure to elevated temperatures (or freezing) and reducing the number of immunization contacts is therefore likely to increase the effectiveness of vaccination programmes. Moreover, unsafe injection practices which can lead to the transmission of HIV, hepatitis B, and hepatitis C, could be avoided by vaccine delivery methods such as mucosal or transcutaneous delivery which avoid or substantially reduce the need for traditional syringes. Taken together, all of the above measures have the potential to decrease the barriers often associated with low coverage and unsafe vaccination. WHO has facilitated the development of mucosal vaccine delivery methods, comparison of mucosal adjuvants and the use of transgenic plants as edible vaccines. Transcutaneous delivery and a measles vaccine that can be delivered by aerosol are now being considered. Considerable effort has also been focused upon methods to reduce multidose immunization regimens to a single dose and one candidate completed VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 8

15 TARGET ONE preclinical evaluation. Work will be expanded on novel drying technologies in order to thermostabilize vaccines and eventually take them out of the cold chain. By 2002: Preclinical evaluation of controlled release tetanus toxoid is completed in collaboration with a vaccine manufacturer. A thermostable vaccine candidate is formulated and preclinically tested for viability. Performance specifications and test procedures for new injection and administration devices are available. Evaluation of a measles aerosol and powder vaccines tested on monkeys is completed. By 2003: Bench studies of aerosol measles vaccine are completed. The results of a study to investigate the influence of intestinal barriers on oral antigen uptake and immunogenicity are available. Studies of safety, field performance and user acceptability of jet injectors are completed. By 2004: A phase I/II trial is completed of a novel, nonparenteral vaccine formulation. Phase I/II studies of an aerosol measles vaccine are completed. Studies are completed of safety, field performance and user acceptability of new injection and administration devices. By 2005: A phase I/II trial is completed of the vaccine formulated in a temperature-stable formulation, such as sugar glass or foam. 9

16 2 TARGET TWO Clinically evaluate vaccines for use in developing countries Critical indicator: Number of targeted vaccines entering efficacy trials (phase III) in a developing country where the disease is endemic WHO has a significant role to play in the development of new vaccines: assuring that at least part of the vaccine R&D effort is directed towards the development of safe, effective and affordable vaccines for the poor countries of the South. Some vaccine candidates that would be highly desirable for low-income countries have actually reached quite an advanced stage of development. These are often vaccines that are also useful in developed economies and consequently, their development has been geared to the requirements of these lucrative markets. The challenges here therefore consist of assuring that such vaccines, their composition, formulation, intended mode of delivery, etc., are adequate for developing countries and accessible to them. Together with international Table 2: of V&B's activities for the clinical evaluation of new vaccines TARGET TWO P1 P2 P3 P4 P5 P6 P7 P8 P9 Vaccines against: Pneumococcal disease: Global state of development V&B activities Serogroup A, C, Y and W135 meningitis: Global state of development V&B activities Serogroup B meningitis: Global state of development V&B activities ETEC: Global state of development V&B activities A- Cholera: Global state of development V&B activities B - Typhoid fever: Global state of development V&B activities Japanese Encephalitis: Global state of development V&B activities Human papillomavirus: Global state of development V&B activities Rotavirus: Global state of development V&B activities HIV/AIDS: Global state of development V&B activities Epidemiological studies Early preclinical studies partners, WHO has developed global R&D agendas for each of the pathogens in this category. Examples of WHO activities identified by these agendas to accelerate the availability of the vaccines in the South include demand forecasting through performance of epidemiological studies, promoting, and if necessary initiating, early clinical trials in high-disease-burden countries, supporting in different ways clinical testing, strengthening the function of national regulatory and ethical authorities and developing novel modes of cooperation with vaccine producers that will speed up access to the new product(s) by populations-in-need. Table 2 represents in broad terms the global state of development of each vaccine type, and indicates the primary targets for V&B activities. Predominant area of activities Late preclinical studies Phase I Phase II Phase III Phase IV post-licensure VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 10

17 TARGET TWO 2.1 Pneumococcal vaccines To accelerate the evaluation and use of vaccines currently available and new vaccines against Streptococcus pneumoniae (Pneumococcus) including assurance of appropriate regulatory pathways and of steps to promote equitable access to new products in developing markets. Globally, pneumonia remains a major cause of childhood mortality, accounting for approximately 2 million deaths annually. Most deaths are caused by bacterial pneumonia with Streptococcus pneumoniae and Haemophilus influenzae being the predominant pathogens. Public health strategies have focused on case management using antibiotics. However, increasing rates of resistance to commonly used, inexpensive antibiotics have limited the benefits of this approach. Vaccines against H. influenzae type b (Hib) have been shown to result in a 20% reduction in the incidence of radiological pneumonia. An effective vaccine against pneumococcus is likely to have an even greater impact on pneumonia and consequently on childhood mortality in developing countries. A pneumococcal polysaccharide vaccine has been available for several years but has limitations, both in terms of its inability to induce immunological memory and its poor immunogenicity in infants and young children. A 7-valent pneumococcal conjugate vaccine was recently licensed in the United States and several other industrialized countries. In a study conducted in the United States, this vaccine provided more than 90% efficacy against invasive pneumococcal disease (IPD). However, the 7-valent vaccine lacks some serotypes that are important in many developing countries. A trial of the 7-valent vaccine in the high-risk native American population in the United States and of the 9-valent vaccine in South Africa have recently been completed. Both studies showed high vaccine efficacy against IPD; the South African trial showed that the vaccine had close to 60% efficacy in HIV-infected children. Trials of the 9- and 11-valent vaccines are under way in the Gambia and the Philippines, respectively, and are expected to be completed by Large-scale phase III trials of 9- and 11-valent candidate vaccines are under way in developing countries, with scientific advice and monitoring to be provided by WHO. There are some issues regarding regulatory requirements for licensure of new pneumococcal conjugate vaccines. First, the scientific issues related to interference when the vaccine is administered in combination with other antigens. Second, regulatory issues regarding the registration of a vaccine in the country of manufacture if, for epidemiological reasons, there is no reason to use that vaccine in that country. Alternative pathways, such as licensing by another competent regulatory agency, then need to be considered. Discussions have been initiated with the FDA, the European Agency for the Evaluation of Medicinal Products (EMEA), and key developing country regulatory authorities to start this process. Work has also begun, in collaboration with the GAVI Financing Task Force, to ensure that the appropriate demand projections and financial incentives will be available to manufacturers to ensure development of and access to these vaccines. By 2002: Work is completed on standardized interpretation of chest radiographs and training and self-assessment software is developed and distributed. A global agenda is prepared for the development and introduction of pneumococcal conjugate vaccines and work is commenced on urgent priority activities. A menu is planned of end-points and methods to generate epidemiological data on pneumococcal infections essential for vaccine introduction. A regulatory pathway is established to allow development of pneumococcal conjugate vaccines that may be appropriate to markets outside, but not in the country of manufacture. Cost-effectiveness estimates are finalized for introducing pneumococcal vaccine in South Africa. By 2003: Recommendations are developed for quality control and production of pneumococcal conjugate vaccines, based on the recommendations for Hib and serogroup C meningococcal vaccines. Field-testing is completed of the generic pneumonia disease burden protocol and a protocol for use in other developing country sites is available. Safety and immunogenicity studies of maternal (PS vaccine) and neonatal (conjugate vaccine) immunization are completed. Pneumococcal cps gene sequence data are generated to enable a PCR-based assay for the detection of multiple pneumococcal serotypes in nasopharyngeal swab specimens to be developed, thereby facilitating surveillance for serotype replacements. 11

18 Advisory groups to determine optimal vaccination schedules for pneumococcal vaccines are established in three regions. Cost-effectiveness estimates of pneumococcal vaccine are available from at least two additional developing countries. By 2004: Trials of two representative conjugate vaccines measuring the efficacy against endpoints of public health importance are completed in at least two developing country sites. Pneumonia disease burden studies are completed in at least two developing country sites. Immunogenicity studies of alternative vaccination regimens appropriate to developing countries are completed. Standardization and validation of serological assays to measure immune responses for pneumococcal conjugate vaccines are available. A head-to-head comparison of antibody responses to various conjugate vaccine candidates in a developing country population is completed. Two-year post-vaccine introduction surveillance is completed in at least one developing country site and in one high-risk indigenous population. A vaccine introduction plan for pneumococcal conjugate vaccines is developed. A mechanism is designed to ensure an adequate supply of pneumococcal conjugate vaccines and an advocacy plan is elaborated. Regulatory pathways in principle are available for all pneumococcal vaccines at the clinical stage, including regulatory oversight to ensure quality and consistency at international level and appropriate epidemiological analysis of clinical data. By 2005: Pneumonia disease burden data are available in at least five developing countries. An efficacy study of pneumococcal conjugate vaccine with mortality as an end-point is completed in the Gambia. Acceptable production sources are available for this product, ensuring access to developing country markets. Phase II studies with at least one candidate protein vaccine are completed. 2.2 Meningococcal vaccines against serogroups A,C,Y,W135 To support the development, clinical evaluation, licensing and introduction of serogroup A containing meningococcal conjugate vaccine in the meningitis belt countries in Africa. All countries suffer from endemic meningococcal disease, primarily in children under the age of five years, at an annual attack rate of around 1 to 3 cases per population. In addition, serogroup A meningococcal disease occurs in explosive epidemics predominantly throughout what is known as the meningitis belt of sub-saharan Africa. The belt stretches from Ethiopia in the east, to the Gambia and Senegal in the west, with a population at risk of over 200 million. Countries within the meningitis belt suffer from recurrent meningococcal epidemics, often in irregular cycles every 5 to 12 years. Epidemics are mostly caused by serogroup A strains, although serogroup C strains also have been responsible for outbreaks. Recently, resurgence of serogroup W135 has also caused concerns. The size of these epidemics can be enormous with attack rates in the order of 400 to 800 cases per population. In individual communities, attack rates as high as 1 in 10 of the population have been reported. A vaccine that can provide long-term protection in children (routine immunization) and adults ( catch-up strategy), that can be administered at the same time as other routine vaccinations and which significantly reduces carriage could prevent epidemics and eliminate the need for chaotic emergency interventions. There are good reasons to believe that serogroup A meningococcal conjugate vaccine could do just that. The technology to produce safe and effective meningococcal conjugate vaccine for Africa has already been available for more than 10 years. Successful serogroup A/C conjugate prototypes previously evaluated in African infants were highly immunogenic, and others against meningococcal C disease have already been shown to be effective in the United Kingdom. Yet, by 1999, vaccine manufacturers halted the development of serogroup A/C meningococcal conjugate vaccine. There are several reasons to explain this. Firstly, serogroup A meningococcus is unusual in industrialized countries. The disease caused by serogroup A is largely limited to sub-saharan Africa and some areas in the Eastern Mediterranean region and Asia. Secondly, the market niche further shrunk when some European countries VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 12

19 TARGET TWO decided to license a monovalent serogroup C meningococcal conjugate vaccine. Finally, the high cost of increasing conjugate vaccine capacity and of vaccine development, and the pressure to produce conjugate vaccines with high profitability, have combined to discourage the development of Africa-specific conjugate meningococcal vaccine. A new approach was needed to deal effectively with the public health problem of epidemic meningococcal disease in sub-saharan Africa. To this end the Meningitis Vaccine Project has been created, a partnership between WHO and the Program for Appropriate Technology in Health (PATH). It has as its central goal the elimination of epidemic meningococcal disease in the African meningitis belt through the introduction and widespread use of conjugate meningococcal vaccine. A US$ 70 million grant from the Bill and Melinda Gates Foundation funds the project. By 2002: A contractual relationship is established between WHO/PATH and a vaccine manufacturer for the development and licensing of serogroup A meningococcal conjugate vaccine for Africa is selected. A global development plan for the serogroup A meningococcal conjugate vaccine is written. By 2003: An advocacy plan for the Meningitis Vaccine Project is elaborated. A regulatory strategy is developed. Specifications and quality control procedures of serogroup A conjugate vaccine are completed based on the recommendations established for serogroup C conjugate vaccine. The importance of serogroup W135 as a potential epidemic strain in the meningitis belt is evaluated. Results from social and economic impact studies of meningococcal disease epidemics in sub-saharan Africa are available. By 2004: Standardization and validation of serological assays to measure immune responses for serogroup A meningococcal conjugate vaccine are completed. A regional-based plan for introduction of meningococcal conjugate vaccine introduction is developed with WHO s African and Eastern Mediterranean regional offices. Phase I safety and immunogenicity study (healthy adults volunteers) of serogroup A meningococcal conjugate vaccine is finished in India. A forecasting demand model for this vaccine is developed in collaboration with countries, and communicated to manufacturer to ensure adequate capacity. By 2005: Clinical trials (phases II and III) starting in Africa. A financing plan for A conjugate vaccine is agreed and implemented in target countries. 2.3 Serogroup B meningococcal vaccines To accelerate the development, clinical evaluation, licensing and introduction of an effective serogroup B vaccine. Serogroup B meningococcus accounts for around half of the cases of meningococcal disease in most developed and middle-income countries. It has also been responsible for outbreaks in Europe, the United States and Latin America. In contrast to epidemics of group A and C disease, which usually resolve in one to three years, the epidemics caused by serogroup B meningococci are characterized by the disease s slow and gradual development, long-duration (approximately 10 years), high clonality and moderate incidence rates (10 to 20 cases per population compared to the 100 to 200 cases per population typically reported in the serogroup A meningococcal epidemics of the meningitis-belt countries). Even using antimicrobial therapy about 10% of patients die and up to 20% suffer from long-term sequelae. For the last 10 years New Zealand has experienced a group B meningococcal disease epidemic with countrywide incidence rates of up to 10 times the background incidence which shows no signs of abating. Serogroup B capsular polysaccharides are poorly immunogenic and attempts to develop polysaccharidebased conjugated vaccines have so far failed. There are additional safety concerns due to potential autoimmune reactions against polysaccharide terminals present in neural cell-adhesion molecules in the fetus. Most efforts have therefore concentrated on the development of vaccines targeting other antigens, specifically outer membrane proteins. Two outer membrane vesicle vaccines were developed in Norway and Cuba in response to epidemics and the latter has been licensed and administered to around 40 million individuals mostly in Latin American countries. These vaccines are 13

20 safe; efficacy ranges from 56% 85%. However, they have important drawbacks: their efficacy in children under four years of age is questionable, they do not elicit high immune responses against heterologous strains and they have limited duration of protection. The epidemiology of group B disease allows for the development of a tailor-made vaccine targeting the different epidemic strains as they occur. This option is currently being evaluated in New Zealand, with WHO support, as a means of epidemic control. By 2003: Recommendations for quality control and production of serogroup B outer membrane vesicle-based vaccines are developed. A WHO-sponsored expert panel evaluates results of the immunogenicity trials in New Zealand and advises on the appropriateness of the implementation programme upon request by the Government. Serum bactericidal assays are standardized and validated for serogroup B outer membrane vesiclebased vaccines. By 2004: Correlates of protection related to serogroup B meningococci are established. Vaccine against enterotoxigenic Escherichia coli (ETEC) To accelerate the development of new enterotoxigenic Escherichia coli (ETEC). In developing countries, diarrhoeal disease caused by ETEC is responsible for an estimated deaths a year among children under five years of age: almost 10% 20% of the global total of deaths from diarrhoeal disease are in this age group. The disease is poorly reported and detailed surveillance data are difficult to obtain. Both live and inactivated oral vaccine candidates have been developed against ETEC and their evaluation and introduction in high-risk populations need to be expedited. The inactivated oral vaccine is the more advanced candidate. By 2002: An update on disease burden estimates is published. An oral live attenuated ETEC vaccine is ready for phase I clinical trial and correlates of protection are defined. Evaluation of immune responses and immunological memory after immunization in a phase II trial with the inactivated oral ETEC vaccine is completed. Evaluation of different methods to determine mucosal immune responses against the ETEC vaccine is completed. By 2003: A phase III trial of inactivated oral vaccine is completed. A live oral attenuated vaccine is evaluated for safety and immunogenicity in a phase II trial in a developing country. By 2004: A live oral attenuated vaccine is evaluated in a phase II trial. By 2005: A phase III trial of the live oral attenuated vaccine will be ongoing in a developing country. Cholera and typhoid vaccines To finalize the development of new cholera and typhoid vaccines. Every year, cholera affects over 5.5 million people and is responsible for about deaths. Over one-fifth of the deaths occur in children under five years of age. Recognizing the limitations of the old parenteral cholera vaccines, WHO has promoted the development and introduction of new candidates. Salmonella typhi, the etiologic agent that causes typhoid fever, affects 16 million people every year and claims at least lives annually. A new improved vaccine is urgently needed as Salmonella is becoming progressively more resistant to drugs. WHO s cholera and typhoid fever vaccine activities have been conducted since 2000 in collaboration with the International Vaccines Institute (IVI), Seoul, Republic of Korea, through the programme on diseases of the most impoverished (DOMI). VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 14

21 TARGET TWO Several new types of cholera vaccines containing O1 and O139 serogroups have been developed and are being evaluated in clinical trials in developing countries. Guidelines for the production and control of inactivated oral cholera vaccines are now completed. Two safe and effective vaccines against typhoid fever are currently licensed and available. The oral Ty21a and the parenteral Vi polyssacharide vaccines are very well tolerated and confer a good level of protection in school-age children, lasting several years. Recently a Vi conjugate vaccine evaluated in South-East Asia provided more than 91% protection in children from two to five years of age. By 2002: Human challenge data obtained with O139 serogroup cholera vaccine are published. A new oral cholera vaccine (Peru15) is evaluated in a phase I trial in Bangladesh. A large effectiveness trial of a locally produced bivalent O1+O139 cholera vaccine in Viet Nam is finalized. A document on typhoid fever diagnosis, treatment, and epidemic preparedness is completed and published. By 2003: A phase II trial of Peru-15 cholera vaccine in Bangladesh is completed. By 2004: Results of the phase III trial cholera vaccine in Viet Nam are published. A phase III trial of Peru-15 cholera vaccine in Bangladesh is completed. annual at-risk birth cohort of 70 million. A very limited amount of internationally licensed inactivated vaccine is produced. Although JE viral transmission, in principle, can be modulated by interventions aimed at the mosquito vector and vertebrate amplifying hosts, the prevention of human disease by vector control or pig immunization is impractical and cannot reduce risk to the same extent as human immunization. Only mouse-brain-derived JE vaccines are currently licensed for international use. However, there is a shortfall between global requirements and the current maximum potential production of 30 million doses per year. The large-scale deployment of a live-attenuated vaccine in China has resulted in the successful control of JE in that country. Before this vaccine could be made available outside China, however, its production and regulation would have to undergo the rigorous evaluation required by WHO prequalification 3 process to ensure that it conformed to international standards. Guidelines for the production and control of the live attenuated SA JE vaccine have already been developed and adopted by the Expert Committee for Biological Standardization in Promising second-generation JE candidate vaccines (inactivated cell-derived, chimeric YF/JE and DNA vaccines) are now under development although licensing is unlikely in less than five years. By 2002: Vaccine-testing areas are selected in a range of developing countries. International standards for human anti-je antibodies and an international standard reference for JE antigen are developed. 2.6 Second-generation Japanese encephalitis vaccine To ensure that the live attenuated vaccine presently being made in China meets international standards and to support the development of a second-generation Japanese encephalitis vaccine. Approximately 3.2 billion people live in countries at risk for Japanese encephalitis (JE), representing an By 2003: Phase I/II trial of chimeric YF/JE vaccine in a developing country is initiated. By 2004: Evaluation of immunogenicity and safety (phase I/II) of one new JE vaccine in a developing countries is completed. 3 Prequalification is a rigorous and lengthy process. If successful, vaccines can be purchased by UN agencies for global use. A critical component of the prequalification process is a fully functional national regulatory authority. See also section 5.2 High-quality, global supply of vaccines used in routine immunization services. 15

22 2.7 Human papillomavirus vaccine To accelerate the clinical evaluation of HPV VLPs vaccine candidates, with a view to facilitating their introduction in developing countries, and to initiate the development of second generation vaccine candidates for global prevention of cervical cancer. Cervical cancer continues to be a serious public health problem worldwide. Globally women die of cervical cancer each year with the majority of these deaths (80%) occurring in developing countries. Cervical cancer is second to breast cancer in terms of global cancer incidence in women. A causal link between human papillomavirus (HPV) infections and the development of cervical cancer has been established. Genital human papillomavirus (HPV) infections are the most common sexually transmitted viral infections diagnosed in clinical practice. The prevalence of chronic infections in developed countries is estimated at 7% and in developing countries at 15%, equalling a total of 630 million infected people worldwide. Because of its contagious nature, approximately two-thirds of all people who have sexual contact with an infected partner will develop an HPV infection within three months. Seventy per cent of genital HPV infections are subclinical, and do not progress to disease. Although cervical cancer develops in a minority of HPV-infected women with persistent premalignant cervical lesions, it nonetheless represents around new cases identified each year. Over half of these cases occur in Asia. An effective vaccine against the major oncogenic HPV types could have a tremendous impact on the global burden of cervical cancer. This is particularly true for developing countries, where other diagnostic and therapeutic options are often not affordable or are simply unavailable. Recombinant DNA technology is being used to produce subunit vaccine, virus-like particles (VLPs), against the most common oncogenic HPV types, 16 and 18. The encouraging preclinical results obtained in the in vivo testing of HPV VLPs have prompted both commercial and public institutions to pursue the clinical evaluation of these candidate vaccines, mostly focused on studies in the Americas. Results from phase I trials confirmed the safety and tolerability of the recombinant viral proteins and showed excellent immunogenicity. Phase II trials are under way, and preliminary data from the one conducted by the United States NCI show a homogeneous serologic immune response. Phase III trials are starting in the United States and Latin America with the aim of demonstrating efficacy in preventing high-grade cervical lesions in vaccinated women. While the current vaccine candidates are bivalent for the oncogenic HPV types 16 and 18, it may be desirable in future to have vaccines including other types, which are more prevalent in different countries or areas. More epidemiological data and analysis will help with decision-making in this regard. By 2002: Evaluation of reference reagents for HPV diagnostics is completed. Assessment of HPV vaccine production by developing country manufacturers is completed. By 2003: Preclinical development of a multivalent vaccine candidate. By 2004: Phase I clinical evaluation of a mucosal VLP formulation is completed. Epidemiological HPV surveys in Asia and Africa are completed. Production of multivalent vaccine candidates is completed. By 2005: Safety and immunogenicity vaccine studies of a bivalent candidate in Asia are completed. Cohorts for vaccine trials in Africa are established. 2.8 Rotavirus vaccine To accelerate the clinical evaluation of new rotavirus vaccines and to ensure that access and quality issues are considered as early as possible in the development process. Rotavirus is the most common cause of severe diarrhoea in children. In developing countries, rotavirus leads to an estimated to deaths each year, accounting for 20% 25% of all deaths due to diarrhoea and 6% of all deaths among children less than five years of age. In developed countries, VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 16

23 TARGET TWO almost all children are infected by three to five years of age, whereas in developing countries, children are infected in their first two years of life. Usually enteric diseases are prevented through basic sanitary and hygiene measures. However, they have proved to be ineffective in reducing the percentage of diarrhoea due to rotavirus in industrialized countries. In fact, the same percentage of cases is reported in Finland, Sweden or the United States, as in Brazil, China or Indonesia. The first vaccine, licensed in August 1998, was the Rhesus Rotavirus Reassortant Tetravalent Vaccine (RRV-TV), given in three oral doses, one month apart. It provided 85% protection against severe diarrhoea and 56% protection against all diarrhoea due to rotavirus infection. WHO had started phase I evaluation in Bangladesh and in India when this vaccine was withdrawn from routine immunization in the United States in October 1999, due to a suggested association between RRV-TV rotavirus vaccination and the development of intussusception. A WHO meeting was convened in February 2000 to redefine research related to rotavirus in developing countries. Issues related to epidemiology, risk factors, ethics and production were discussed resulting in six major recommendations. Other candidate live attenuated oral vaccines are under development. One is a paediatric strain representing only one serotype. The other is a bovine-based vaccine including several serotypes of rotavirus strain. WHO is partially supporting several projects related to three major activities (i) strain surveillance and disease burden assessment (African and Asian networks); (ii) intussusception estimation; and (iii) new oral candidate vaccine evaluation in Bangladesh, Brazil and South Africa. Several quality and safety issues need attention especially those related to the cell substrates used for production, non-target effects of vaccine in recipients and the standardization of assays, including the development of reference materials. Methods are developed and data extracted from the literature for estimating the economic and disease burden of rotavirus. Information critical to defining technology-sharing agreements is identified and developed for contracts. By 2003: Economic and disease burden estimates for rotavirus are available and documented for expert review and national consultation. The rotavirus rapid assessment tool (RAT) is developed and field-tested. The training curriculum is in place for national regulatory authorities in key developing countries to evaluate preclinical to clinical transition. Recommendations on the production and control of rotavirus vaccine are available. Reference materials for calibrating laboratory assays are available. By 2004: An expert review and national consultation are completed for economic and disease burden estimates related to rotavirus; estimates are documented and published. The rotavirus rapid assessment tool is introduced in regions and countries. Clinical data review committees are in place in key developing countries for all rotavirus products about to enter developing country clinical trials. By 2005: The phase III efficacy trial is completed of at least one second-generation candidate vaccine in the developing world. Regulatory pathways are developed for two rotavirus vaccine products. By 2002: A literature-based global report on acute intussusception in infants and children is published. Data on the safety and immunogenicity of a secondgeneration rotavirus vaccine candidate are available from Bangladesh and South Africa. A generic protocol for the assessment of rotavirus burden is finalized and field-tested. 17

24 2.9 HIV/AIDS vaccines To promote development, facilitate evaluation, and address future availability of preventive HIV vaccines, with a focus on the needs of developing countries. AIDS has only been known about for 20 years yet today it is one of the most damaging infectious diseases. It is the most common cause of death in Africa, and the fourth such cause worldwide. Approximately 3 million people died of AIDS in 2001, placing it above the other two major infectious killers, malaria and tuberculosis. Today, some 40 million people are living with HIV infection or AIDS, 95% of them in developing countries, especially in Africa, which is home to more than 27 million of those infected. Meanwhile, HIV continues to spread through the world. In 2001 alone more than 5 million people became infected with HIV, at a rate of more than new infections each day. A safe, highly effective and affordable preventive vaccine offers the best long-term hope to control the pandemic, especially in developing countries. However, a vaccine cannot be expected to completely replace other preventive interventions, especially if the first generation of vaccines have only modest protective efficacy. These vaccines would need to be delivered as part of comprehensive HIV prevention and care packages, including other health promotion and behavioural interventions. being explored in the laboratory and some are also moving to phase I/II clinical trials. At least two, or perhaps three new phase III trials are expected to be initiated in several developed and developing countries in Numerous institutions are collaborating in the global HIV vaccine effort, including the United States National Institutes of Health, the United States Military HIV Research Programme, the United States Centers for Disease Control and Prevention, the French Agency for Research on AIDS, the European Community, the International AIDS Vaccine Initiative (IAVI), and several others, including the pharmaceutical industry. The urgent need to accelerate the development of an HIV vaccine prompted UNAIDS and WHO to join forces establishing the WHO-UNAIDS HIV Vaccine Initiative (HVI) to boost HIV vaccine efforts, taking advantage of their complementary expertise. The HVI mission is achieved through activities in the following five areas: Guidance and coordination of the international HIV vaccine research and development effort, providing scientific and ethical advice through its international AIDS Vaccine Advisory Committee. Promoting the development of appropriate vaccines for global use, especially in developing countries (although HVI is not directly involved in product development activities, it provides information and advice to vaccine manufacturers, especially in relation to strains to be used to develop candidate vaccines). VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY The first phase I trial of an HIV vaccine was conducted in Subsequently, more than 30 candidate vaccines have been tested in over 60 phase I/II trials, involving approximately healthy volunteers. Most of these trials have been conducted in Europe and the United States but several have also been conducted in developing countries (Brazil, China, Cuba, Haiti, Kenya, Peru, Thailand, Trinidad and Tobago, and Uganda). The first phase III trials began in the United States in 1998 and in Thailand in 1999, to assess the efficacy of the first generation of HIV vaccines (based on the envelope protein, gp120). Definitive results from the United States phase III trial will be available early in 2003, and those from the trial in Thailand in A second phase III trial, using a prime-boost combination (canarypox-hiv vector followed by gp120), is being planned, to start in Thailand in In addition, numerous other HIV vaccine concepts are Facilitating the conduct of clinical trials in developing countries, through research, training, and capacity building. Addressing issues of future access to HIV vaccines. By 2002: Protocols for all international HIV vaccine trials are reviewed by the AIDS Vaccine Advisory Committee (ongoing activity). Comprehensive analysis of the global distribution of HIV-1 subtypes is published (data obtained from research supported by the WHO-UNAIDS Network for HIV Isolation and Characterization). Several training workshops on virus isolation and characterization and vaccine-related immunology conducted in developing countries (an ongoing activity of the WHO-UNAIDS Network for HIV Isolation and Characterization). 18

25 TARGET TWO A WHO-UNAIDS laboratory manual for HIV isolation and characterization is published. The African AIDS Vaccine Programme (AAVP) is launched at an international forum. Regional networking of other countries participating in HIV vaccine trials is initiated (i.e. among Caribbean and Latin American countries). Support is provided for the development and implementation of National AIDS Vaccine Plans in developing countries. Comprehensive analysis is published of policy issues which would guide the introduction and use of future HIV vaccines, as well as estimates of future needs and probable uptake of these vaccines. By 2003: The results from the first phase III HIV vaccine trial (gp120bb in the US) are available (HVI contribution: review of protocol, scientific oversight, and planning for future use if efficacy is demonstrated). Phase III trial of a prime-boost combination vaccine (canarypox-hiv E vector plus gp120 E) is initiated in Thailand (HVI contribution: selection and provision of the subtype E strain used to develop the canarypox- HIV vector, and scientific and ethical review of the protocol). The AAVP initiates the process of strengthening sites for HIV vaccine trials in several African countries (HVI contribution: technical and financial support). By 2004: The results from the second phase III HIV vaccine trial (gp120 BE in Thailand) are available (HVI contribution: establishment of the vaccine cohort, support for corresponding phase I trial, protocol review and continuous scientific and ethical oversight, planning for future use if efficacy is demonstrated). Two (or three) new phase III trials are launched in several industrialized and developing countries, by the NIH-sponsored HIV Vaccine Trial Network (HVTN) and possibly by IAVI (HVI contribution: strengthening sites in Africa, protocol review, scientific oversight of HVTN-sponsored trials). By 2005: Continuation of the above activities. 19

26 3 TARGET THREE Accelerate the introduction of licensed new and underutilized vaccines Critical indicator: Proportion of countries that have introduced hepatitis B vaccine As at March 2002, 152 of the 214 (71%) reporting countries had introduced hepatitis B vaccine into their routine immunization schedule, up from 116 countries in This accounts for approximately 57% of the annual surviving birth cohort of all 214 countries. Figure 3: Global status of countries using HepB vaccine in their national immunization system, March 2002 (126 countries introduced) HepB3 > 80% (62 countries or 32%) HepB3 > 80% (32 countries or 17%) HepB vaccine introduced but no coverage data reported (32 countries or 16%) HepB vaccine not introduced (65 countries or 35%) Source: WHO/UNICEF 20

27 TARGET THREE Critical indicator: Proportion of countries that have introduced Hib vaccine As at March 2002, 94 of 214 (43.9%) reporting countries had introduced Haemophilus influenzae type b (Hib) vaccine into their routine infant immunization schedule, up from 63 countries in This accounts for approximately 19% of the annual surviving birth cohorts of all 214 nations. Figure 4: Global status of countries using Hib vaccine in their national immunization system, March (25 countries introduced) Hib vaccine introduced but no coverage data reported (25 countries) Hib vaccine not introduced (166 countries) 2001 (77 countries introduced 40%) Hib3 > 50% (42 countries) Hib3 > 50% (4 countries) Hib vaccine introduced but no coverage data reported (31 countries) Hib vaccine not introduced (114 countries) Source: WHO/UNICEF Overall status In addition to HepB and Hib vaccines, six countries in the African Region received support from the Vaccine Fund to introduce yellow fever into their routine immunization services. About 21 countries are now in various stages of introducing the new vaccines with support from the Vaccine Fund. Rapid assessments of the introduction process were carried out in a few of these countries. Some of the key lessons learned are: The introduction of a new vaccine is an opportunity to strengthen the routine immunization service. Although countries are beginning to address some weaknesses in their national programmes, increased financial and technical support is still needed to allow many of the countries to address the issues adequately. Cold chain and logistics management have become even more important. The new vaccines require special care, particularly with regard to preventing them from freezing. In many countries, there is little evidence of logistics management skills and the cold chain is either inadequate or functioning poorly. In addition, the cost of new vaccines makes vaccine wastage a matter of great concern. Critical considerations for the introduction of new vaccines are therefore to strengthen both the cold chain and logistics management. The sudden shortage of combination vaccines has resulted in some delay in the uptake of new vaccines. If the international capacity to meet the demand for combination vaccines is not addressed adequately, this situation will have a negative impact on the future potential for new vaccine introduction. 21

28 3.1 A high-quality global supply of new vaccines Specific indicator: Percentage of candidate vaccines for which the evaluation process is completed within one year To assess the acceptability in principle of priority vaccines for United Nations agency purchase. The list of vaccines prequalified for acceptability in principle for UN agency purchase 4 is used not only by UN agencies but also by many countries and many procurement agencies as acceptable sources for procurement. In addition to the vaccines particularly highlighted under target 3 (hepatitis B and Hib), the vaccines to be assessed for prequalification under this target will include those that are the subject of priority activities in other parts of WHO. These may include new combination vaccines containing hepatitis B and Hib, cholera and typhoid vaccines, and rabies vaccines, for example. Based on an overall list of priority vaccines for this purpose, candidates will be evaluated for prequalification on request by manufacturers, and evaluation will proceed in line with the date of request and priority for the programme. WHO will work on this activity in partnership with the UNICEF Supply Division and the PAHO Revolving Fund to ensure that all vaccines procured meet internationally agreed standards of quality. Financing for this activity comes from the manufacturers through a system of user fees, and from UNICEF in connection with follow-up of problems encountered in field use of vaccines. By 2002 and continuing each year: 100% of all priority vaccines for which applications are submitted are evaluated within one year. 3.2 Technology development initiatives to increase access to new vaccines Specific indicator: Proportion of developing-country manufacturers having membership in the Developing Country Vaccine Manufacturers Network. To promote innovative technology development initiatives that increase the ability of domestic manufacturers to access new production technologies. Manufacturers in developing countries have previously been a source of vaccines for local needs, focusing mainly on traditional products such as BCG and tetanus toxoid. However, increasingly, these manufacturers are taking steps to enter the international market and are developing mechanisms to access new technologies to make them globally competitive. WHO s work in this context has first focused on ensuring that manufacturers were effectively regulated by a functional national regulatory authority, and second, on making sure that these manufacturers had in place long-term goals (to ensure meeting of international quality standards, to develop reliable and consistent vaccine supplies, and to be able to access new technologies so as to manage change). Formerly, these attributes were measured by an assessment of manufacturer viability. 11 of 52 members of the network with 21 manufacturers participating in network activities. In the period there have been many changes in the supply of vaccine from domestic manufacturers. Following a meeting hosted by WHO in March 2000 manufacturers which were already supplying vaccines to the international market led a drive to form a Developing Country Vaccine Manufacturers Network. The Network has now met several times. It is organized with the clear goals of assuring availability of technology for developing-market vaccines to qualifying developing-country manufacturers, and representation on the GAVI Board. The requirements for full membership in the Network reflect attributes of manufacturer viability. Thus, membership is now an indicator of progress in improving the viability of this segment of the vaccine production structure. By 2003 and continuing: All developing country vaccine manufacturers are members of the Developing Country Vaccine Manufacturers Network and/or are have products that are prequalified for UN agency purchase. By 2005: At least one new developing-market vaccine is produced by a developing-country vaccine manufacturer and acceptable for international use. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY

29 TARGET THREE 3.3 Strategies to decrease financial barriers to the introduction of new vaccines Specific indicators: Proportion of countries with a multi-year immunization plan which includes a line item for purchase of new vaccines (hepatitis B and/or Hib) Proportion of countries in which 80% or more of their multi-year plan budgets are financed To provide support to countries in ways that will improve their capacity to sustainably finance introduction of new vaccines. New vaccines now available for national immunization services are potentially very cost-effective for developing countries; however, they are generally more expensive to buy than traditional vaccines. With the availability of financing through the Vaccine Fund to 74 of the poorest countries, countries can now receive funding awards to pay for some of these products over a five-year period. They must, however, develop plans to take over the financing eventually. GAVI partners are developing information packages and support to countries to improve mobilization and use of resources for vaccine purchase and to support immunization services in general. A June 2001 meeting hosted by WHO and sponsored by the GAVI Financing Task Force examined potential indicators of financial sustainability and the components of sustainable financing plans. These indicators are being refined. Guidelines for developing financial sustainability plans were drafted and fieldtested in the first quarter of 2002 in Cambodia and Ghana. These guidelines will be shared and further tested in the 13 countries to have received support from the Vaccine Fund and will be finalized at the end of In April 2002, the financial sustainability diagnostic took (FSDT) was developed to be used by countries as a self-assessment tool to monitor progress towards financial sustainability. The FSDT is included as an annex to the guidelines and will be tested in the 13 countries together with the guidelines. Specific information for countries on various financing mechanisms are being developed in the form of a Briefcase on financing options which is now available. Countries eligible for vaccine purchase support through the Global Fund are expected to develop sustainable financing plans with the support of their respective interagency coordinating committees. Wealthier countries will also be eligible for technical support including access to the Briefcase, budgeting and resource mobilization assistance, and monitoring of achievements in financial sustainability. This work will be done in partnership with the GAVI Financing Task Force. By 2002: The briefcase of financing options is published and available to countries. Guidelines for financial sustainability plans are published and support is provided to all countries to develop them. By 2003: 50% of countries have a line item in their multi-year plans for vaccine purchase. Support is provided to all countries to develop financial sustainability plans. By 2005: 80% of countries have a line item in their multi-year plans for vaccine purchase. 80% of countries have mobilized funding for at least 80% of their multi-year plan budgets. 3.4 Tools, materials and methods to support decision-making on immunization Specific indicators: Proportion of countries for which final estimates of hepatitis B burden have been reviewed by national authorities. Proportion of countries for which final estimates of Hib burden have been reviewed by national authorities. Proportion of countries using Hib vaccine with satisfactory surveillance performance indicators and reporting of Hib disease. To provide methods and materials that will provide necessary information to policy-makers about issues related to new vaccine introduction, disease burden and cost effectiveness. Certain licensed, but underused vaccines (e.g. hepatitis B, Hib) could have great public health impact in many countries. Major obstacles to introduction of new and underused vaccines include lack of diseaseburden data, poor information about the utility of the vaccines, evidence of cost-effectiveness and lack of 23

30 guidance on how to introduce specific vaccines. New methods and materials are needed to support the collection of this critical information. Surveillance guidelines have been prepared for monitoring of Hib and hepatitis B diseases. WHO has sponsored six studies (Bulgaria, Dominican Republic, Guatemala, India, Poland and Russian Federation) to assess the Hib burden using a standard protocol. Five of these have been published or submitted for publication. A guide for costing new vaccine introduction has been published, as has a guide for rapid assessment of Hib disease. Guidelines for introduction of Hib and hepatitis B vaccine have been developed and are now being implemented. Work has begun on guidelines for measurement of the impact of introducing hepatitis B vaccine. Finally, WHO is developing global estimates as well as country-specific estimates of the Hib and hepatitis B disease burden and the cost effectiveness of vaccination. By 2002: A protocol is developed for the evaluation of the impact of new vaccine introduction on immunization services. Documented hepatitis B disease burden and vaccine cost-effectiveness estimates (by country, age group and sex) are available for and reviewed by national authorities. Advocacy guidelines are completed for Hib and hepatitis B vaccines. A paper is completed on the lessons learnt from the Hib disease burden studies. The new curriculum for evaluation of clinical trial data is published and training is implemented. A global review of studies on Hib meningitis is published. By 2003: Hib and hepatitis B introduction guidelines are revised in the light of the experience of early introducers. Documented disease burden and cost-effectiveness estimates for Hib (by country, age group and sex) are available and reviewed by national authorities. The protocol to assess the impact of hepatitis B immunization is developed and field-tested. By 2004: Cost-effectiveness estimates for Hib vaccine are available for all regions 3.5 Technical support for new vaccine introduction Specific indicators: Proportion of countries using hepatitis B vaccine in routine infant immunization services achieving HepB3 coverage equal to DTP3. Proportion of countries using Hib in routine infant immunization services achieving Hib3 5 coverage equal to DTP3. Proportion of countries using hepatitis B vaccine that report HepB3 coverage to WHO. Proportion of countries using Hib vaccine that report Hib3 coverage to WHO. To support countries introducing new vaccines into national immunization services. Hepatitis B causes at least deaths each year, primarily from liver cirrhosis and cancer, while Hib is the major cause of bacterial meningitis in children. In 1991, the World Health Assembly recommended routine use of hepatitis B vaccine in all infant immunization services. In 1997, WHO recommended integration of the vaccine against Hib disease into routine infant programmes as appropriate to national capacity and priorities. Currently, 130 countries use a vaccine against hepatitis B and 73 countries vaccinate against Hib as part of their routine infant programmes. Evaluation of programme status, disease burden and financial sustainability is needed before new vaccines are introduced into national programmes. Technical support with introduction, planning and implementation of vaccination programmes is critical for optimal use of these powerful new prevention tools. New vaccine officers have been positioned in each region to facilitate prioritization and implementation of new and underused vaccines. Additional technical support is provided through coordination of input within WHO and from other partners. Areas of activity include incountry disease burden assessment, development of country-specific introduction and training plans, support with initiation of new disease surveillance and coverage monitoring activities, and support of new vaccine training for national regulatory authorities. Since 2000, rapid Hib burden assessments have been performed in 10 countries, a study on costeffectiveness was begun in the Russian Federation alongside a Hib burden study, and training for initiation of bacterial meningitis surveillance in Africa VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 5 Hib3:Third dose of Hib vaccine. 24

31 TARGET THREE has taken place. This work is being done in collaboration with a large number of partners, including the Children s Vaccine Program at PATH; USAID; UNICEF, the World Bank, and CDC. By 2002: Meningitis surveillance and laboratory capacity is established in the African Region with performance monitoring and routine monthly reporting for 50% of participating countries. Disease burden and cost effectiveness data on Hib disease is made available by the Russian Federation. Evaluation of experience with new vaccine introduction is completed in six countries introducing new vaccines through the Vaccine Fund (three for hepatitis B and three for Hib). By 2003: Bacterial meningitis surveillance and laboratory capacity is established in the Eastern Mediterranean Region with performance monitoring. 80% of countries using hepatitis B in routine infant immunization services achieve HepB3 6 coverage equal to DTP3. 80% of countries using Hib in routine infant immunization services achieve Hib3 coverage equal to DTP3. 90% of countries using HepB by 2001 have routine HepB3 coverage reported to WHO. 90% of countries using Hib by 2001 have routine Hib3 coverage reported to WHO. By 2004: Complete evaluation of the impact of Hib vaccine on disease in four countries not using a booster dose of Hib. 3.6 Adequate demand forecasting to ensure appropriate production capacity for priority vaccines Specific indicators: Proportion of priority vaccines for which valid demand forecasts are aggregated and shared with manufacturers. Proportion of priority vaccines for which potential capacity information is collected and regularly updated. To ensure adequate systems for predicting demand and assuring sufficient capacity. Until now WHO has not established a system to centralize global vaccine demand. Adequate estimates of the demand for priority vaccines within routine immunization are needed. This information should be used by purchasing agencies to estimate the supplies required and transmitted to manufacturers in a timely and clear manner to minimize risks to both manufacturers and users. A demand database is being developed through the GAVI Financing Task Force Subgroup on Forecasting. This needs to be supplemented by a database that will aggregate data on potential global capacity as a function of presentation for priority new products. Both databases should provide complementary information that can assess various scenarios for vaccine utilization. By 2002: A database is in place for aggregating global demand and supply for priority vaccines. By The database is maintained and updated at least quarterly. Outputs are shared with and used by countries, manufacturers, and procurement agencies. 3.7 Combination vaccines To ensure that combination vaccines proposed for development meet programmatic objectives and standards of quality, and that those combination vaccines agreed as priorities are available in appropriate quantities at equitable prices. A large number of combination vaccines are now on the market, some of which are not optimally formulated for developing countries. The existence of so many products limits flexibility in the use and availability of products for the developing market because of regulatory, production and pricing decisions. Both countries and manufacturers are requesting more guidance in this area as in the past WHO has not provided clear enough information about combination vaccines Hib3:Third dose of Hib vaccine.

32 Combination vaccines are already in wide use in national immunization services based on DTwP, 7 including DTwP-HepB. There is also the possibility of additional combinations including Hib, and others based on measles vaccines. As new products are developed and come to market, the feasibility is raised of incorporating new antigens into already-existing or new-combination products. Combination vaccines can, in some cases, facilitate the addition of new antigens into a programme. They can also help to minimize negative impacts on cold storage and transport capacity, multiple injections, and exposure to thiomersal, among other things. However, their selection must be made carefully, based on clear epidemiologic and operational criteria. Already the existence of some combinations has limited product selection and availability, and impacted price. By 2002: A position paper outlining the criteria for combination-vaccine selection is developed, agreed by key partners, and disseminated. By 2003: Clear advice on appropriate combination products and a quantification of demand are available for antigens in the clinical stage of development. By 2004: Regulatory pathways for combination vaccines (including clear guidance on formulation when serological correlates of protection are lacking) are available for all combination products proposed. By 2005: New combination vaccines containing antigens in the clinical phase of development are available in adequate quantities at equitable prices for target countries. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 7 DtwP: Diphtheria, tetanus, whole cell pertussis 26

33 TARGET FOUR 4 TARGET FOUR Assess, apply and promote relevant new technologies and methods for the standardization and control of biologicals Critical indicator: Proportion of priority biological medicines for which necessary regulatory research is under way and/or have production and control recommendations consistent with latest scientific developments Priority biological medicines for regulatory research are considered to be: oral poliovirus vaccine neurovirulence testing (8);* standardization of assays for inactivated poliovirus vaccine (8);* master file for WHO Vero cell bank; viral safety and standardization of antivenoms; standards for HIV humoral and cellular immune responses and viral load; standards for gene transfer products; reference materials for standardization of diagnostic assays for transmissible spongiform encephalopathy agents; simplified batch release assays for diphtheria and tetanus containing vaccines; molecular characterization of BCG seeds and vaccines (1);* introduction of modern technologies for control of yellow fever vaccine (6);* reference materials for standardization of rotavirus vaccines (2);* standardization of assays of immune response for pneumococcal vaccines (2)* standardization of assays of immune response for meningococcal A, B and C vaccines (2).* Out of these 15 priority biological medicines, regulatory research, supported by WHO, is under way in 9. Priority biological medicines for new or revised WHO recommendations/guidelines are considered to be: pneumococcal vaccine (2;)* serogroup A meningococcal vaccine (2);* serogroup B protein-based meningococcal vaccines (2);* hepatitis B vaccine; inactivated influenza vaccine; live attenuated rotavirus vaccines (2);* antivenoms; transmissible spongiform encephalopathies and biological medicines; cell substrates for the production of biologicals; preclinical evaluation of vaccines; combination vaccines; stability testing of vaccines; batch release of vaccines; vectored vaccines for prophylactic use. Out of these 14 priorities, work is under way in 7. Critical indicator: Proportion of WHO international biological reference materials issued in the last five years There are 301 different international reference materials in the WHO catalogue. As an indicator of the relevance of these materials to the scientific community the proportion which have been issued in each preceding five-year period will be monitored. * Numbers in brackets refer to other targets in the Strategic Plan to which this activity will contribute. 27

34 4.1 Coordination of regulatory research through the Expert Committee on Biological Standardization To coordinate laboratory studies on a complex array of issues related to the quality and safety of biological products. Biological products, which include vaccines, blood products and biological therapeutics, have historically played a dominant role in improving world health and are expected to make increasingly important contributions to public health in the twentieth century. Recent scientific and technological developments have opened the way to new kinds of products, methods of manufacture, and highly sensitive assay procedures. However, the nature of biologicals, and especially of new vaccines and therapies, raises particular questions regarding standardization and quality control. Those questions relate to efficacy and safety, not only for the individual recipients but also for the population at large. Such advances continue to highlight complex issues surrounding standardization and control which require coordinated research and consideration on an international level. For over 50 years WHO has provided technical leadership on issues related to the quality and safety of biological products. WHO s role is to identify emerging quality and safety issues and to coordinate appropriate laboratory studies. The data generated is used for evidence-based decisions and to develop international consensus. The network of laboratories available for this work needs strengthening to facilitate the expected increased demands in the next few years. The partnerships which will support this are with the two WHO International Laboratories for Biological Standards; the WHO Collaborative Centre on Biological Standardization; national regulatory authorities; and the International Association of Biologics. By 2002: An updated and validated database sufficient for current regulatory purposes is available for the WHO cell bank of Vero cells. A WHO working group on antivenoms is established to coordinate the necessary laboratory studies to improve viral safety and standardization of antivenom products. A WHO working group on reference materials and testing methods is established for biotechnology products. A working group on the standardization and control of vaccines against bioterrorism/biowarfare is established. By 2003: A WHO working group on HIV vaccines is established to review and seek consensus for the standardized measurement of humoral and cellular immune responses and viral load. Laboratory work is completed by a WHO working group on the evaluation of reference materials for standardization of diagnostic procedures for transmissible spongiform encephalopathies. Globally acceptable simplified batch release assays for D and T vaccines, and for vaccine combinations containing these antigens, are available through work coordinated by the WHO working group on potency measurement of D and T vaccines. By 2004: A validated WHO cell bank of MDCK (Madin Darby canine kidney cells) for isolation and production of influenza vaccine is available. A new WHO International Laboratory for Biological Standards is established. By 2005: A potency assay for acellular pertussis vaccine suitable for regulatory use is available. 4.2 New and updated recommendations for the production and control of biological products To provide timely and authoritative international consensus on procedures and criteria needed to assure the quality and safety of biologicals. Recommendations and guidelines on production and control of biological medicines published by WHO are intended to be scientific and advisory in nature. They constitute guidance for national regulatory authorities and manufacturers of biological products. They are adopted by many such authorities as definitive national requirements or as the basis of such national regulations. They often contain useful additional guidance notes. WHO recommendations and guidelines on production and control of biological medicines are established by the Expert Committee on Biological Standardization after extensive consultation with national regulatory authorities, and the scientific community and manufacturers. They reflect the international consensus at that time. New assays and production technologies are constantly being developed in the field of biological medicines. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 28

35 TARGET FOUR These may lead to new ways of assuring the quality and safety of biological products. New biological medicines, for which there are no WHO recommendations or guidelines, may also be introduced internationally for prophylactic or therapeutic use. A programme of work is thus in place to revise, where appropriate, existing WHO recommendations or guidelines and to develop new documents as they are needed. The partnerships which support this work are with the two WHO International Laboratories for Biological Standards; the WHO Collaborative Centre on Biological Standardization; the various national regulatory authorities; and the International Association of Biologics. Production and control recommendations Smallpox Revised New Transmissible Spongiform Encephalopathies guidelines Preclinical evaluation of vaccines Preclinical evaluation of vaccines Inactivated influenza Cell substrate Serogroup A meningococci Serogroup B meningococci Live rotavirus Stability testing of vaccines Antivenoms Hepatitis B Pneumococci Batch release of vaccines Combination vaccines Vectored vaccines standards, used routinely in the laboratories of manufacturers, regulatory authorities and others. They often form the basis for the licensing of biologicals and in the case of therapeutics, for clinical dosing. In this way the potency of biological medicinal materials is directly traceable to the WHO primary standards and are expressed in comparable units worldwide. A rolling programme of establishment of new or, when stock levels become low, replacement International Reference Materials is in place and will continue for the future. The continuity of the International Unit depends on the stability of International Reference Materials. A programme of work is to be initiated to monitor the real time stability of selected reference materials to supplement data on predicted stability that is available at the time a material is established. As International Reference Materials are not available for use as working reference reagents, and in response to requests from national regulatory authorities, highquality working reference materials for selected biological medicines will be developed. Work in this area is supported by partnerships with the two WHO International Laboratories for Biological Standards; the WHO Collaborative Centre on Biological Standardization; national regulatory authorities; the International Association of Biologics; and the Council of Europe (European Pharmacopoeia) International reference materials for biological substances used in medicines To provide the international reference materials needed to ensure the global comparability of activities for biological preparations used in prophylaxis, therapy and diagnosis of diseases. International biological standards and other reference materials are critical to the standardization, quality control and potency estimation of biological medicinal products. Many are calibrated in International Units of biological activity, established by consensus following extensive international studies involving many laboratories. There exists a hierarchy of standards, with the WHO International Standards being the primary standard against which secondary standards are calibrated. Secondary standards may be national, regional (e.g. European Pharmacopoeia) or manufacturer working By 2002: A process is implemented to monitor the continuity of the International Unit for selected biological standards. By 2003: Revised guidelines are established for the preparation, characterization and establishment of international and other standards and reference reagents. High-quality working reference materials for selected biological medicines are developed and provided. By 2004: Reference reagents and standards for immunological and virological assays of candidate HIV vaccines are available. By 2005: International standards for candidate malaria vaccines are available. Reference reagents and standards for gene transfer products are developed.

36 5 TARGET FIVE Assure adequate supply and quality of all vaccines delivered by national immunization services up to and including the time of administration Critical indicator: Proportion of countries using vaccines of assured quality Out of 190 WHO Member States, 175 are using oral polio vaccine of assured quality. For all vaccines the overall figures are 160 out of 190 (84%). Critical indicator: Proportion of countries using vaccines with vaccine vial monitors (VVMs) where relevant Out of 164 WHO Member States where VVMs are recommended for use, 82 countries are using VVMs on oral polio vaccine (OPV) (unchanged). The fitting of VVMs on other vaccines used in national immunization services has been delayed. However, three major vaccine manufacturers are now complying with VVM application to vaccines other than OPV. There are 37 countries receiving BCG, yellow fever, measles and MMR vaccines fitted with VVMs. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY Table 3: Where are they? VVM implementation by vaccine type (as at 27 March 2002) Type of vaccine Manufacturer Recipient countries OPV BCG Yellow fever Measles, MR, MMR Hepatitis B All manufacturers Japan BCG Pasteur Dakar Chiron LG Chemical Inv. Ltd. All countries receiving OPV from UNICEF and/or using UNICEF procurement services for OPV purchase Bangladesh, Cambodia, Democratic People s Republic of Korea, Jordan, Myanmar, Nepal, Syrian Arab Republic, Pakistan, Philippines, East Timor Angola, Benin, Burkina Faso, Central African Republic, Chad, Gambia, Kenya, Mali, Pakistan Albania, Burundi, Colombia, Congo, Croatia, Cuba, Ghana, India, Jordan, Kenya, Lebanon, Macedonia, Morocco, Nigeria, Pakistan, Rwanda, Sierra Leone, Syrian Arab Republic, United Republic of Tanzania, Uganda, Viet Nam, Yugoslavia, Democratic Republic of the Congo Albania, Azerbaijan, Bangladesh, Benin, Cambodia, Cape Verde, Fiji, Gabon, Kyrgyzstan, Lebanon, Moldova, Mongolia, Morocco, Pakistan, Russian Federation, Spain, Turkmenistan, Uzbekistan, Yemen, Yugoslavia, Zambia TT (UniJect TM ) Bio Farma Source: Compiled data from WHO, Vaccine manufacturers, LifeLines Indonesia, Mali, Uganda 30

37 TARGET FIVE Effective and sustainable logistics systems for vaccine distribution Specific indicators: Proportion of countries with expanded training on VVMs (denominator is countries receiving vaccines with VVMs). Proportion of countries adopting global vaccine management policies into national use among targeted countries by vaccine management training project. Proportion of countries with cold stores certified. Establishment of governance system for Technet21. Proportion of countries with secured funding for the purchase of cold chain equipment. Proportion of countries reporting regularly on wastage rates. To build sustainable logistics systems for the management of vaccines in the context of health care reform. A logistics system that functions well is essential to the efficient operation of any health programme. A well-run vaccine distribution system should maintain a constant supply of vaccine, injection equipment and waste management supplies in good condition, present in sufficient quantities and at the right time and place. Increasing pressure has been put on the cold chain and logistics over the last few years, with health sector reform resulting in integrated delivery of essential services and the establishment of GAVI creating the potential availability of new vaccines in lower-dose presentation. This area of work will include assessments of cold chain and logistics systems, development of multi-year plans integrating strategies and activities to ensure strategic purchase, deployment, maintenance and timely replacement of cold chain equipment and supplies, and regular reporting of vaccine wastage rates. Previous immunization service reviews in many countries have highlighted logistics problems as a barrier to substantial progress in immunization. Vaccine management, one of the major logistical components of immunization, plays a major role in the low performance observed in these programmes. The vaccine management training project, with its focus on countries in Africa, aims to address these problems to ensure appropriate implementation of policies that can facilitate good vaccine management practice. VVMs have proved to be an effective management tool, however, despite being available for all vaccines, implementation is rather slower than expected. Factors impeding implementation of VVMs have to be addressed immediately by all involved parties. Health workers take vaccines with VVM out of the cold chain to reach the unreached during national immunization days in the United Republic of Tanzania Photo:WHO, P. Blanc In the second half of 2002, the Cold Store Certification Initiative (CSCI) will be launched by WHO and UNICEF to encourage countries, national and subnational vaccine stores to adopt practices that fully protect vaccines, and promote and support efficient stock management and vaccine distribution systems. Ten global criteria for effective vaccine store management Over a period of 12 months: Pre-shipment and arrival procedures have ensured that all shipments received in the primary store were in satisfactory condition. All vaccines have been stored within WHO recommended temperature ranges. The capacity of cold storage has been sufficient to meet the demand. The standards of buildings, equipment and transport arrangements have been appropriate for the function of the cold store. Stock management has been effective. All equipment, transport and buildings have been routinely maintained. Deliveries of vaccine to the next level have been timely, sufficient and correct. No damage has occurred to the vaccine during distribution. The facility has followed standard operating procedures. Human and financial resources have been sufficient to run the store. With the introduction of new vaccines, vaccine wastage has started to receive more attention and has to be addressed to provide appropriate guidance to countries to build links with global policies and management practices. A network of experts and organizations working in logistics for health was established in 1998, called Technet (later Technet21, 8 ) with a focus on the management and operational logistics of national 8 In 2001 Technet was redefined as Technet21, being a network to ensure availability of experts in immunization service delivery, through the posting of needs on the Technet Forum, and through a validated database of experts; a mechanism for generation of ideas on how to improve immunization services at the national level, working with GAVI and its partners, and with countries and regional working groups; and a reality check on policy and technology options proposed by WHO and other GAVI partner organizations, bringing a field perspective to these proposals

38 immunization services and the integration of other logistics elements into primary health service delivery in developing countries. WHO s role as secretariat allows it to use Technet 21 as a sounding board for policies related to immunization service strengthening within the context of health systems. Technet 21 aims to reach more developing country managers, including those at sub-national and district levels, WHO and UNICEF country staff, plus the traditional Technet logistics members. Product information sheets are another logistics tool for developing country managers, as well as for manufacturers and procurement agencies. Provision for their development and updating need to be maintained. UNICEF, both Supply and Programme Divisions, is a major partner in activities dealing with logistics, as is the Children s Vaccine Program at PATH, and other key GAVI partners. By 2002: A protocol for monitoring wastage rates is developed and in use. Target countries action plans are developed to adopt global vaccine management policies into national programmes. VVM training guidelines are updated and published. The WHO-UNICEF cold store certification initiative is launched. VVMs are implemented in all UNICEF-supplied vaccines. Technet 21 working groups function fully. A new loose-leaf version of the product information sheets (PIS) is developed. A field performance feedback system for PIS is established. By 2003: The vaccine management training project third phase involves at least two countries from each region in addition to the African Region. At least 50% of countries in each region have trained assessors for cold store certification. At least 50% of developing countries will have a multi-year plan that includes logistics and vaccine management and addresses wastage. By 2004: The vaccine management training project (first phase) country reassessments are carried out. Specific indicators: Proportion of countries with expanded training on VVMs (denominator is countries receiving vaccines with VVMs). Proportion of countries adopting global vaccine management policies into national use among targeted countries by vaccine management training project. Proportion of countries with cold stores certified. Establishment of governance system for Technet21. Proportion of countries with secured funding for the purchase of cold chain equipment. Proportion of countries reporting regularly on wastage rates. 5.2 High-quality, global supply of vaccines used in routine immunization services Specific indicators: Proportion of candidate vaccines for which the evaluation process is completed. Proportion of vaccines for which the reassessment process is completed. To ensure the ongoing availability of high-quality vaccines for international purchase through reassessment every two years of all vaccines included in the WHO prequalified list, including assessment of the relevant national regulatory authorities. The quality of vaccines used in immunization services cannot be compromised. Through a published assessment procedure, vaccines are evaluated and, where appropriate, deemed prequalified for supply to international agencies that procure vaccines, including UNICEF and WHO. As at June 2002, there were 24 suppliers and over 60 vaccines on the WHO list of prequalified vaccines. The assessment process includes all the activities necessary to place and maintain new vaccines on a list of WHO prequalified products, including reassessment every two years. One of the most important aspects of the current system is its reliance on the capability of the producing country s NRA to oversee vaccine quality effectively. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY By 2005: At least 80% of developing countries have a multiyear plan that includes logistics and vaccine management and addresses wastage. All vaccines currently on the list are reassessed for continuing acceptability on a two-year basis. Apart from a couple of manufacturers who are still submitting files, reassessments corresponding to the period

39 TARGET FIVE were completed by the end of During the same period producers of three candidate vaccines have applied for evaluation, and the respective assessments have been completed. Summary lot protocols for all vaccines on the list have been reviewed as well as inserts and labelling materials. All routine vaccines for which new applications for UN supply are submitted are evaluated within a year of the date of submission. (Includes TT, DT, DTP, polysaccharide meningococcal vaccines, BCG, OPV.) All vaccines due for reassessment and actual supply to UN agencies are evaluated within two years of their previous evaluation. 5.3 Promote an effective vaccine regulation system Specific indicators: Proportion of countries exercising all functions of NRAs relevant to their vaccine supply. Proportion of countries which have increased/ improved NRA functions according to their vaccine source. To strengthen national regulatory authorities to ensure implementation of all relevant regulatory functions through NRA assessments; institutional development planning and technical support including training provided to regulatory and vaccine production institutions through the Global Training Network; and to improve communication among NRAs. Since the assessment system started in October 1998, assessments against indicators have been carried out in 38 countries, followed by agreed institutional development plans. Within the context of these plans, technical support and training has been provided through the Global Training Network, a network of 13 Centres of Excellence providing training in specific areas relevant to vaccine regulation and control. New curricula are developed based on needs assessments conducted by the NRA. In 2000 a decision was taken to include formal NRA assessments as part of the process for prequalification of products for acceptability in principle for purchase by United Nations agencies, thus strengthening the impact of this assessment. Also during 2000, the Developing Country Vaccine Manufacturers Network agreed to use NRA assessment results as a criterion for full membership. Progress reports were made to the Secretariat of the Strategic Advisory Group of Experts in 1999 and 2000, resulting in a request by SAGE that WHO works to improve the impact of the Global Training Network through a network of NRAs. This effort was launched at a planning meeting in Utrecht, Netherlands in November This NRA network will augment the follow-up activities already in place as part of the Global Training Network activity. By 2002: 90% of countries national immunization services are using vaccines of assured quality. 90% of countries procuring vaccines are exercising the appropriate regulatory functions or are sourcing vaccines from UN procurement agencies. At least two new training centres join the Global Training Network. There have been several World Health Assembly resolutions mandating that all vaccines used in national immunization services should meet WHO requirements. One aspect of WHO s evaluation of vaccine quality is in regard to the regulatory system in place to oversee a nation s purchase, procurement or production of its vaccines. The present approach is to ensure that all countries have a national regulatory system that is appropriate to their vaccine source and that these regulatory systems should be fully functional (as assessed against indicators). This allows progress to be assessed in a standardized and systematic way, using an assessment tool that has been developed through wide consultation (and that is now being used for assessment of regulatory functions for pharmaceutical products as well). By 2002 and ongoing: 80% of trainee countries increase/improve their NRA functions on follow-up assessment. NRA assessment or follow-up is conducted for 100% of vaccine-producing countries accounting for 90% of the global vaccine volume (see table below). An NRA network is in place to facilitate communications on regulatory advances. By 2003 and ongoing: 100% of countries national immunization services are using vaccines of assured quality. 100% of countries procuring vaccines are exercising the appropriate regulatory functions or are sourcing vaccines from UN procurement agencies. The NRA network is used to communicate advances in standardization and control of biological products. 33

40 Figure 5: Global training network: status in BBR Canada-NRA 1-Inst Finlay, Manufacturer CECMED-NRA, Cuba Courses 1 Good manufacturing practice 2 Quality control methods 3 Laboratory quality systems 4 Licensing (for producing countries) 5 Animal husbandry 6 Short course in DTP 7 Lot release and lab access 8 Postmarketing surveillance AEFI 9 Licensing (for procuring countries) 1, 9-IVP manufacturer USA 5-CECAL/Fiocruz manufacturer, Brazil 2, 3-NIBSC UK-NCL AFSSAPS France-NRA 2, 5, 6-RIVM manufacturer, Netherlands 8-University of Cape Town NRA contract work South Africa Participants 1 NRA staff with institutional development and training plan 2 Staff of manufacturer with NRA and institutional training plan 3 NRA staff and EPI staff (for AEFI course only) 2-Biken manufacturer, Japan 4-TGA NRA, Australia IVI Research Institute The Republic of Korea 2-BioFarma manufacturer Indonesia VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY Source: WHO/V&B Table 4: The vaccine-producing countries which impact 90% of the global volume Canada China Cuba Egypt France Germany Hungary India Indonesia Italy Islamic Republic of Iran Japan Mexico Pakistan Republic of Korea Russian Federation Senegal Switzerland Thailand Ukraine Viet Nam 34

41 TARGET SIX 6 TARGET SIX Establish a comprehensive system to ensure the safety of all immunizations given by national immunization services Critical indicator: Proportion of non-developed countries with sterile injection practices (absence of risk for the patients) Immunization safety ensuring and monitoring the safety of all aspects of immunization, including vaccine quality, vaccine administration and the disposal of sharps remains one of the challenges of immunization services. Despite the increasing number of countries reporting the use of AD syringes for immunizations, unsafe immunization injections remains a significant problem, especially in non-developed countries (i.e. least-developed countries, developing countries and economies in transition). The current baseline estimates of the proportion of non-developed countries with sterile immunization injection practices is based on an algorithm developed by WHO using data reported through the WHO/UNICEF Joint Reporting Form 2000, and data from injection safety assessments (based on the standard Tool for the assessment of injection safety WHO/V&B/01.30). In consultation with regions efforts are ongoing to identify additional sources of data to improve the WHO algorithm. As at December 2001, 18 countries had undertaken an injection safety assessment using the standard tool. Only 20% of non-developed countries are estimated to have sterile immunization injection practices, however, for the majority (80%) the status is unknown. Figure 6: Estimated percentage of non-developed* countries with sterile immunization injection practices, Sterile practices Unsterile practices Unknown** 80 % of countries All n = 188 African Region n = 48 Region of the Americas n = 45 Eastern Mediterranean Region n = 24 European Region n = 30 South-East Asia Region n = 10 Western Pacific Region n = 31 * Includes least-developed countries, developing countries and economies in transition ** Unknown considered as not meeting indicator of sterile immunization injection practices The baseline estimates are derived from data from the WHO/UNICEF Joint Reporting Form and injection safety assessments (where those had been done as at November 2001). Lack of reported data on the Joint Reporting Form accounts for a large proportion of unknowns but estimates are improved when based only on countries that report data relevant to a specific indicator. 35

42 6.1 Assurance of vaccine safety through quality control procedures and quality specifications Specific indicator: Proportion of countries using internationally accepted cell substrates for vaccine production and implementing up-to-date quality control procedures. To develop quality control procedures and quality specifications to ensure vaccine safety from the level of vaccine development through clinical trials to routine vaccine production. The potential risks associated with new technologies used in vaccine development as well as new safety issues with some existing production technologies should be addressed by the scientific community. WHO coordinates and facilitates collaborative laboratory studies designed to evaluate these risks and to develop new quality control procedures and quality specifications. WHO production and control recommendations and guidelines are updated, if necessary, to accord with current scientific knowledge of risks. A taskforce on the safety assessment of all cell substrates used in vaccine production has been established to coordinate collaborative studies on significant safety issues which may have long-term consequences; and to promote the exchange of reagents and expertise between laboratories. Guidelines have been developed emphasizing the need to address safety systematically as a major endpoint in vaccine clinical trials. This is to be followed up by development of guidelines for the preclinical evaluation of vaccines. These new guidelines will also systematically address safety concerns. The risks and benefits of preservatives in vaccines, especially thiomersal, are currently under consideration. WHO considers that the benefits of vaccines containing thiomersal far outweigh the risks (if any) of exposure to this preservative via the vaccines. Nevertheless there are circumstances where reduction of thiomersal may be feasible. Whether this would lead to an improved risk/benefit ratio is unknown. There is therefore a need to assess the safety of vaccines with reduced thiomersal content or alternative preservatives in both monodose and multidose containers. New quality control procedures have recently been introduced to monitor the consistency of production of a live attenuated virus vaccine (OPV) at the molecular level. The principles are applicable to other live attenuated vaccines; yellow fever vaccine is considered a good candidate for further progress in this area. By 2002: Guidelines are established for preclinical evaluation of vaccines. Results of a study are available to evaluate whether vaccines with reduced amounts of thiomersal, or containing alternative preservatives, can be used safely in the context of the current multidose vial policy. Guidelines are developed for laboratory and clinical evaluation of vaccines with reduced thiomersal in monodose containers and/or filled in monodose devices. Risk assessment is conducted of maximum safe intake levels of mercury in the context of thiomersal in vaccines. By 2003: Guidelines are completed on antigen content and quality of diphtheria and tetanus vaccines used as boosters in adults. Recommendations from the taskforce on cell substrates are implemented. Criteria are developed for the use of preservatives in multidose containers. By 2004: Methodologies for quality control of yellow fever vaccine are reviewed and updated. 6.2 Tools to ensure vaccine quality and safety up to vaccine administration Specific indicator: Proportion of countries receiving vaccines from UNICEF having implemented UN agency-supplied vaccines, ensuring quality of vaccines at country level, a guideline for health staff. To implement guidelines to ensure the quality and safety at country level of UNICEF-supplied vaccines, including response to complaints from the field and reports of adverse events following immunization. A range of activities is needed to ensure safe administration procedures during routine vaccination and mass immunization campaigns. WHO must VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 36

43 TARGET SIX promote respect for precautions and contraindications, proper administration routes and techniques, and encourage limiting the number of unnecessary vaccinations. Procedures must also be in place for the proper handling of vaccines, and should eliminate practices which could result in administration of the wrong product. WHO and UNICEF together are making a huge effort to ensure that vaccine supplied by United Nations agencies are of excellent quality and meet specifications important for programmatic considerations. In addition, WHO is investigating all reports of complaints of quality defects and possible adverse events following immunization (AEFI) with UN agencysupplied vaccines. However, to date, no country has introduced effective and appropriate tools to monitor the adequacy of vaccine shipments, nor have most countries established procedures for receipt and release of UNICEF-supplied vaccines. This has been addressed by the development of UN agency-supplied vaccines, ensuring quality of vaccines at country level, a guideline for health staff. By 2002: Guidelines on international packaging and shipping of vaccines (WHO/V&B/01.05) are updated and published. UN agency-supplied vaccines, ensuring quality of vaccines at country level, a guideline for health staff is distributed to national immunization services and a plan is developed and implemented to ensure that key national immunization staff in each country facilitate the guideline s implementation. By 2003: Implementation of the guideline for health staff, on ensuring the quality of UN agency-supplied vaccines at country level, is monitored in selected countries in different regions. By 2002 and ongoing: All complaints related to quality and possible AEFI are addressed within one month of receipt of the report, and where possible, resolved. 6.3 Safe and efficient vaccine administration and disposal technologies Specific indicators: Proportion of non-developed countries with national safe injection plans, including safe immunization strategies and a sharps waste management component detailed down to district level, as part of their national immunization plans. Proportion of non-developed countries using AD syringes. Proportion of non-developed countries with sterile immunization injection practices (absence of risk for the patients). Proportion of non-developed countries with proper sharps disposal (absence of risk for the health care worker). Proportion of non-developed countries with proper sharps waste management (absence of risk for communities). To ensure safe and effective systems for vaccine delivery, which include safe management of sharps and wastes. Up to one-third of immunization injections are not carried out in a way that guarantees sterility. A priority for WHO is to promote safer injection practices. With the use of AD syringes, the reuse of unsterile equipment is prevented (as outlined in the 1999 WHO-UNICEF- UNFPA joint statement on injection safety). This change of injection technology represents a major challenge for some countries, in particular in the area of sharps waste management. Recently, TT-UniJect TM, an AD syringe-vaccine construct, has been prequalified for UN agency purchase. An increasing number of countries have safe injection plans. However, sharps waste disposal policies at the national level are rare and management systems to handle sharps waste at the health centre level are rarer still. Thus, few countries are implementing recommended sharps waste technology and techniques. The joint statement encourages partners of immunization services and countries to consider goodquality vaccines, AD syringes and safety boxes as three components that must be part of a bundle, i.e. each component must contain the other two; and none of these component items must be considered alone. Safety boxes are not yet systematically distributed with injection equipment as recommended in the bundling 37

44 policy. In 2001, more than 600 million AD syringes were purchased for vaccination-related activities including supplied through UNICEF procurement. This figure will further increase in the coming years. WHO is promoting phased introduction of AD syringes including safe disposal and waste management practices in countries. Several documents have been published to help this transition: on safe health care waste management, on waste management during mass immunization campaigns, and other documents related to the introduction of AD syringes. The challenge is now to help countries implement these changes by ensuring that all assessments are accompanied by plans for injection safety. Several partners support WHO in this crucial area of work, including UNICEF, the Children s Vaccine Program at PATH, and USAID. The Safe Injections Global Network (SIGN) has also provided tremendous support to these activities throughout its network and membership. By 2002: 40 countries conduct an injection safety assessment and develop a plan to meet identified gaps. At least 50 of the poorest countries use safest recommended devices and practices The joint statement on use of AD syringes is endorsed by all partners supporting immunization services. A costing study is done on waste management with financing tools developed. All countries develop plans for phased introduction and safe disposal of AD syringes. By 2003: All countries are using only AD syringes for immunization activities. 80% of countries have sterile injection practices (absence of risk for the patients). 80% of countries have proper sharps disposal (absence of risk for the health care worker). 80% of countries have proper sharp waste management (absence of risks for communities). By 2004: 12 countries conduct a second injection safety assessment and demonstrate significant improvements in injection safety. Figure 7: Countries including injection safety as a component to the national work plan Yes (110 countries 58%) No (49 countries or 26%) No data or not applicable (32 countries16%) Source: WHO/UNICEF 38

45 TARGET SIX 6.4 Mechanisms to monitor and respond to adverse events following immunization Specific indicator: Proportion of countries with a monitoring system for AEFIs. To establish efficient mechanisms, involving national regulatory authorities, immunization managers and vaccine producers, that detect serious or potentially serious adverse events following immunization, and enable prompt and effective response in order to minimize negative impacts on health and immunization services. Vaccines are regarded as one of the most cost-effective public health interventions. However, adverse events or rumours of adverse events following immunization are often poorly managed. As infectious diseases continue to decline, people become increasingly intolerant of risks associated with vaccines. Allegations of adverse effects related to vaccines, if not rapidly and effectively dealt with, can undermine public confidence in immunization. Ultimately, this can result in dramatic consequences for immunization coverage and disease incidence. At country level, documents and training activities have been made available and several guidelines and background documents on adverse events have been prepared and/or are being updated. A Global Training Network course on AEFI has incorporated a new component on partnership building with the media. These courses have been given for a total of 30 participants from anglophone Africa and countries of the Commonwealth of the Independent States in 2000 and for a total of 33 participants from francophone Africa in WHO is also helping countries to establish efficient AEFI monitoring systems, especially in the context of measles mass immunization campaigns. A systematic process will be developed to provide technical support in establishing or assessing such systems for prevention and management of AEFI, first in the context of campaigns and later in the routine system. WHO has established the Global Advisory Committee on Vaccine Safety to provide a reliable and independent scientific assessment of vaccine safety issues through: rigorous review of the latest knowledge concerning any aspect of vaccine safety of global or national interest, in close collaboration with all parties involved, including experts from national administrations, academia, and industry; determination of causal relationships between vaccines and/or their components and adverse events attributed to them; creation, where necessary, of ad hoc task forces with a mandate to commission, monitor and evaluate appropriate methodological and empirical research on any purported association of specific vaccines/ components and adverse event(s). WHO is also supporting other activities related to AEFI such as the Brighton Collaboration, an international voluntary collaboration to facilitate the development, evaluation, and dissemination of high quality information about the safety of human vaccines. By 2002: All countries planning a measles mass immunization campaign have an AEFI monitoring system in place. By 2003: All countries with a national regulatory authority have an AEFI monitoring system which includes proper collaboration between the NRA and the immunization service. 15 AEFI monitoring systems are established or strengthened through assessments and the planning process. 39

46 7 TARGET SEVEN Strengthening key immunization functions and public health managerial capacity at national and district levels Critical indicator: Percentage of districts with at least 80% DTP3 coverage As at the end of 2000, 38 of 188 developing countries (20%) had achieved this critical indicator (100 % of districts with at least 80% DTP3 coverage). District-level data are now available from 114 countries (61%). 7.1 Improve efficiency and access to immunization services, particularly by building on the experiences of polio eradication Specific indicator: Proportion of districts in developing and least-developed countries that have reached more than 80% DTP3 coverage. To provide policy guidance and technical support for countries in the coverage, efficiency and reach of their immunization services, while taking advantage of the infrastructure created for the eradication of poliomyelitis. At least 18 countries globally have immunization coverage that has remained at around 50% since Reasons for low coverage are complex, but two issues are clear: if the situation is to improve, access to immunization services must be increased both for remote populations and the urban poor; and the efficiency of immunization services must be improved by reducing drop-out rates. Since the global goal is to increase coverage in every district of every country, the key to success is high-quality district planning and implementation. Countries are dealing with concurrent disease control initiatives for measles and neonatal tetanus. Plans should include all these activities in an integrated manner. The model is the polio eradication initiative in which there are many examples of reaching the unreached based upon district data analysis and microplanning. Technical guidelines and tools for increasing access and reducing drop-out rates have been developed. District microplanning is a strength of polio eradication, and needs to be systematically used to strengthen routine immunization. There are good examples of countries that have prepared integrated disease control plans. The appropriate transition of the polio eradication resources and infrastructure will be essential for these efforts. By 2003: At least 25% of the developing and least-developed countries reach 80% coverage in all districts. All regions have a regional transitional plan. 50% of the least-developed and developing countries reduce national drop-out rates to less than 10%. By 2005: At least 80% of the developing and least developed countries reach 80% coverage in all districts. Regional transitional plans are implemented in all regions. 30% of the least-developed and developing countries reduce national drop-out rates to less than 10%. 7.2 Strengthen human and institutional resources through management and technical training Specific indicators: Number of countries for which procurement assessments have been done as part of the procurement training strategy. Proportion of countries that hold at least one annual coordinating meeting (e.g. ICC) for routine immunization services. Proportion of countries that conduct training of midlevel managers. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 40

47 TARGET SEVEN Proportion of countries that reduce national drop-out rates to less than 10%. Proportion of countries that conduct training workshops for national-level managers. To strengthen national capacity for management and institutional coordination by training immunization managers in essential management functions including planning, implementation, and providing technical training to subnational level. Management problems are often cited as the causes of poor performance of immunization services. In the context of renewed global interest in immunization, and new international partnerships and alliances, national managers need to be able to deal with many more complex issues than previously. Today, financing, new vaccine introduction, partner coordination, and regular training of health staff are just some of the many challenges. A training strategy based on problem solving has proved a useful approach. This needs to be institutionalized and backed by technical resource material. At the mid-management level, revised materials are needed for training managers to respond to the many new technical issues confronting immunization services. At least one region and one large country have independently developed their own revision of the mid-level management modules, indicating a global need. A training initiative in vaccine procurement, which will be important as countries move from financial sustainability to self-sufficiency, began in the biennium, based on centres of excellence. This activity will be continued with the twin goals of increasing technical abilities at national level and of recognizing systems that can serve as resources to neighbouring countries. A problem-solving strategy and national-level resource materials have been developed, and will be field-tested in several countries. This work will need to be expanded to include training for mid-level management to cover a wide range of issues facing immunization services that were not included in previous versions. An assessment tool has been developed for the vaccine procurement initiative, 11 countries nominated by the WHO regional offices have agreed to take part in the initiative, and a procurement mapping activity has taken place in four of these. A procurement manual (posted on the V&B web site) has been revised and updated, and will be available in Russian in early For 2002: Two country sites are chosen as procurement centres of excellence. Procurement training curriculum is completed. Pilot testing of national management-strengthening workshops is completed initially in eight countries. A management and training resource centre is established to disseminate updated immunization management resources and information. For 2003: Intensive procurement training begins in procurement centres of excellence. All developing and least-developed countries will have regular interagency coordinating committee (ICC) meetings. A new global version of the mid-level management modules is published by WHO headquarters with regional participation. Pilot-testing for national management strengthening workshops is conducted in at least one country within each region. For 2005: Procurement centres of excellence are in place as resources for other countries. 50% of the least-developed and developing countries conduct one mid-level management training course. 7.3 Global, national and regional monitoring and assessment systems Specific indicators: Proportion of countries providing complete reports on core immunization system information. Proportion of countries with estimates of countryspecific case/death due to vaccine-preventable diseases as well as cases/deaths averted. Proportion of countries conducting assessments of immunization services using the standard methodology. To monitor and assess selected policies, activities and impact of national immunization systems. To ensure that all countries that have conducted self-assessment of data quality are implementing remedial actions that include improvement of the quality of data, the capacity to analyse data, and the use of data at the national and district level for planning, action and monitoring. 41

48 Immunization systems throughout the world involve a mixture of disease control goals and vaccination strategies. Data are collected from countries on immunization schedules, coverage, disease incidence, supplemental immunization activities and surveillance performance, as well as indicators reflecting sustainability, managerial capacity, safety, and efficiency of immunization systems. Periodic assessments are needed of the immunization services themselves, or of some of their components, especially when the introduction of a new vaccine is being considered. A standard methodology is needed to facilitate the collection of such information and to standardize the results of such assessments. Collected data are then consolidated, analysed and disseminated to interested parties. In addition, country-specific estimates are made of cases and deaths due to selected vaccine-preventable diseases as well as cases and deaths prevented due to immunization. There is great potential for improving access to immunization when planning is based upon reliable district information. Technical support is provided to improve the efficiency and usefulness of national and regional immunization monitoring systems. Materials and methods are also developed such as software tools, guidelines on surveillance system functions, disease-specific monitoring guidelines as well as methods for serosurveys, laboratory diagnostics, and data quality assessment. Currently 214 countries/territories report data to WHO, however, completeness of reporting and the quality of data vary widely by indicator. A standard tool to assess immunization services is being prepared in close collaboration with UNICEF and the World Bank. An inventory of materials and methods for vaccine assessment and monitoring is available and undergoing constant revision. Technical support to assess routine monitoring systems has been initiated, but needs further refinement and expansion. A tool to audit the quality of immunization coverage monitoring systems has been developed and field-tested in 10 countries. By 2002: Global monitoring: A global set of core system indicators is revised and finalized. A data managers meeting is held to build consensus and streamline reporting procedures. Materials/methods: Standard methodology for data quality audits is available, disseminated and utilized by GAVI Three of the modules for the Making surveillance work series are completed. New software tools (beta versions) are available for monitoring immunization/laboratory systems. Cluster survey methods (and software tool) that assess immunization coverage are revised and field-tested. The data quality self-assessment tool is field-tested and introduced in regions and countries. Methods for making best estimates of coverage are developed. Estimates through modelling: Country-specific estimates of cases/deaths are documented for diphtheria, measles, neonatal tetanus, and pertussis, and sent to countries for review. Global costing database and methods for estimating the cost of national immunization systems are developed. By 2003: Materials/methods: Guidelines on monitoring and evaluation of immunization services are revised. Lot quality assessment methods that assess immunization coverage levels are revised. Monitoring/surveillance modules from the mid-level management series are revised. Various methods/tools recently developed and fieldtested to improve data quality are compiled as a set and made available to countries. Estimates through modelling: Country-specific estimates of cases/deaths are documented for diphtheria, measles, neonatal tetanus, yellow fever and pertussis, and sent to that country for review. By 2004: Annual regional reviews of data quality are held. Regular reporting for additional vaccine-preventable disease is initiated By 2005: Estimates of measles, diphtheria, pertussis, and maternal and neonatal tetanus are revised and updated. Costing estimates are revised and updated. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 42

49 TARGET SEVEN 7.4 Enhance advocacy, information, and social mobilization for immunization Specific indicator: Existence of a joint WHO/UNICEF global immunization advocacy plan for community and health workers To develop a communications strategy that promotes basic immunization services with a focus on specific issues for the community and for health workers. Advocacy and communication efforts for disease reduction initiatives have been very successful, but have not always been directed towards promoting routine immunization. Many technological developments and expertise in the world of advertising and communication provide a tremendous opportunity to reach large segments of the community with simple messages promoting immunization. The same approaches can be used to inform health workers and provide them with tools for their day-to-day work. In this context communication messages can be used to support specific issues for increasing immunization coverage such as reducing drop-out rates. Advocacy, communication and social mobilization are often uncoordinated. The challenge will be to provide a strategy of communication that promotes the value of immunization as a desirable product at every level from high-level advocacy to community social mobilization. By 2002: Plan and strategies are developed. By 2003: Advocacy plan is launched. 43

50 8 TARGET EIGHT Certify all WHO regions as polio-free in 2005 Critical indicator: Number of WHO regions certified as polio-free The Global Polio Eradication Initiative (PEI), the largest public health initiative in history, is on track to certify the world polio-free in Polio cases have declined by 99% since the Initiative s launch in 1988, from estimated cases in 125 countries, to 2880 reported cases (as at 11 September 2001) in 20 countries in Polio eradication has been certified by an independent commission in three of the six WHO regions: the Americas (1994), the Western Pacific (2000) and Europe (2002). Polio cases are now at their lowest point in history, their number having been halved between 1999 and 2000, even with a substantial increase in surveillance sensitivity. This progress has continued in As at September 2001 there was clinical or virological evidence of endemic polio transmission in only 10 countries and one-third of the number of confirmed cases compared with the same period in The remaining polio-endemic countries are in West and Central Africa, the Horn of Africa and the Asian subcontinent. Even within the remaining disease-endemic countries, ongoing polio transmission is limited to smaller geographic areas. Completing the final 1% of the PEI is a challenging and expensive task. It requires accessing all children with vaccine against polio, even in areas affected by conflict, and maintaining political commitment in the face of a disappearing disease. However, the single greatest threat is a US$ 400 million funding gap for activities planned until Figure 8: Polio eradication progress, VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY Certified polio-free regions (113 countries) Not certified but non-endemic (68 countries) Endemic with wild polio virus in 2001 (10 countries) Source: WHO/AFP surveillance data 44

51 TARGET EIGHT Figure 9: Progress in polio eradication estimated and reported polio cases, Number (thousands) WHA resolution to eradicate polio 1988 Surveillance acceleration begins Reported 2000 Original target date for interruption of transmission Reported cases: 2971 Estimated cases: 3500 Estimated 2005 Original target date for global certification Polio eradication: Global coordination and strategic planning To establish consensus on strategic and programmatic priorities across partner agencies, WHO regional offices and Member States. The sheer scope and magnitude of the Global Polio Eradication Initiative (PEI) has required a strong and well-structured partnership. The PEI is spearheaded by national governments of disease-endemic countries, WHO, Rotary International, CDC, and UNICEF. The polio eradication coalition also includes private foundations, development banks, donor governments, nongovernmental organizations and corporate partners. This partnership has been critical in providing technical expertise and support, increasing operational and financial transparency and coordinating inputs. Its strength has been apparent in the increased interest and participation of other UN agencies, bilateral donors, NGOs and especially the polio-endemic countries themselves. Strong institutional arrangements have been established to facilitate policy development, strategic planning, priority setting, resource mobilization and partner coordination. WHO provides the overall technical and strategic direction for the Global Polio Eradication Initiative. To facilitate policy development, strategic planning and priority-setting, WHO established the Global Technical Consultative Group (TCG) in 1989 and has convened annual TCG meetings since 1993 (similar bodies have been established in each WHO region). During these meetings, WHO brings together expert technical advisers, researchers, field staff, national programme managers and partner agencies to coordinate policy, strategic priorities and operational aspects of the PEI. Since 1997 WHO has convened biannual meetings of the Global Polio Management team (including representatives from headquarters and each of the six regional offices) in Geneva to discuss specific issues relating to programme implementation and management. WHO also convenes an annual meeting with its technical partners, CDC and UNICEF, to coordinate operational and research work. Coordination of global strategic planning and priority setting Indicators Number of annual reports for the: Global Technical Consultative Group (1) Management Team (2) Core Technical Partners (1). Four meetings convened and consensus reports generated. Four meetings convened and consensus reports generated. Four meetings convened and consensus reports generated. Four meetings convened and consensus reports generated. 45

52 8.2 Polio eradication: Strategy implementation To ensure the effective application of surveillance and supplementary immunization activities (SIAs) at regional and country levels through direct technical support, an effective global monitoring system, an accredited global laboratory network and an adequate supply of high-quality polio vaccines. Effective surveillance and monitoring is critical to the Initiative. Country-specific data are needed on acute flaccid paralysis (AFP) cases, confirmed polio cases, surveillance performance, laboratory findings, and SIAs to track chains of transmission and identify areas of high risk or weak performance so that appropriate action can be taken. Central to global surveillance is the need for proficient laboratory services, capable of accurately and efficiently isolating and characterizing polioviruses. Network laboratories are reviewed and accredited annually. Essential equipment and supplies, and extensive training of laboratory staff in standardized techniques must be provided. The genetic sequence information generated on all wild poliovirus isolates by such a system is crucial for targeting SIAs on remaining foci of virus transmission. Methods are being evaluated for environmental surveillance and investigation of non-afp cases to provide additional documentation for global certification of polio eradication. Since the acceleration of polio eradication activities in 1999, the annual requirement for vaccine to cover SIAs has increased to 2.2 billion doses of OPV. Given the narrow margin between supply and demand, these OPV requirements must be regularly reviewed to ensure the appropriate quantity and timing of delivery. Close communication must be maintained with countries and with the UNICEF Supply Division. WHO is also coordinating efforts to increase overall OPV availability, through improvements in local production, bulk filling, and global procurement processes. Given the global nature of the Initiative, it is important for WHO to ensure that consistent policies are applied across countries and regions and best practices shared. Direct technical and operational support is provided to regions and countries by staff from several teams, for example, V&B provides tools and technical support to support countries in achieving certification-standard AFP surveillance and to collate, analyse and publish global surveillance and laboratory data. Support is focused on polio-endemic and high-risk countries, in coordination with regional and country staff, and aims to improve the quality and effectiveness of AFP surveillance and SIAs. Over the past two years the quality of AFP surveillance and SIAs in most polio-endemic and high-risk countries has improved consistently. All countries have increased the number of SIA rounds conducted and adopted a house-to-house strategy to increase the number of children reached. It is increasingly possible to identify areas of wild poliovirus transmission and focus on these areas to ensure high-quality activities. However, ongoing transmission in a number of countries demonstrates the need for close technical support. The global monitoring system for the PEI has been defined as i) case-based data on AFP/polio cases on a weekly/monthly basis and in a standardized format; ii) SIA data on a monthly and six-monthly basis with standardized data elements, reporting formats, and data flow; iii) laboratory data on results and performance; iv) feedback mechanisms for information dissemination on a weekly basis to core partners, biweekly on the web site and quarterly through the Weekly Epidemiological Record. Laboratory data management still needs considerable improvement. As the global monitoring system for PEI is being strengthened, there is a simultaneous focus on how to integrate the monitoring of other diseases into this system. All countries now have access to a WHO accredited polio-laboratory. Out of 146 subnational, national, regional and global specialized laboratories in the network, 130 (89%) have been fully accredited, 7 (5%) provisionally accredited and 9 either failed to attain accreditation status or are pending evaluation. Regional and subregional centres for distribution of essential laboratory supplies and reagents have been established in all WHO regions. All laboratories are reporting results and performance indicators on a weekly or monthly basis. Molecular sequence data is being provided to the Polio Eradication Initiative within 90 days of onset of paralysis for only a limited number of wild poliovirus isolates. OPV demand and supply is being closely monitored and in 2001 supplies have in general been available in a timely way to allow SIAs to take place. However, the margin between available vaccine supply and demand is low and very careful management and monitoring remains important. Support has been provided to national regulatory authorities in some countries where OPV is being produced or handled to help to improve the quality of local supplies. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 46

53 TARGET EIGHT Application of SIAs and surveillance strategies Indicators Proportion of countries achieving certification-standard AFP surveillance All polio-endemic and high-risk countries are using virological classification criteria. Certification-standard surveillance is achieved in all countries of the European Region. Four meetings convened and consensus reports generated. Certificationstandard surveillance is achieved in more than 90% of countries of the African, Eastern Mediterranean and South-East Asia regions. Four meetings convened and consensus reports generated. Certification standard surveillance is maintained in all polioendemic and high-risk countries. Certification standard surveillance is maintained in all polioendemic and high-risk countries. Proportion of polio-endemic or highrisk countries implementing highquality SIAs as measured by standard process indicators. All polio-endemic and high-risk countries are conducting high-quality house-to-house NIDs and adding mop-up activities in response to wild virus. High-quality SIAs are conducted in all countries polio-endemic in High-quality SIAs are maintained in all areas with <80% OPV coverage. High-quality SIAs are maintained in all areas with <80% OPV coverage. Effective global monitoring system Indicators Proportion of countries providing needed AFP/polio data, SIA data, and laboratory data according to global standards. Global surveillance and laboratory summaries for 90% of countries (100% of polio-endemic and high-risk countries) are available to all regions and partners on a monthly basis. Global surveillance and laboratory summaries for 90% of countries (100% of polio-endemic and high-risk countries) are available to all regions and partners on a monthly basis. Global surveillance and laboratory summaries for 100% of all countries are available to all regions and partners on a monthly basis. Global surveillance and laboratory summaries for 100% of all countries are available to all regions and partners on a monthly basis. Proportion of regional laboratory networks providing standard information according to global specifications. An integrated system of surveillance and laboratory data allows the monitoring of cases from onset through sequencing of viral isolates. 80% of regional laboratory networks are providing standard information according to global specifications. 100% of regional laboratory networks are providing standard information according to global specifications. 100% of regional laboratory networks are providing standard information according to global specifications. Proficient global virological surveillance network Indicators Proportion of countries with access to an accredited polio laboratory. 100% of countries have access to an accredited laboratory, 95% of laboratories in the network are accredited, and 30% are accredited for intratypic differentiation. 100% of laboratories in the network are accredited. 100% of laboratories in the network are accredited. 100% of laboratories in the network are accredited and providing documentation of certification-standard performance. Proportion of poliovirus isolates with genetic sequence information reported within 90 days of onset of paralysis. 80% of wild virus isolates have genetic sequence information available within 90 days of onset of paralysis. 90% of wild virus and appropriate VDPV 9 isolates have genetic sequence information available within 90 days of onset of paralysis. Guidelines for laboratory activities in postcertification era are surveillance produced. All WHO regions have polio laboratory network capable of effective postcertification surveillance vaccine-derived polioviruses

54 Reliable, high-quality supply of polio vaccines Proportion of planned SIAs in polioendemic and high-risk countries conducted with no vaccine supply problem. Proportion of polio-endemic and at-risk countries using OPV released by a fully functional NRA. Proportion of countries using IPV (inactivated polio vaccine) released by a fully functional NRA. 8.3 Indicators Polio eradication: Optimizing the impact on health systems To identify, document and optimize the impact of polio eradication investments and infrastructure on routine immunization, surveillance and health systems. World Health Assembly resolution WHA41.28 which launched the Global Polio Eradication Initiative in 1988 explicitly stated that eradication should be pursued in ways which strengthened the delivery of primary health services in general and immunization services in particular. Since 1988, there has been widespread consensus that this eradication initiative has made substantial progress toward the elimination of the target pathogen. By contrast, there is considerable controversy as to whether the pursuit of this goal has strengthened or compromised the development of health systems and delivery of other health services, including routine immunization. Over 20 studies and evaluations have been conducted to date to examine the impact of polio eradication on other health services. These studies can be classified under the following five areas in terms of the primary aspect of the evaluation: Adequate vaccine of assured quality is available for 100% of planned SIAs in all polioendemic and high-risk countries. Mechanisms for ensuring the quality of OPV blenders are established and an implementation process for new quality control tests for OPV is established. 100% of countries are using OPV released by a fully functional NRA. 100% of countries are using IPV released by a fully functional NRA. Adequate vaccine of assured quality is available for 100% of planned SIAs in all countries. At least one OPV blender is prequalified. 100% of countries are using OPV released by a fully functional NRA. 100% of countries are using IPV released by a fully functional NRA. Adequate vaccine of assured quality is available for 100% of planned SIAs in all countries. Sufficient OPV blenders are established for 2005 to % of countries are using OPV released by a fully functional NRA. 100% of countries are using IPV released by a fully functional NRA. Adequate vaccine of assured quality is available for 100% of planned SIAs in all countries. 100% of countries are using OPV released by a fully functional NRA. 100% of countries are using IPV released by a fully functional NRA. 1. immunization service delivery; 2. disease surveillance; 3. health systems and service delivery; 4. other preventive services, especially vitamin A delivery; 5. broader social and societal benefits. To discuss and disseminate the lessons learned from these studies and evaluations WHO convened a meeting in December 1999 entitled Impact of Targeted Programmes on Health Systems A Case Study of the Polio Eradication Initiative. This meeting brought together a broad range of investigators, polio eradication partners, donors and other interested parties. As a result of the studies, reports and meeting outlined above, between 1995 and 2000 the polio partnership developed a better understanding of the broader health systems context in which the eradication initiative was operating and the difficulty in quantitatively evaluating and optimizing its impact on those areas. The response to the recommendations of the meeting include: (1) development of a polio eradication/epi checklist; (2) inclusion of strengthening of immunization and surveillance systems as one of the five major areas of work in the Global Polio Eradication Strategic Plan ; (3) mapping of the polio investment ; and (4) polio transition planning. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 48

55 TARGET EIGHT Experience to date suggests that the greatest opportunities in long-term national capacity building through polio eradication investments are in the following areas: human resources, institutional arrangements, expansion of surveillance and immunization strategies and supporting processes. V&B is now establishing standard indicators to guide and monitor the work of transitioning the polio investment, infrastructure and lessons learned to a broader health agenda. The workplan targets three specific areas: (1) routine immunization (four indicators including access, vitamin A supplementation, social mobilization and cold chain) (2) surveillance (two indicators including surveillance for epidemic-prone diseases and expansion of the laboratory network) and (3) health systems (indicators of the linkages between PEI and health systems strengthening). At its meeting in 2001, the Scientific Advisory Group of Experts (SAGE) assumed responsibility for monitoring the progress towards optimizing the impact of the PEI on health systems. Beginning in 2002, the Polio Eradication Team will report back to SAGE on progress against the indicators in this area. Transferring of best practices to routine immunization Indicators Proportion of countries achieving the four standard indicators for transferring PEI lessons to EPI. Indicators developed and distributed, and baseline status in countries established. 25% of countries achieve targets. 50% of countries achieve targets. 80% of countries achieve targets. Expansion of the AFP surveillance system Indicators Proportion of countries with laboratory diagnostic capacity for measles. 25% of countries achieve targets. 50% of countries achieve targets. 75% of countries achieve targets. 90% of countries achieve targets. Proportion of countries with integration of AFP and appropriate epidemic-prone disease surveillance. 25% of countries achieve targets. 50% of countries achieve targets. 75% of countries achieve targets. 90% of countries achieve targets. Promotion of linkages for health systems strengthening Indicators Proportion of countries using polio lessons to guide health systems strengthening. 25% of countries achieve targets. 50% of countries achieve targets. 75% of countries achieve targets. 90% of countries achieve targets. 49

56 8.4 Post-certification polio immunization policies To realize the ultimate benefits of polio eradication through global containment of laboratory stocks and vaccine production facilities, completion of the global certification process and establishment of an international consensus on the cessation of OPV. The full benefits of the Global Polio Eradication Initiative will only accrue after cessation of OPV immunization. The final phase of the Initiative includes the three major areas of work that must be completed prior to stopping polio immunization: 1. Containment: Containing existing laboratory stocks of wild poliovirus and IPV production processes to prevent inadvertent release into human populations. 2. Certification: Ensuring the process of certifying the interruption of wild poliovirus worldwide. 3. Cessation of immunization: Reaching consensus on when and how to stop administration of OPV. Laboratory containment of wild polioviruses must be ensured to prevent accidental reintroduction of wild poliovirus into the population from laboratory stocks or IPV production sites. An effective mechanism to guarantee containment of wild polioviruses must be established before immunization with polio vaccine can stop. The WHO global action plan for laboratory containment of wild polioviruses and Guidelines for implementing the pre-eradication phase of the global action plan for laboratory containment of wild polioviruses have been developed and outline activities to be implemented in three phases. Implementation of laboratory containment in each region is closely linked to polio eradication progress, the process of regional certification, and the eventual global certification of polio eradication. In terms of volume, vaccine manufacturers will be a significant source of polioviruses, and containment (for IPV or OPV producers) may require new facilities, with substantial implications for supply. In 1995, the Global Certification Commission was established, and developed the criteria, mechanisms and timeline for global eradication. The process of certification of each WHO region as polio-free is an intensive process that requires exhaustive documentation demonstrating the absence of wild poliovirus transmission in every country. Regional certification commissions in each region are responsible for reviewing the documentation gathered by national certification committees. Ultimately, the Global Certification Commission will make a decision based on evidence provided by the regional commissions. In summary, certification will proceed on a regional basis and will require polio-free status for at least three years in the presence of excellent surveillance. Global certification will ultimately require the certification of all regions and completion of phase 1 of the containment process. In planning for cessation of polio immunization two distinct issues are being considered: OPV cessation and post-immunization outbreak response. Genomic sequencing of polioviruses isolated from Egypt, Haiti/Dominican Republic, Madagascar and the Philippines has confirmed that sustained circulation of vaccine-derived polioviruses (VDPV) can occur and cause paralysis, particularly if population immunity is low. Therefore, it is essential to plan an appropriate immunization strategy to protect the population and ensure that VDPVs do not circulate after OPV immunization stops. The transitional immunization strategy for the OPV cessation era will be designed to minimize the risks from natural sources and the containment plan is designed to minimize the risks from man-made sources. In the postimmunization era, it will be essential to have outbreak response strategies and stockpiles of appropriate vaccines available, in case of reintroduction of wild poliovirus into the population. One hundred and ten countries have appointed a national task force responsible for implementing laboratory containment activities and have created a national plan of action. Eleven countries have completed the activities of phase 1 (pre-global eradication) and have submitted national inventories. Almost 400 laboratories with wild poliovirus materials have been identified to date. A draft plan of action for containment procedures in IPV production facilities has been developed. The Global Commission has established clear guidelines for the certification process which regional commissions are applying. As of 1996, all regions had established certification commissions, and requested Member States to establish national certification committees to verify data. As of 1997, committees had been established in all countries of the European Region and the Western Pacific Region. The Region of the Americas (1994) and the Western Pacific Region (2000) VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 50

57 TARGET EIGHT have both been declared polio-free by their regional certification commissions, and in other WHO regions the commissions meet at least annually to review the situation in each country and outline the evidence and documentation required. The European Regional Certification Commission has almost completed the review of the evidence for certifying polio-free status in that Region. A comprehensive programme of work has been defined for guiding the development of a strategy for eventually stopping OPV immunization. This programme consists of i) programmatic work (e.g. IPV price and supply; frequency of VDPV circulation), ii) scientific research (e.g. IPV efficacy in developing countries) and iii) consensus-building (e.g. political and communications agendas). The research agenda has been defined to address the remaining gaps in scientific knowledge. A steering committee on OPV cessation research has been established and a communications and public information plan is being developed. Ensuring adequate stocks of vaccine for the postcertification era requires coordinated planning with the quality and supply of IPV already being addressed. Containment of laboratory stocks of wild polio virus Indicators Number of countries completing phase 1 of the Global action plan for laboratory containment of wild polioviruses. National task force/coordinator and national plans of action are established in every country not endemic for polio, and national inventories are completed in all countries of the Western Pacific Region. Establishment of guidelines for laboratory containment in IPV vaccine production facilities. National inventories of laboratories are completed in all countries of the Americas, the European and South-East Asia regions. Establishment of guidelines for containment in production facilities using Sabin strains. National inventories of laboratories are completed in all countries of the African and Eastern Mediterranean regions. Mechanisms for verification of conformity to laboratory containment guidelines for IPV and vaccines produced using Sabin strains. Verification of global certification containment conditions completed for all regions and IPV vaccine manufacturers by a global advisory group on laboratory containment. Final global plan of action published for post- OPV era laboratory containment procedures, including containment of vaccine viruses. Certification of polio eradication Indicators Proportion of countries with full documentation for certification. 100% of all countries in the European Region have full documentation for certification. The European Region is certified as polio-free. 50% of all countries in a non-certified region have full documentation for certification. All African Region countries have a national certification committee. 75% of all countries in a non-certified region have full documentation for certification. Provisional documentation from all countries reviewed by a regional certification commission. 100% of all countries have full documentation for certification. All WHO regions are certified polio-free and global certification is achieved. 51

58 Consensus on cessation of OPV immunization Completion of the programmatic, scientific research and consensusbuilding agendas in 2002, 2003 and 2004 respectively. 8.5 Indicators Polio eradication: Resource mobilization, advocacy, communications To mobilize the financial resources and political commitment required to eradicate polio in 2002 and certify the world polio-free in 2005, and to provide the communications tools necessary to facilitate the active engagement of key stakeholders in all facets of the Polio Eradication Initiative. Polio eradication activities have been supported both by multilateral and bilateral donor (external) contributions, as well as by the polio-endemic countries themselves (internal contributions). Funding provided by external sources between 1985 and 2001 totalled nearly US$ 1.8 billion dollars. During that period, 24 private and public sector donors each contributed more than US$ 1 million to polio eradication. Of these, 18 made contributions of US$ 5 million or more. The Global Technical Consultative Group has declared that the funding gap of US$ 400 million for activities constitutes the Initiative s single greatest challenge. Maintaining high-level political commitment is also a major challenge in the face of a disappearing disease. Such commitment is critical in polio-endemic countries, to support the continued acceleration of high-quality eradication activities, and to establish necessary multisectoral support. As countries become polio-free, political commitment will be needed to achieve consensus on containment and cessation of immunization, particularly given the cross-sectoral implementation of these areas of work. The development of communications tools to facilitate the engagement of key stakeholders in the PEI has been and will continue to be an important enabler of the Completion of the programmatic research agenda (e.g. IPV price and supply, frequency of VDPV circulation). Completion of the scientific research agenda (e.g. standardization and control of Sabin IPV, IPV efficacy, long-term excretors). Completion of consensusbuilding (strategy and mechanisms for stopping OPV, vaccine stockpile) and funding mechanisms. International plan and timeframe agreed by World Health Assembly. Initiative s ability to achieve global certification. As the PEI gets closer to its 2005 certification target, and to becoming only the second disease to be eradicated, it can be expected to come under increased scrutiny. Transparent sharing of key information will be critical. The total external resource requirements for are estimated to be US$ 1 billion. With US$ 600 million in pledges and projections, the funding gap for activities through 2005 is US$ 400 million. In addition to maintaining the existing donor base, WHO s efforts to fill this funding gap will focus on new public sector opportunities (including the World Bank and the European Commission) and will extend to working with WHO Representatives to mobilize resources at country level. WHO will play a key role in support of the Rotary Foundation/United Nations Foundation private sector fundraising campaign targeting corporations and individual philanthropists. In , unprecedented cooperation between countries to synchronize national immunization days (NIDs) has demonstrated strong political commitment to polio eradication, especially in West and Central Africa. Ensuring the engagement of heads of state in the PEI, to enhance access to children for immunization and to ensure high-quality surveillance activities, will be a focus of the next two years. The World Health Assembly will eventually be the forum for negotiating and coordinating the collective action required globally before OPV immunization can stop. Advocacy efforts will also be directed to the issue of containment as, once transmission of wild poliovirus in human populations around the world has been stopped, uncontrolled laboratory stocks will be the greatest threat to maintaining a polio-free world. WHO has developed a significant communications capacity and communications tools that include VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 52

59 TARGET EIGHT position papers and fact sheets, annual progress reports, the quarterly Polio News newsletter, monthly articles in the Weekly Epidemiological Record (WER) and the web site polioeradication.org. A communications team made up of members from WHO, UNICEF, Rotary and CDC works together to develop joint messages and to coordinate media events at global, regional and country levels, all in support of the Initiative s technical, resource mobilization and advocacy objectives. Resource mobilization Indicators Proportion of financial needs met. 100% of required financial resources secured for 2002 and mid-2003 (US$ 380 million for 2002). 100% of required financial resources secured for 2003 and mid-2004 (US$ 280 million for 2003). 100% of required financial resources secured for 2004 and mid-2005 (US$ 200 million for 2004). 100% of required financial resources secured for 2005 and mid-2006 (US$ 140 million for 2005). Advocacy Indicators Number of identified priority countries with improved head of state commitment. Access to children for polio immunization; and quality of surveillance activities. 100% of identified endemic/high-risk priority countries with appropriate head of state engagement and improved access to children for polio immunization and improved quality of surveillance activities. 100% of identified priority countries in uncertified regions with appropriate head of state engagement and improved access to children for polio immunization and improved quality of surveillance activities. 100% of identified priority countries in uncertified regions demonstrating the political support necessary to meet certification and containment targets. 100% of identified priority countries demonstrating the political support necessary to meet certification and containment targets. Political mapping of end game issues completed. Communications Indicators Timely production of up-to-date, relevant information, adequately distributed to appropriate audiences. Communications product and placement targets met, i.e. monthly WER articles, quarterly Polio News publication, biweekly web site updating. Communications product and placement targets met, i.e. monthly WER articles, quarterly Polio News publication, biweekly web site updating. Communications product and placement targets met, i.e. monthly WER articles, quarterly Polio News publication, biweekly web site updating. Communications product and placement targets met, i.e. monthly WER articles, quarterly Polio News publication, biweekly web site updating. Stakeholder understanding of programme achievements and challenges, especially issues of access, quality and funding. Stakeholder understanding of laboratory containment issues. Stakeholder understanding of issues relating to cessation of immunization. Global recognition of certification. 53

60 8.6 Polio eradication: Effective administration To provide effective administrative support to PEI in the areas of human resources, procurement, financial management and general management at global, regional and country levels. As the largest public health initiative in history, the Global Polio Eradication Initiative will manage over US$ 2.5 billion in financial resources and up to 2000 staff in over 60 countries between 1988 and Since the majority of resources (both financial and human) and supplies are managed through WHO, a correspondingly high level of administrative capacity and commitment is required at all levels. One of the main challenges of the PEI that WHO now faces is addressing the administrative issues that arise in relation to implementation of polio eradication activities in difficult circumstances (e.g. transfer of cash in the absence of a banking system). Since 1988, when the first medical officers were appointed in WHO/HQ to support polio eradication activities, the number of polio-funded immunization and surveillance staff has grown to over 1979 persons in 63 countries as at October 2001 (this figure includes all national and international polio-funded immunization staff on contracts of six months or longer). Of these staff 90% are employed at the country level, 7% at regional level and 3% at headquarters. The majority of staff (79%) are nationals of the country in which they work. All staff require support in the form of contracts, salary payments, office space and equipment, communications and transport. In order to monitor staff recruitment and support, V&B maintains a global database for all consultant, short-term and fixed-term contracts. The PEI has been the largest single source of funding for the refurbishment of the physical equipment required for routine immunization and surveillance in much of the developing world since the mid 1990s. For example, the WHO Regional Office for Africa has estimated that over 30% of the cold chain in sub- Saharan Africa has been refurbished with polio eradication funding. Other elements of the physical infrastructure funded through the Initiative include vehicles, communications technology, office and computer equipment and laboratory supplies and equipment. In 2000, WHO alone spent US$5 million on 343 vehicles and 179 motorcycles, US$ 2.4 million on cold-chain equipment (refrigerators and cold boxes) and US$1.94 million on laboratory supplies and equipment. V&B maintains a procurement tracking system to monitor purchases made directly by WHO headquarters as well as the location of all large equipment anywhere in the world. In 1988, the funding provided for the Initiative globally amounted to less than US$ 12 million per year (of which US$ was through WHO). By 1995, this figure had grown to US$ 50 million (of which US$ 8 million was through WHO), and in 2000, to over US$ 350 million in external funding (of which US$ 242 million was through WHO). To track funding requirements, donations and unmet needs, a financial database is maintained by V&B, and regularly updated with information from the six WHO regions and UNICEF. Since 2000, an annual report has been produced detailing the external financial resource requirements, pledged and projected donations and the corresponding unmet needs. To address specific administrative issues related to the implementation of polio eradication activities, WHO headquarters (as well as each of the remaining polioendemic regions) established an administrative task force, which is responsible for the rapid resolution of such issues. The headquarters task force has been in existence since April 1999, and meets as required. Through these taskforces, administrative reviews have been conducted in priority regions and countries, and technical officers and/or administrative officers recruited as required. VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY 54

61 TARGET EIGHT Human resource management Indicators Proportion of staff hired against Global Management team recruitment targets for headquarters, regional offices and countries. 90% Tracking system for recruitment targets and staff hired is in place. 100% Tracking system for recruitment targets and staff hired is maintained; expansion of system to V&B as required. 100% Tracking system for recruitment targets and staff hired is maintained. 100% Tracking system for recruitment targets and staff hired is maintained. Supplies management Indicators Proportion of supplies delivered by the anticipated delivery date. At least 80% (procured through WHO headquarters). At least 80% (procured through WHO headquarters). At least 80% (procured through WHO headquarters). At least 80% (procured through WHO headquarters). Completeness of regional inventories of transport equipment. Maintenance of an up-todate global inventory of transport equipment. Maintenance of an up-todate global inventory of transport equipment. Maintenance of an up-todate global inventory of transport equipment. Maintenance of an up-todate global inventory of transport equipment. Financial and grant management Indicators Proportion of grants fully implemented by expiry date. 90% 100% 100% 100% Proportion of monthly and annual reports on financial requirements, donations and unmet needs. 80% 100% 100% 100% 55

62 9 TARGET NINE Define and implement control and elimination strategies for priority diseases and conditions that are vaccine preventable Critical indicator: Measles. Proportion of countries achieving measles control/elimination goals As of October 2002, 156 out of 191 (82%) countries have implemented the second dose opportunity for measles immunization and 88 countries (36%) have a coverage with measles containing vaccine above 90%. Figure 10: Countries implementing measles mortality reduction strategies Achieving 90% measles coverage, 2001 > 90% (88 countries or 46%) < 90% (81 countries or 42%) No data (22 countries or 18%) VACCINES, IMMUNIZATION AND BIOLOGICALS STRAGETY Providing 2nd opportunity,* Yes 2nd opportunity (156 countries or 82%) No 2nd opportunity (35 countries or 18%) * 2nd opportunity: Country has implemented a two-dose routine measle schedule and/or withing the last four years has conducted a national immunization campaign achieving > 90% coverage of children < 5 years Source: WHO/UNICEF Critical indicator: MNT. Proportion of developing countries achieving maternal and neonatal tetanus elimination goal As of October 2002, 131 out of 188 (70%) countries have achieved maternal and neonatal tetanus elimination. 56