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Immunization, Vaccines and Biologicals


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines
Including Minutes of the Steering Committee Meeting Geneva, 2728 April 2005

Immunization, Vaccines and Biologicals


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines
Including Minutes of the Steering Committee Meeting Geneva, 2728 April 2005

The Department of Immunization, Vaccines and Biologicals thanks the donors whose unspecified financial support has made the production of this document possible.

This document was produced by the Initiative for Vaccine Research of the Department of Immunization, Vaccines and Biologicals Ordering code: WHO/IVB/06.09 Printed: August 2006

This publication is available on the Internet at: Copies may be requested from: World Health Organization Department of Immunization, Vaccines and Biologicals CH-1211 Geneva 27, Switzerland Fax: + 41 22 791 4227 Email:

World Health Organization 2006

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Abbreviations and acronyms .......................................................................................... v Acknowledgements ........................................................................................................ vii Preface .............................................................................................................................. ix 1. Objectives and strategies of the Steering Committee ..................................... 1 2. Dengue ....................................................................................................................... 3 2.1 Meeting reports on dengue............................................................................... 3 2.2 Evaluation of dengue vaccines ........................................................................ 5 2.3 Recommendations for dengue standard sera ............................................... 10 2.4 PDVI activities update .................................................................................... 11 3. Japanese Encephalitis (JE) ................................................................................... 12 3.1 JE vaccine pipeline .......................................................................................... 12 3.2 JE vaccine supply and introduction ............................................................... 17 3.3 JE correlates for protection ............................................................................ 18 3.4 A retrospective JE study proposal ................................................................ 19 3.5 PATH activities update ................................................................................... 20 4. Other flaviviruses .................................................................................................. 22 4.1 Epidemiology of West Nile virus update ...................................................... 22 4.2 YF vaccine safety 20002005 ........................................................................ 23 5. Discussion and recommendations ...................................................................... 25 5.1 Dengue vaccines .............................................................................................. 25 5.2 JE vaccines........................................................................................................ 26 5.3 Other flavivirus vaccines ................................................................................ 26 Annex 1: List of Participants ..................................................................................... 27



Abbreviations and acronyms

Ab ADE AE AES AFRIMS BHK cDNA CI CMI CSF CTL DF DHF DV ECBS ELISA ELISPOT EPI GACVS GAVI GCV GMT GSK HIV IFN IgG IgM IND IVD antibody antibody dependent enhancement adverse events acute encephalitis syndrome Armed Forces Research Institute of Medical Sciences baby hamster kidney copy deoxyribonucleic acid confidence interval cell mediated immunity cerebrospinal fluid cytotoxic T lymphocyte dengue fever dengue haemorrhagic fever dengue virus Expert Committee on Biological Standardization (WHO) enzyme-linked immunosorbent assay enzyme-linked immunospot expanded programme on immunization Global Advisory Committee on Vaccine Safety (WHO) Global Alliance for Vaccines and Immunization geometric coefficient of variation geometric mean titre GlaxoSmithKline human immunodeficiency virus interferon immunoglobulin G immunoglobulin M investigational new drug immunization and vaccine development


Initiative for Vaccine Research (WHO department) Japanese encephalitis live attenuated virus material transfer agreement modified vaccinia Ankara neutralizing antibody National Institute for Biological Standards and Control National Institutes of Health Program for Appropriate Technology in Health Paediatric Dengue Vaccine Initiative product enhanced reverse transcriptase primary green monkey kidney plaque reduction neutralization quality assurance quality control Quality Safety and Standards (WHO team) research and development ribonucleic acid reverse transcriptase polymerase chain reaction serious adverse events Steering Committee (Dengue & other Flavivirus Vaccines) WHO Regional Office for South-East Asia standard operating procedure specific pathogen free tick-borne encephalitis UNDP/World Bank/WHO Special Programme for Research & Training in Tropical Diseases T helper (cell) United Nations United States Centers for Disease Control and Prevention vaccine adverse event reporting system West Nile virus WHO Regional Office for the Western Pacific Walter Reed Army Institute for Research yellow fever yellow fever virus



Special thanks is given to the Chair of the Steering Committee Meeting, Dr Alan Barrett, and to the rapporteur, Dr Alan Rothman.




Introduction: context of the meeting. The World Health Organization (WHO) Steering Committee (SC) on dengue and other flavivirus vaccines met for its annual meeting on 2728 April 2005 at WHO headquarters in Geneva, Switzerland. The meeting agenda comprised a scientific forum, held all day on 27 April and 28 April in the morning, followed by a closed meeting for SC members on the afternoon of 28 April. The SC was organized to run in tandem with two other WHO meetings covering dengue, namely a two-day meeting (2526 April 2005) on dengue diagnostics, organized by WHO/Special Programme for Research & Training in Tropical Diseases (TDR) and co-sponsored by the Paediatric Dengue Vaccine Initiative (PDVI), and a one-day meeting (on 29 April 2005) organized by WHO/CSR, on control and surveillance of dengue. The clustering of the dengue meetings within one week, gave experts the opportunity to attend several meetings at once, and helped coordination between the different activities. Several SC members attended all of the meetings. The SC meeting was opened by Dr Thomas Cherian (WHO). He reminded participants of the objectives of the SC and highlighted the importance of remaining use-inspired, keeping the ultimate objective of making vaccines available for populations in need alive throughout the discussions on research needs and on the obstacles to flavivirus vaccine development. Dr Joachim Hombach (WHO) explained the context of the meeting and introduced the new Chair of the SC, Professor Alan Barrett of the University of Galveston, Texas, the United States of America. He thanked the outgoing Chair, Dr Ichiro Kurane (National Institute of Infectious Diseases, Japan), for his work and dedication towards flavivirus vaccines, as well as his support for WHO. Dr Kurane has been a long-serving member and Chair of the SC and is stepping down from membership in accordance with WHO procedures. Dr Barrett briefly presented the Minutes of the last SC meeting, which was held in Bangkok, the Kingdom of Thailand. Minutes of the meeting, as well as the agenda of the 2005 meeting, were adopted by the Steering Committee.


1. Objectives and strategies of the Steering Committee

The specific responsibilities of the SC are to: assist the Secretariat of the Initiative for Vaccine Research (IVR) in providing guidance to, and coordination with, the international vaccine research and development (R&D) effort to develop and improve dengue and other flaviviruses vaccines; assist IVR in preparing its workplan on flavivirus vaccines and identifying opportunities for new lines of research; review the public health relevance, scientific quality, and budgets of all relevant research projects proposed to IVR, and monitor technical and scientific progress of these research activities; make recommendations on scientists and institutions suitable to formulate and carry out specific research and development projects, or other studies for IVR.

For dengue vaccines, the strategies are to: facilitate evaluation of, and provide guidance on new vaccines, by providing a platform for exchange of information for vaccine developers, researchers, and public-health experts; support targeted research on new dengue vaccines in accordance with research needs identified by the SC and WHOs comparative advantage; provide technical and normative support for evaluation of dengue vaccines, including, jointly with WHO/Quality, Safety and Standards (QSS), the provision of standardized research materials.

For Japanese encephalitis (JE) vaccines, the strategies can be summarized to: support the development of new and improved JE vaccines through technical advice, coordination and monitoring of clinical trials; provide technical and normative support for evaluation of JE vaccines, including the provision of standardized research materials (jointly with WHO/QSS); provide technical support and guidance on activities related to disease-burden assessment, vaccination strategies, and accelerated vaccine introduction.


With regard to other flavivirus vaccines, such as yellow fever (YF), West Nile virus (WNV) and tick-borne encephalitis (TBE), the strategy is to monitor the field in relation to disease burden, vaccine development and vaccine safety. The SC should provide advice to WHO on these issues on an ad hoc basis.

2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

2. Dengue


Meeting reports on dengue

Dr Jane Cardosa (University of Malaysia) presented a report of the TDR/PDVI meeting on dengue diagnostics held 2526 April 2005. The group held a first meeting in October 2004 which generated a consensus on areas of need for new diagnostics for patient management, disease surveillance, and vaccine evaluation, and on that basis a sketch for a strategic plan was produced. The second meeting objectives were to raise awareness of the WHO strategy, and to develop an action plan and a consensus on public-private partnerships for test development and evaluation. The required product profile of a good diagnostic test depends on its utilization, and includes sensitivity in the acute phase, specificity for dengue versus other flaviviruses, and among the dengue serotypes, simplicity, rapidity of use, and finally cost. All tests need to be validated in real-use conditions. Concerns were raised in relation to cost, and questions concerning specifications, intellectual property, requirements for standardized reagents, and well-characterized specimens. However it was felt that these perceived obstacles should not prevent an exploration and evaluation of all the diagnostic options. WHO/TDR has an established strategy on diagnostics development, including evaluation and procurement, and it plans to apply this to dengue diagnostics. The strategy involves: the establishment of specimen banks; networking of laboratories (including reference centres); research on test introduction; guidelines for use; bulk procurement and negotiated pricing. Opportunities to support test development identified by the group include a large prospective multicentre clinical study of dengue disease planned in Latin America and South-East Asia (five sites, 5000 subjects), as well as the PDVI field sites. The group discussed the need for a WHO/TDR laboratory network for evaluation and quality control (QC) of diagnostic tests, including regional reference laboratories, a network of evaluation sites, corporate participation, and a serum and virus strain bank. QC issues include identifying the laboratories, developing standardized reagents (antigens and antibodies), and setting standards for ribonucleic acid (RNA) tests. Although the focus is on rapid diagnostic testing for case management, the need for advanced diagnostic testing was discussed briefly, including neutralization tests serving as correlates of protection and with better scalability, and cell mediated immunity assays of B cell, T helper (Th), and cytotoxic T lymphocyte (CTL) responses. The action plan developed during the meetings closed session included assembling development and evaluation specimen panels, and selection of reference and evaluation laboratories. Promising candidate tests under commercial development included the detection of NS1 antigen, which could be suitable both for early case detection and disease-burden studies.
WHO/IVB/06.09 3

Discussion: Additional points raised during the discussion included the suitability of nucleic acid tests, the value of immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA)/dipstick tests, and the opportunities for integration with JE diagnostic efforts. Vaccine developers voiced their interest in being affiliated to these activities, even though the diagnostic needs in clinical trials go beyond these types of acute disease tests. However, it was recognized that they have much value for trial cohort characterization and volunteer recruitment. Dr Kurane presented a report of the meeting of the clinical trial task force held in Bangkok, Thailand, on 17 October 2004, and chaired by Dr Francis Ennis (University of Massachusetts, USA). The objectives of this meeting were: to review the current status of dengue vaccine development; to analyse the data and provide advice to manufacturers; to identify common obstacles and recommend activities to advance the field; to provide a forum for scientific exchange; and to review progress in preparation for clinical field trials and determine the immunologic parameters to be assessed. Summaries of progress on vaccine development were presented at the meeting from representatives of GlaxoSmithKline (GSK), Walter Reed Army Institute for Research (WRAIR), Sanofi-Pasteur, Acambis, National Institutes of Health (NIH), and Hawaii Biotech. Additional presentations reviewed the human challenge model, efforts by Sanofi-Pasteur to develop a field site in the Socialist Republic of Viet Nam, immune responses to dengue, parameters to be measured in a vaccine study, and new immunological assays. The recommendations of the task force meeting were: that standardized reagents should be provided to vaccine companies; that priority should be placed on development of high throughput neutralization (or other functional) assays; that efforts be coordinated with TDR and PDVI to collect samples and encourage a WHO-sponsored workshop on immunologic correlates. Discussion: Major points raised addressed the question of the possible correlates of protection against dengue. Several groups, including WRAIR and Sanofi, reported that they were actively working on new assays of humoral and cellular immune responses, but that these require more complex quality assurance (QA) efforts. Some urgency to develop tests to support field trials was noted, especially in establishing correlates or surrogates to support licensing applications. New methods should be validated and published to instruct regulatory authorities on new assay methods. However, given the complexity of the immune response, and the clinical need, there was general agreement that vaccine trials should not be delayed because of a lack of ideal immunologic assays.

2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines


Evaluation of dengue vaccines

Dr Mammen Mammen, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand, reviewed the monkey viraemia model as a tool for vaccine development. After reviewing other animal models, he noted that viraemia, immunogenicity and neurovirulence could be assessed in the monkey model, with applications for studies of dengue pathophysiology, drug therapy, and vaccine evaluation. However the monkey could not serve as a disease model, as no dengue disease develops in infected animals. Reviewing data published in the 1960s and 1970s, he concluded that the monkey model could distinguish solid and partial protection afforded by candidate vaccines through a sequential infection experimental design. Reactogenicity, safety, and immunogenicity could also be assessed in this model. Dr Mammen reviewed the recent experience of the WRAIR group in using the monkey model to test candidate tetravalent live attenuated vaccines, where incomplete protection was observed against viraemia during challenge. Further optimization of the monkey model was suggested, including species, age, gender, and selection of assays for viraemia. He concluded that the monkey model was useful for preclinical down selection of vaccine candidates, but noted the high costs of the model, which are likely to increase with regulatory requirements. Discussion: There was discussion around what constitutes the preferred species for dengue studies, and whether wild monkeys would provide a better model. Several different species have shown reproducible viraemia and different groups reported using different species. It was noted that occasionally monkeys do show disease symptoms, and rare deaths have been reported, but there is no reproducible clinical illness. Data presented by Dr Mammen showed surprisingly high viraemia titres in tertiary dengue infections. To summarize, although the value of the monkey model was recognized for down selection of candidate vaccines, there was less interest in developing a standard model, given its limited predictability for humans. Dr Penelope Koraka (Erasmus University, Rotterdam, the Netherlands) presented a summary of the universitys studies of dengue infection in cynomolgous macaques. This research has been supported by an IVR grant. The aims of the study were to assess this primate model for dengue vaccine evaluation, and if possible, to standardize methods. Four groups of six animals were infected with a different dengue serotype. Six to nine months later the D1, D2, and D4 groups were challenged with D3 virus, and the D3 group and a fifth dengue-nave group were challenged with the GSK tetravalent live attenuated virus (LAV) vaccine. Early evaluations performed daily for 14 days after virus challenge, included telemetry and collection of blood samples for reverse transcriptase polymerase chain reaction (RT-PCR) and analysis of inflammatory gene expression. Later, samples were collected for antibody (Ab) IgM and immunoglobulin G (IgG) ELISA and IFN-gamma enzyme-linked immunospot (ELISPOT) assays. Viraemia in primary infection was generally short, and was not detected in half of the animals receiving D2. In secondary D3 infection, viraemia could not be detected in any of the animals. All animals seroconverted however, suggesting that an infection occurred, and antibody responses were similar to humans. Primary D1 induced the highest interferon (IFN) -gamma responses. Responses to D2 and D3 were low but responses in D2-immune animals were boosted by secondary D3 infection. Overall, T cell responses appeared to be quite variable. Primary infection with the GSK tetravalent vaccine produced encouraging IFN-gamma responses to all four serotypes, with a pattern of antibody


responses similar to those seen in primary and secondary responses with challenge virus. Dr Koraka concluded that despite the lack of symptoms, virus replication occurs in macaques and antibody responses are similar to humans, suggesting that virus-infected macaques could be used as a model. Further studies of cell-mediated immune responses, serotype-specific antibody responses, and gene expression profiles, are ongoing. A second challenge of all animals is pending. Discussion: Unlike the response observed in humans, it was noted that in heterologous secondary virus infection, the IgM response was noted to be very low in the macaques. Not all D2-infected animals were viraemic, and cell mediated immune responses (CMI) to this serotype were low. There was also discussion on the viraemia observed in this study which appeared to occur very early after virus injection, triggering the question as to whether this represented injected virus. A quantification of viraemia in this model should be contemplated. Dr Wellington Sun (WRAIR) presented the results of experimental dengue virus (DV) challenge of human volunteers. He firstly reviewed the background for the studies, including their application for other diseases, their objectives, history, and ethical issues generally affecting challenge studies, as well as the specific rationale of challenge studies with DV. He reported that experiments at WRAIR with D1 and D3 challenge strains have shown promise, and other challenge strains are now under development. Challenge of DV-nave subjects with D1 strain 45AZ5 FRhL-8 led to seroconversion in all subjects and measurable viraemia in five out of six subjects. With D3 strain CH53489 PGMK-4, C6/36-7 all seven subjects showed both viraemia and seroconversion. Further studies were done to assess whether vaccination with the GSK-WRAIR tetravalent live attenuated vaccine induced protective immunity. For each of the challenge strains, five vaccinated subjects and two unvaccinated control subjects were challenged; all subjects were hospitalized for observation between days 4 and 17 post-challenge. All vaccinated subjects were protected against D1 challenge. Three of the five vaccinated subjects challenged with D3 developed illness and viraemia; these subjects had low titres of neutralizing antibody against D3 pre-challenge. Additional immunological studies planned include investigation of antibody avidity and cell-mediated immune responses. Dr Sun then reviewed the implications of this data for a future comparison of the efficacy of two vaccine candidates. Assuming vaccine efficacy of ~70% with 20% difference between groups would require 62 subjects per group. In summary, he concluded that the human challenge model showed sufficient promise to warrant further development, but that intense clinical supervision and larger sample sizes would be needed. Dr Sun suggested that further directions for development of this model could include studies of D2 and D4, better definition of the optimal dose and route of challenge (needle versus mosquito inoculation), and expansion of the trial capacity to conduct these studies.

2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

Discussion: Sample size assumptions would be affected by the anticipated use of this model; possible scenarios for using the challenge model to support licensing of a vaccine versus its use as a gatekeeper in selecting vaccine candidates for advanced clinical development. The use of the model in helping to define surrogates for protection was also given as a rationale. Overall it was felt the models best justification was to be used as a selection criterion for moving into field efficacy testing. The approach to further development of the model (e.g. how to select challenge strains of D2 or D4), and expectations of the time required for development, were also discussed. It was suggested that efforts be made to draw correlations between the data from challenge studies in humans, and in non-human primates. Dr Jean Lang (Sanofi-Pasteur) provided a summary of observations related to viraemia in recent clinical trials. He reviewed results from four vaccine trials, a study of the Sanofi tetravalent live attenuated vaccine in Thai adults (DEN04), a study of the tetravalent vaccine in Thai children (DEN06), a study of a monovalent D3 vaccine in adults in Hong Kong (DV01A), and a study of a monovalent Chimerivax-D2 vaccine in adults in the United States. He began by discussing the relationship between viraemia and reactogenicity. Study DEN06 involved two tetravalent formulations differing in the titre of D2 and D4, each given in three doses (0, 35, and 12 months); viraemia was assessed only at one time-point 10 days after injection. Viraemia ~1 log was noted after the first dose for all serotypes, whereas after the second dose there was only low D2 viraemia and after the third dose only a few subjects had D4 viraemia. Symptoms were present after the first dose, but were absent after the second dose, and lower but present after the third dose. Most manifestations were mild, but some subjects experienced fever and headache after dose 3. Study DV01A studied a monovalent biologically-cloned D3 strain. This strain caused low-level viraemia in the monkey model; however, in volunteers, viraemia of up to ~105 was noted in association with significant symptoms, including fevers up to 39C, leukopenia, and lymphopenia. The study of ChimeriVax-D2 involved doses of 3 or 5 logs of the vaccine strain in YF-immune or nave subjects. The vaccine was well tolerated, and less than one out of three subjects were viraemic. Dr Lang then discussed the relationship between antibody pre-vaccination titres and viraemia in the tetravalent vaccine studies. For D1, neutralizing antibody (NAb) titres of 1:30 and above were associated with absence of viraemia with subsequent doses, while for D3 absence of viraemia appeared to be associated with NAb titres of 1:100 and above. For D2 and D4, NAb titres after the first dose were low, and viraemia occurred with subsequent doses. Dr Lang concluded that the data suggested that viraemia and reactogenicity are closely related for dengue vaccines. He also concluded that the data suggested that there is a protective level of NAb against D3, whereas a mix of suppression and enhanced vaccine take may occur for the other serotypes. He therefore recommended analysis of similar data from other studies to confirm or refute these findings.


Discussion: Discussion centred on the findings in study DEN01A and the lack of correlation between monkey viraemia data and observations made in humans. The matter had previously been discussed in the context of the clinical trial task force. The question of which is the lowest level of viraemia associated with symptoms cannot be answered from study DEN01A, as all subjects had at least 4 logs of viraemia as well as symptoms. The serotype-dependent minimum NAb titres observed to correlate with absence of viraemia, are an important consideration for the discussion of correlates of protection. Dr Alan Rothman (University of Massachusetts, USA) presented a summary of data on correlation between pre-existing antibodies and protection from disease. Data were obtained in a prospective cohort study in Kamphaeng Phet, Thailand, which had been conducted in collaboration with AFRIMS and the Thailand Ministry of Public Health. Plasma was collected from more than 2000 school children, and subjects were followed for five years with active surveillance for febrile illness and dengue virus infections which were detected by serologic responses and virus detection/isolation from ill subjects. Illness severity was categorized as hospitalized dengue haemorrhagic fever (DHF), hospitalized dengue fever (DF), non-hospitalized DF, or sub-clinical infections. NAb titres in plasma samples obtained between six and nine months prior to secondary dengue virus infections, were determined to both prototype strains and, when available, to the subjects own isolate. NAb titres as high as 1:100 to the subjects own isolate were noted in some cases. Among subjects with secondary D3 infections, NAb titres showed an inverse correlation with levels of viraemia and disease severity. However, a similar protective association could not be shown among subjects with secondary D1 or D2 infections, and there were too few D4 infections for analysis. Plasma samples obtained prior to secondary D2 or D3 infections were also tested for activity in assays of antibody-dependent enhancement (ADE) in K562 cells, using low passaged Thai virus strains. Although many subjects had measurable ex vivo ADE activity, it did not show a significant correlation with viraemia or disease severity among subjects with D2 or D3 infections. Dr Rothman concluded that data from this prospective study of naturally-acquired antibodies suggested a protective effect induced by cross-reactive humoral immune responses to secondary D3 infection, but not in secondary D1 or D2 infection. This might be due to inefficient titre or antibody affinity. Also, in relation to D3, this study did not point to a specific NAb titre that could reliably indicate protection against infection or disease.

2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

Discussion: Both sets of data presented were considered to be highly relevant to the safety and efficacy of live attenuated tetravalent dengue vaccines. The question was raised as to whether NAb titres were measured in subjects with sub-clinical/asymptomatic infections or whether IgG subclasses were examined. Dr Rothman indicated that these studies had not been done, but noted that the serotypes causing sub-clinical infections could technically not be determined. Dr David Vaughn (Military Infectious Diseases Research Program, USA) chaired a discussion on the need for and potential value of a dedicated workshop on correlates of protection for dengue vaccines. The elements of such a workshop, as well as the utility of correlates for vaccine development and licensure were briefly addressed. In discussion, it was pointed out that severe dengue is rare, and that perhaps the correlates of protective immunity would be more apparent in people who do not get sick. It was also noted that the immune response in non-apparent infections has been under-investigated, and that this should be a research priority. Prospective cohort studies or specific epidemiological situations, such as those encountered in Cuba, should be further investigated. Questions were raised as to whether identification of correlates of vaccine safety should also be a workshop topic, but it was felt that topics should be kept separate. An effort was made to differentiate between correlates and surrogates, and whether from a regulatory perspective the surrogate is more stringent. Additional discussion centred upon whether vaccine efficacy would need to be shown against all four serotypes or whether demonstrated efficacy against one serotype would be sufficient for licensure. It was noted that a workshop on correlates of protection for Japanese encephalitis (JE) vaccines had recently been held. Dr Harold Margolis (PDVI), indicated interest on the part of PDVI in involvement in organizing a workshop on this topic.



Recommendations for dengue standard sera

Dr Ferguson of the National Institute for Biological Standards and Control (NIBSC) presented the results of their assessment of the suitability of candidate reference material as an international standard for antibodies to dengue virus. She reviewed the rationale for definition of an international standard, which was to facilitate standardization of assays for vaccine trials across different laboratories. The candidate standards tested were derived from plasma donations in Thailand where a pool, prepared from two donations, was freeze-dried and tested to exclude the presence of hepatitis viruses or human immunodeficiency virus (HIV). Two collaborative studies were conducted, the first of which involved eight participating laboratories in six countries, and the other seven laboratories, including vaccine developers. Samples were coded for analysis, and these included a negative control, a duplicate coded sample of plasma with NAb to all four dengue serotypes, and each of the four monovalent plasma samples (NAb present to only one of the four serotypes). In the first study, participating laboratories were also supplied with Vero cells and virus strains for each of the serotypes, as well as a protocol to harmonize assays. Participating laboratories were requested to perform three independent NAb assays using the test panel, including a series of dilutions of the plasma samples. Plaque counts were provided to NIBSC and PRNT 50 values were calculated. The results with the four monovalent plasma samples were less convincing, with overall low titres (except for the D3 plasma), false negative results (particularly for the D1 plasma), and occasional cross-reactive neutralization of other serotypes. The candidate tetravalent standard had mean NAb titres to the four serotypes in the range of 80320, and results from the different laboratories were relatively closely grouped. Nevertheless, the geometric coefficient of variation (GCV) between labs was >100%. Dr Fergusons conclusions were that the candidate tetravalent serum had reasonable titres to all four serotypes and its use as a standard for expression of NAb titres did improve the variance in NAb titres measured between laboratories. The monovalent plasma samples were not felt to be suitable as international standards however, given their overall low titres. They could however be useful reagents for use by laboratories. Dr Ferguson would disseminate a study report to participants and the SC by mid-June for final comments, prior to submission of the report to the WHO Expert Committee on Biological Standardization (ECBS) in November 2005. Discussion: A number of technical questions were raised, for instance how neutralising end points (e.g. PRNT50s) were calculated, whether a different breakpoint (e.g. 70%) would yield different results, and reasons governing the variation in NAb titres measured. There was general agreement that the variability in the data was problematic but probably reflected the status of the field. It was also pointed out that most participating laboratories did not follow the assay protocol provided, but preferred to use their in-house assay. Potential recommendations were discussed regarding the utility of an international standard and how such a standard would be used (e.g. for calibration of assays or reporting of NAb in units). It was proposed, and unanimously agreed by participants, that the tetravalent plasma be proposed as a first-generation international standard for anti-dengue antibodies.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines


PDVI activities update

Dr Margolis (PDVI) presented an update of PDVI activities and plans. He described the goal of PDVI as accelerating the evaluation and introduction of a paediatric dengue vaccine, for use in developing countries. He then went on to review the challenges to development of such a vaccine, and presented the logic model for PDVI activities along the vaccine development pipeline from basic science to implementation and improvement of vaccines. He noted PDVI areas of interest as: vaccine evaluation; development of the case for vaccine use; public-private partnerships; and advocacy. In developing a case for dengue vaccine utilization, he cited PDVI activities: improving epidemiologic information; assessing the cost of dengue illness; developing models of the burden of illness; assessing the cost-effectiveness of vaccines; strengthening surveillance; performing comparative economic analysis; and improving vaccine access. In the area of vaccine evaluation, he cited PDVI activities in preclinical studies (12 investigators funded), vaccine safety, diagnostics, development of field sites for vaccine evaluation (one site funded so far), and development (in collaboration with WHO), of guidelines for evaluation of candidate vaccines. He described PDVIs plans for co-sponsorship, with WHO, of a Science Forum on Evaluation of Dengue Vaccines, with the objective of bringing together experts in dengue and other vaccine-related fields. Potential topics would include trial endpoints, target efficacy, trial duration, safety issues, role of Phase IV studies, and the potential confounding effect of other flaviviruses. The meeting format proposed would be an invited meeting, with plenary presentations and workshops to discuss key issues. It was tentatively scheduled for November 2005 at the Fondation Mrieux, and would be co-chaired by Dr Burke and Dr Plotkin.



3. Japanese Encephalitis (JE)


JE vaccine pipeline

Dr Thomas Monath (Acambis) reviewed the status of clinical development of ChimeriVax-JE, the chimeric flavivirus vaccine based on the prM-E genes of JE strain SA14-14-2 inserted into the background of a yellow fever virus (YFV) 17D infectious of copy deoxyribonucleic acid (cDNA) clone. Trials for adult indication are currently entering Phase III. Beyond the travellers market, the companys objective is to produce an affordable single-dose vaccine safe for paediatric use down to nine months of age, which is suitable to be co-administered with other vaccines, in particular measles vaccine. He noted that the vaccine gave good results in preclinical safety and efficacy testing in multiple models, and that passive immunization with sera from mice immunized with ChimeriVax-JE was protective. Similarly, the published Phase I/II clinical studies showed a good safety and immunogenicity profile. Dr Monath reviewed in detail a Phase II trial conducted in Australia on 200 subjects. He noted that additional Phase II studies were in progress and that Phase III studies were planned to begin in the second half of 2005. The Phase II study tested a single dose (3.8 logs) of ChimeriVax-JE versus placebo in a double-blind crossover design with the primary endpoints to assess antibody response to primary vaccination and booster dose, as well as the durability of antibody over 24 months post-vaccination. Subjects were predominantly young male Caucasians, and there had been no deaths in the study. Three severe adverse events (SAE) were reported, one of which was thought to be treatment-related, but which was finally identified in the placebo group. Adverse events (AEs) were reported in 50% of the subjects, but were not significantly different between the treatment and placebo group. Seroconversion was noted in 82% of ChimeriVax-JE recipients at day 14 and in 99% at day 28, with geometric mean titres (GMTs) >300 at day 28. NAb were detected in 99%, 92%, 99%, and 89% of subjects in response to genotypes I, II, III, and IV respectively (the vaccine belongs to genotype III). Ninety-five percent of subjects remained seropositive at 6 and 12 months post-vaccination, with GMTs of 150 and 97 respectively, at these two time points. After a booster dose, all subjects were seropositive at one month, with 26% showing a 4-fold rise in titre; 99% remained seropositive at 12 months after the booster dose, with GMT of 181. In order to test for any interaction with YFV vaccine, a study looked at each sequence with an interval of 30 days versus simultaneous administration of both vaccines. At day 30 after completion of both vaccines, seroconversion to JE and YF occurred in 91100% and 94100% of subjects respectively. Seroconversion rates and GMT to JE were somewhat lower when ChimeriVax-JE was administered after or with YF vaccine, whereas Ab responses to YFV were similar in the three groups.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

Dr Monath concluded that ChimeriVax-JE was well tolerated, giving high rates of seroconversion after a single dose, good Ab persistence over 12 months postvaccination, and showing minimal interaction with YFV vaccine. Discussion: In relation to vaccine virus viraemia, Dr Monath stated that the company was no longer studying this in detail, but noted that published data showed viraemia with ChimeriVax-JE to be similar to that with YFV 17D, i.e. low titre during the first several days after immunization. A negative correlation had been observed between viraemia and antibody response. Dr Monath stated that the evaluation of single-dose immunization with ChimeriVax-JE was planned for an upcoming Phase III study. Dr Jane Cardosa (University of Malaysia) described work being done in collaboration with Bavarian Nordic to develop a modified vaccinia Ankara (MVA)-BN-vectored JE vaccine. MVA-BN was derived from the Ankara smallpox vaccine, and is a clonal virus grown in serum-free medium, that is more attenuated than other MVA strains for in vitro growth in Vero, CV1, and HeLa cells. BN has programmes for development of MVA-BN-based vaccines against measles, dengue, and JE. The MVA-BN-vectored JE vaccine contains the prM-E gene region from a genotype II Sarawak strain of JE which was isolated from a fatal human case. The gene insert has been verified and the virus produces JE antigen in baby hamster kidney (BHK) cells in vitro. The group is also beginning mouse immunization studies with the virus. Mice were immunized with the MVA-JEpME or an MVA-D3pME virus (dengue construct), two doses being administered with an interval of three weeks. After the second dose, pooled sera from the JE and D3-immunized groups showed GMTs of 1:40 and 1:10 respectively, with mice showing neutralizing antibody only to the homologous virus in each group. Ongoing work includes further mouse immunizations, process development, toxicity/stability studies, and development of T cell and antibody assays. Discussion: Dr Cardosa explained that the group was planning to study whether the vaccine virus produces flavivirus-like particles. It was noted that vector immunity could be a problem for the MVA-BN vaccines, as it has been for avipox-vectored vaccines. Dr Yuhua Li (Chengdu Institute of Biological Products) provided an overview on both preclinical and clinical data of the SA14-14-2 live attenuated JE vaccine. Reviewing preclinical studies, she emphasized the absence of neurovirulence of the SA 14-14-2 vaccine strain in mice, including nude mice. The virus was found to be phenotypically stable and genetic analysis showed no changes over time at the nine vaccine markers. Regarding safety of production, the master seed was screened and found negative of retrovirus activities as demonstrated by product enhanced reverse transcriptase (PERT) assay, and negative for a large variety of adventitious viruses. A specific pathogen free (SPF) animal facility for golden hamsters has been established with the capacity for 4000 animals per year for vaccine production. The target product profile for the vaccine is a single-dose vaccine that can be co-administered with measles vaccine at the age of nine months. Lot consistency has been good for 14 lots of vaccine. Moving to clinical data, Dr Li reviewed the clinical



safety experience from 19791991. Over 600 000 individuals have received vaccine in the context of efficacy and safety studies, with no vaccine-associated encephalitis cases reported. All of these studies were observational. Long term immunogenicity was assessed in non-endemic regions, and demonstrated that some 89% of vaccinees remained seropositive six years after receiving two doses of vaccine, as opposed to 100% after the second dose. Vaccine efficacy and effectiveness had been analysed in case control studies. With regard to long-term effectiveness, mortality from JE in vaccinated subjects has been ~1 in 100 000 individuals, yielding an estimated vaccine efficacy of 7399%. A case-control study resulted in a calculated vaccine effectiveness of 8099%. In a small number of volunteers, the vaccine was co-administered with measles vaccine with no apparent difference in febrile reactions. Currently the vaccine is included in the expanded programme on immunization (EPI) in most JE-endemic provinces of China, and demand for the vaccine has been increasing, both from within and outside China. Discussion: It was noted that the data on high seroconversion rates with a single dose of vaccine stood in contrast to older published data. This might be due to the fact that the earlier data was obtained with a different vaccine of higher attenuation (SA 14-5-3), which achieved some 70% seroconversion after one dose, in contrast to 92% seroconversion with one dose of SA14-14-2. Nevertheless, it was pointed out that the second dose represented an extra opportunity to ensure coverage, and also that long term protection by a one-dose schedule had yet to be confirmed. In relation to production capacity, Dr Li explained that the SPF facility could raise some 180 000 hamsters per year, which would yield some 70 million doses. This figure is higher than the one that had been previously communicated. Dr Erich Tauber (Intercell) presented an update on the inactivated JE vaccine, IC51 vaccine, being developed by Intercell, a biotech company based in Vienna, Austria. IC51 is based on the SA14-14-2 vaccine strain. It is produced in Vero cells, and purified, inactivated, and formulated with alum. Apart from the cell expansion phase, the process is fetal calf serum free. The company has two target markets, travellers and the military, and also endemic countries. For the adult indication, Phase I and II studies have been conducted under an investigational new drug (IND) in the United States through WRAIR. Data to date demonstrates increasing seroconversion rates with escalating doses of vaccine. In Phase I studies, doses of 0.4 to 2 mg were given, with 23 dose regimens. In Phase II studies, doses of 6-12 mg were given with seroconversion in close to 100% of subjects; specifically 21 of 22 subjects were seropositive 28 days after one dose of 12 mg, and 18 of 19 were seropositive at day 56 (primary study endpoint) after a single 6 mg dose. Antibody persisted in all subjects for one year, and in 85100% of subjects for two years beyond vaccination, which appeared superior to comparator vaccine JE-VAX. GMT of neutralizing antibody were 300 at day 56 and 80200 at two years after vaccination. Notably, all neutralization assays in the study were performed against the IC51 homologous SA14-14-2 virus. Dr Tauber then went on to describe the companys licensing strategy. For the adult indication, the target application will be pre-travel immunization of adults. As a field study is not deemed feasible, the company will demonstrate non-inferiority based on seroconversion rates and antibody titres. The pivotal immunogenicity trial is planned to involve ~400 subjects, who will receive two doses of vaccine. The safety database will include


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

information on ~3000 subjects. The company will subsequently perform a single-dose study and will show antibody persistence and the efficacy of a booster dose of vaccine. The companys projected timelines for travellers is to begin Phase III studies in mid-2005, submit the Biological License Application (USA)/Marketing Authorization Application, European Union (EU) in 2006, with the target for licensure in the USA and EU in 2007. Dr Tauber concluded by saying that the IC51 vaccine is safe and efficacious, that it can reduce the number of doses required for immunization (from three to two), and that it comes in a more convenient liquid formulation. For the JE endemic countries, the company has formed an alliance with Biologicale E, an Indian company, and is building a manufacturing facility. Technology transfer is planned for 2005, with Phase II and III studies to be conducted in 2006 and licensure and WHO pre-qualification targeted for 2007. Discussion: Several questions were directed at the approach to neutralizing antibody testing. Dr Tauber noted that SA14-14-2 was used in the assay for Phase I and II studies. He affirmed that the company had not yet done any testing with other JE strains/genotypes but intended to include those assays as part of Phase III studies. This will be important information to confirm the relatively high titres observed with IC51, and to address the potential of cross neutralization of heterologous genotypes. Dr Hideo Takahara (The Research Foundation for Microbial Diseases of Osaka University, BIKEN) presented an update on the development of the Biken BK-VJE vaccine. This is an inactivated vaccine prepared from virus grown in Vero cells, using the Beijing-1 vaccine strain. The final product has passed all local specifications. Pre-clinical studies included single and multiple dose toxicity testing. In 2001 a Phase I study of a 2-dose regimen showed the vaccine to be well tolerated (with only mild elevations of liver function tests), and immunogenic, with seroconversion in 100% of seronegative subjects and 9 of 10 seropositive subjects. A Phase III trial was conducted to test the safety and immunogenicity of the vaccine as a primary series of two doses. This study involved ~110 children per group, with subjects and their parents blinded to assignment. The BK-VJE vaccine induced seroconversion in all subjects with neutralizing antibody GMT of 2.69 logs. There were no serious AEs; local reactions were noted in 10% of subjects and fever in ~9%. A second Phase III open-label trial studied the vaccine as a booster dose as compared to an active control. Neutralizing antibody GMT rose from 2.65 logs to 4.08 logs at 46 weeks after immunization. There were no serious AEs; local reactions and fever were approximately as common as seen for primary immunization. Dr Takahara concluded that the BK-VJE vaccine has a satisfactory safety and immunogenicity profile. The planned timeline for development of the vaccine includes applying for licensure in Japan in 2005, and Phase III studies and licensure in the US was expected to take between three to five years.



Discussion: When comparing BK-VJE to JE-VAX, neutralizing antibody GMTs appear to be higher with the BK-VJE vaccine. Notably, neither vaccine is formulated with alum. The company has currently no strategy to distribute the vaccine to countries outside Japan. Dr Yoichiro Kino (Kaketsuken) presented an update on the development of the Kaketsuken JE vaccine. Kaketsuken is a producer of the mouse brain-derived JE vaccine, and is pursuing a 78 year development effort for a Vero cell-derived vaccine. The vaccine is based on the Beijing-1 strain, the same strain used in their mouse brain vaccine. A column chromatography step has been added, reducing impurities to ~200 pg/mg for Vero cell DNA (several pg per dose) and ~150 ng/mg for Vero cell protein (several ng per dose). In a Phase I single-blind active control study of JE seronegative adults (30 per group), there were no serious AEs and only mild local reactions, less than seen with the mouse brain vaccine. Seroconversion was observed in 100% of individuals in both groups after three doses, with no significant difference in GMTs (2.35 vs. 2.03 logs). A Phase II double-blind active control study has been completed, involving healthy children aged 690 months (200 per group), and using a 3-dose schedule. Seroconversion was noted in all subjects receiving the Vero cell-derived vaccine after the second dose as opposed to 99.5% of subjects receiving the mouse brain vaccine. GMTs in recipients of the Vero cell vaccine were 2.49 logs after the second dose and 3.96 after the third dose, slightly higher than titres in recipients of the mouse brain vaccine. There were no differences between groups in AEs, which occurred in 45% of subjects after the first dose and 30% after the third dose. Adverse reactions were noted in ~10% of subjects, but there were no serious AEs. Dr Kino concluded that these data show the Vero cell-derived vaccine to be comparable or superior in safety and immunogenicity to the current vaccine. The company plans to file a new drug application in Japan soon, and hopes for licensure in 2007. Discussion: On the formulation of the vaccine, Dr Kino explained that formulation without adjuvant followed the approach of the current vaccine, which was that the Vero cell vaccine does not contain gelatine or thimerosal. The specific antigen content is 15 mg/dose. Dr Kino explained that the dosing schedule used in the clinical studies was the standard schedule used for the current vaccine, with the second dose at 14 weeks and the third dose at 612 months. Hence the target product profile is adapted to current vaccine recommendations in Japan, which is adapted to the traditional neural tissue vaccine. In that context it was noted that the GMTs were high after the second dose, questioning the need for a third dose. Given the fixed target product profile, no data is available for this. However, Dr Kurane (NIH, Japan) noted that discussions are ongoing in Japan about the possibility of reducing the number of doses of vaccine recommended for children. It was noted that there is no standard in Japan for Vero cell DNA content, but that the relevant standard in the United States is 100 pg/dose. When asked about the adult dose for the vaccine, Dr Kino indicated that licensure was being pursued for use in children, and that in the Phase I study the dose used was the same as the paediatric dose.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines


JE vaccine supply and introduction

Dr Pem Namgyal (WHO/SEARO/IVD) presented a summary of a bi-regional WHO South-East Asia Region (SEAR) and WHO Western Pacific Region (WPR) meeting on JE held on 3031 March 2005 in Bangkok, Thailand, which was co-sponsored by the Program for Appropriate Technology in Health (PATH). A similar bi-regional meeting held in 2002 in Thailand had called for intensified efforts against JE. Nevertheless, it was noted that JE remains endemic in many countries in these two WHO regions, but in many countries it was either not considered a public health issue or it was felt that there were no viable options for control or prevention. The expected outcomes of the 2005 meeting were: to share country experiences on JE control; to update countries on vaccine status; to discuss draft surveillance standards; to identify options to strengthen laboratories in the region; and to recommend diagnostic options. The main challenges to JE control and prevention that were identified, were incomplete information on disease epidemiology and burden, variable surveillance activities and disease reporting, and the lack of an affordable vaccine in sufficient quantity. As a result, few countries have integrated JE vaccine into the EPI. Common grounds were seen by meeting participants on the need for the following efforts: development of a national control strategy for each country affected; progressive introduction of routine vaccination, with initial priority on populations at highest risk; use of vaccine in addition to vector control; acceleration of prequalification of safe and efficacious vaccines (with SA 14-14-2 being mentioned as a first line candidate); establishment of standards for JE surveillance and diagnosis; and establishment of a laboratory network. The next steps recommended by participants were: to finalize and publish surveillance standards; to develop standard operating procedures (SOPs) and manuals for diagnostic laboratories; to support country-specific surveillance; to define the minimum data needed for decision-making respecting vaccination; to set up communication between WHO and countries in the region; and to advocate for putting JE vaccination on to the Global Alliance for Vaccines and Immunization (GAVI) Phase II agenda for the whole Asia-Pacific region. Discussion: Several questions by meeting participants addressed the focus on the SA14-14-2 vaccine. Dr Namgyal noted that affordability was felt to be a key point. A specific criteria for affordability was not stated, but he estimated it to be in the range of $1 per dose. While there is unconfirmed expectation that SA 14-14-2 might become available at that price, it was felt that the vaccine should undergo WHO prequalification to become eligible for UN procurement, prequalification providing assurance that the vaccine is safe, effective and suitable for public health use. It was noted that the mouse brain vaccine is not prequalified, and has never been submitted to WHO by the manufacturers. It remains a national decision to register a product, but prequalification opens opportunities for effective procurement. Several questions were raised on prequalification, and these were addressed by Dr Hombach. There was considerable discussion about advocacy strategies to increase support for JE vaccination efforts. It was noted that the GAVI board meeting was scheduled for the same week as this SC meeting. Dr Jacques Franois Martin (PartEurope) suggested that GAVI was planning to define priorities for the next 10 years, that it was essential to make a coordinated push in the next several months in order to be included, and that success depended on a clear presentation of priorities as well as leadership by countries.




JE correlates for protection

Dr Joachim Hombach (WHO) presented a summary of a WHO Consultation on Immunological Endpoints for JE Vaccine Trials, co-sponsored by the JE programme at PATH and held on 23 September 2004. The context of the meeting was the pipeline of new or improved JE vaccines and the inability to conduct clinical efficacy trials on ethical or practical grounds, necessitating new efficacy trials using surrogate endpoints. Although this meeting was a scientific consultation with a final publication, the objective was to provide guidance to manufacturers and national regulatory authorities (NRAs). This requires adoption of the recommendations by the WHO Expert Committee on Biological Standardization (ECBS). The agenda of the meeting included a discussion of immune mechanisms and trial design, and a closed session to draft the conclusions of the meeting. The scientific rationale for the conclusions was felt to be the evidence that neutralizing antibodies provide the best evidence of protective immunity based on passive immunization, the linear relationship between antibody titre and protection, and corroborating data from efficacy trials. Nevertheless, it was recognized that low neutralizing antibody levels did not exclude the existence of protective immunity. Based on this information, the group recommended that the primary endpoint for clinical trials be a quantitative analysis of neutralizing antibody levels, with comparison to a licensed product following a non-inferiority design with predefined margins, and using percent seroconversion and GMTs as the measures. With regard to measurement of neutralizing antibodies, the group recommended that the threshold for protection be considered a PRNT50 greater than or equal to 1:10, that calibration of neutralizing antibody titres as International Units (IUs) should be considered, and that WHO should provide guidance on design and validation of in-house assays and on selection of time points post-vaccination for serologic testing. For design of clinical trials, the group recommended that the margin for non-inferiority should be 95% confidence intervals for the difference in seroconversion rates of less than or equal to 0.10, and that the ratio of GMTs to the new vaccine and licensed vaccine should be greater than or equal to 0.5. Additional information that might be used to support registration of a new vaccine could include: evidence for an anamnestic response (immunological memory); qualitative neutralizing antibody data including cross-neutralization of other genotypes; T cell responses induced by vaccine (although this was still seen as a research area); and passive protection of animals by vaccine-induced immune responses. The next steps planned by the group were publication of the meeting report, and convening of a small expert group to discuss additional technical details and draft guidelines. These guidelines would be submitted for peer review and later submission to the ECBS. Discussion: There was considerable discussion regarding the role of T cells and related assays in JE vaccine-mediated protection. Most participants felt that these assays were interesting, but not standardized and therefore should not hold up clinical trials of new vaccines. There was also discussion regarding technical aspects of the neutralizing antibody assay, in particular the selection of viral strains and genotypes. Although this was the responsibility of the national control authority, it was felt that guidance on that topic was necessary and should be provided. Several participants suggested that selection of virus strains might affect GMT readouts more than percent seroconversion, whereas the latter endpoint might be more important for assessment of protective immunity. There was general agreement that neutralizing antibody responses should be the priority immunologic endpoint for clinical trials, but that further research on T cell responses and other antibody assays should be encouraged.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines


A retrospective JE study proposal

Dr Mammen presented a proposal for a retrospective study of the long-term susceptibility for dengue after JE vaccination. The specific aim of the study would be to determine whether JE vaccination affects the risk for hospitalized dengue. As a background for this proposal he noted that there is potential unknown interaction between flavivirus vaccine and co-circulation of flaviviruses, noting that these interactions might be beneficial, or harmful. With one virus and one vaccine (model A) there are two possible sequences, and the sequence of wild-type virus followed by vaccine would be included in the safety evaluation. With two viruses and one vaccine (model B) there are six different sequences possible, with several raising important safety considerations; with two viruses and two vaccines (model C) the situation becomes progressively more complex, etc. Dr Mammen noted that the situation in Thailand currently fits model B but with a need to prepare for model C, as JE and dengue co-circulate in Thailand and JE vaccine was introduced into the EPI in 1991. JE vaccine is currently being given at 18 months, 18.5 months, and 30 months, but there is interest in earlier vaccination, even before 12 months. In his proposal, Dr Mammen plans to take the opportunity provided by the JE efficacy vaccine trial conducted in Kamphaeng Phet, Thailand, in 19841985, which looked retrospectively at dengue hospitalization rates. In the JE trial, some 43 000 children received JE vaccine and 20 000 received a tetanus booster as a control. Vaccine efficacy against JE was 91%. In the first year after vaccination, 75 subjects were hospitalized with dengue, with estimates of protection by vaccination of 33% against DHF and 22% against DF; no continued surveillance for dengue was conducted after the first year however. Dr Mammen described the proposed study to involve 16 000 children in each group matched for age and location. Preliminary work has been done to assess the feasibility of the study, the original study data has been recovered, and AFRIMS has an extensive database on admissions to the Kamphaeng Phet Provincial Hospital with fever, including serologic testing for dengue. The study strategy would involve name comparisons between databases to identify study subjects admitted with fever between 1986 and 2002. A potential problem is the chance for cross-over vaccination; placebo recipients received a letter offering JE vaccination, but information on subject follow-up to the letter is available. Assumptions of the study will be: (a) the 16 000 placebo recipients who did not return with the letter did not receive JE vaccination, since JE vaccination was not included in the EPI until 1992 and at that point was limited to younger children (except for limited catch-up vaccination in 19941997); (b) exposure to dengue is the same in the two groups matched for age and location; (c) a high proportion of the ~17,000 cases of hospitalized dengue in the province were reported from the KPPH, yielding an estimate of 4.3 cases expected per 1000 children. The analysis will examine the relative risk of hospitalized dengue and the average age of hospitalization for dengue. Discussion: It was asked whether country data could be assessed for a possible protective effect of JE vaccination on dengue; as in Viet Nam where the severity of dengue appeared to have decreased after JE vaccine was introduced. There were several questions about the study design, including: whether there would be sufficient power to detect small increases or reduction in risk; whether the potential confounders could be evaluated further; whether the lack of pre-screening for dengue in the original study would be accounted for. Dr Mammen replied that the study should allow to detect 15% increase in severity and 37% decrease in severity with a confidence interval (CI) of 95%. Participants agreed this was an important question and should be followed up.




PATH activities update

Dr Julie Jacobson (PATH) gave an update on PATH activities related to JE over the previous year. In the area of surveillance, draft WHO guidelines were complete and had been presented in March at the bi-regional meeting; the WHO working group expected to finalize the guidelines in June and anticipated publishing a paper on the rationale for the guidelines. New surveillance activities had been initiated by PATH in Cambodia and Indonesia, and activities strengthened in five other countries to make year-round laboratory diagnosis available. Development of a simplified commercial IgM ELISA for use on cerebrospinal fluid (CSF) or serum was supported, with assessment being done by the AFRIMS laboratory, and results of these studies was expected in May. If the results were positive, the new assay would be field tested for suitability for integration into the WHO laboratory network. In the area of vaccine development, Dr Jacobson reviewed the ideal target product profile PATH had defined, which constitutes a vaccine that can be incorporated into the EPI and can be administered as a single dose at nine months of age at the same time as the measles vaccine. PATH sent a technical expert to visit the manufacturer of the SA14-14-2 vaccine in China, to review the manufacturing facility, as well as the preclinical and clinical data on this vaccine. Outside China, from Nepal, data is available on duration of immunity for up to five years after vaccination. Preliminary data on safety of co-administration with measles has been generated, but more data needs to be produced, additionally to cover immunogenicity in co-administration. Dr Jacobson also noted the need to re-analyse data from China on single dose efficacy, and to perform a human study of vaccine-related viraemia in non-immune adults. Finally, she reviewed PATH activities towards forecasting the potential demand for a JE vaccine. The goal of this work is to predict the number of doses needed and to plan vaccine supply; this information being equally important both for manufacturers and international donors. The models start from the assumption that a pre-qualified affordable vaccine is available, and go on to consider the level of current government commitments to JE, and the strength of the immunization system in various countries. The assumptions are that six countries would introduce the vaccine within the next three years, five additional countries in years 46, seven additional countries in years 79, and three additional countries after year 10. The calculations take into account total demand from 20072015 based on the institution of a campaign to vaccinate all individuals in high risk areas as well as vaccination of new birth cohorts. These calculations predict that vaccine demand could be up to 8590 million vials, with substantial peaks due to catch-up campaigns. Discussion: On JE surveillance and the lack of epidemiological data in some areas, Dr Jacobson noted that PATH was working with WHO and other organizations to address the problem, and was also helping in the area of diagnostics. With regard to the lack of resources in the endemic area for JE surveillance and laboratory diagnosis, she indicated that current emphasis by WHO and PATH was on trying to integrate with established surveillance systems, for instance the polio surveillance and measles diagnostic laboratories. It was noted that specific diagnosis of JE as a cause of encephalitis is difficult in the endemic areas, particularly as lumbar punctures are performed in a minority of cases. This is addressed in the draft WHO surveillance standards, which are based on the clinical case definition of acute encephalitis syndrome (AES) for resource-poor settings, with confirmatory diagnosis of serum or CSF in sentinel facilities. There was agreement with the suggestion of preserving samples for additional laboratory studies to identify aetiologies of non-JE AES.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

Such work would require informed consent, and would need to be conducted in the context of dedicated research projects. It was also felt that discussion of the vaccine forecast scenarios might require more detailed discussions in a different setting than this SC meeting. Dr Barrett led a general discussion session to address open research questions related to JE, particularly with reference to vaccine safety. Dr Hombach noted that the Steering Committee was charged to advise other WHO committees to assess potential open research and safety issues in relation to JE vaccines or vaccination, in the context of the rapidly advancing JE vaccine pipeline and the anticipated requests for product prequalification. It was also reported that the SA14-14-2 vaccine was to be discussed at an upcoming meeting of the WHO Global Advisory Committee on Vaccine Safety (GACVS). No imminent research and safety issues were identified by the meeting participants, however continued and strengthened post-marketing surveillance of JE vaccines was recommended. Several areas were also mentioned that might benefit from continued research, such as the in vivo pathogenesis of live virus vaccines, and the characterization of sites of replication and induction of immune responses. This research is aimed at building on the knowledge base of JE. Additional research could also include further studies into potential viral recombination to counter allegations of safety of live vaccines, as well as assessing the effects of interaction between flaviviruses and heterologous vaccines.



4. Other flaviviruses


Epidemiology of West Nile virus update

Dr Ned Hayes (Centers for Disease Control and Prevention, Colorado, USA) gave an update on the epidemiology of West Nile virus (WNV), especially in the western hemisphere. In the United States, the virus has spread west and south and has been detected in all states except Maine, Alaska, and Hawaii. In Canada, there have been human cases in five provinces, notably in Quebec and Ontario. In the Caribbean zone, human cases have been seen in the Cayman Islands, and virus transmission has also been detected in the Republic of Cuba, in the Dominican Republic, and in Puerto Rico. In Central America, there has been one human case in the United Mexican States, and non-human cases in Belize and the Republic of El Salvador. In South America, the virus has only been detected in the Republic of Colombia. Between 1999 and 2004 a total of 16 700 human cases were reported in the United States, including ~7000 cases of neurological syndromes and 664 deaths. While most cases have been thought to be acquired from mosquitoes, other mechanisms of transmission have been identified in the United States, including blood transfusion, organ transplantation, intrauterine transmission (one documented case and several suspected cases), and aerosol transmission in a laboratory. There have also been cases suspicious for transmission through breastfeeding, dialysis, and non-laboratory aerosol transmission. Dr Hayes then reviewed those population groups who appear to be at higher risk for disease and who might be candidates for at-risk vaccination. The best documentation of increased risk is for older adults (> age 60) and transplant recipients. Other groups possibly at increased risk are other immunosuppressed patients, and patients with diabetes mellitus, hypertension, or stroke. Dr Hayes noted that a gene for flavivirus resistance has been identified in mice but is not known to affect risk for disease in humans. The main mosquito vectors for WNV in the US have been Culex mosquitoes, and the vertebrate reservoirs appear to be crows, sparrows, finches, and grackles; alligators may also be a reservoir, but mammals do not appear to serve as a reservoir. The peak season for WNV transmission is between April and December. Molecular studies of virus isolates have demonstrated two WNV lineages, the first covering isolates from Africa, North America, Asia, Australia and Europe, and the second including isolates from Africa and the Republic of Madagascar. The NYC99 (New York City 1999) virus is close to an isolate from the State of Israel and appears to be more virulent; viral mutants have been isolated from Texas, USA, and Mexico. Two vaccines have been approved for veterinary use against WNV; one an inactivated vaccine and the other a recombinant canarypox vaccine. Vaccines for human use are currently in development and include inactivated vaccines, chimeric flavivirus


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

vaccines, vaccines based on other live attenuated vaccine vectors (e.g. measles virus), and DNA vaccines. Dr Hayes noted that recommendations regarding potential use of a vaccine are in preparation, and preliminary estimates are that universal vaccination could be cost-saving if >2.1% of the population was infected each year, if the vaccine cost was <$9, and if the cost of lifetime disability was >$3.2 million. Discussion: In response to a question on oral transmission, such as from meat of infected animals, Dr Hayes noted that oral transmission has been demonstrated in alligators and possibly in cats, and that cases of suspected transmission through breastfeeding also support this as a possibility. It was suggested that improved surveillance activities throughout the region of the Americas was needed, and it was commented that confusion with dengue in diagnosis, and the need for BL3 laboratory facilities to work with WNV, were additional challenges in this regard. The possibility of using the chimeric YFV-WNV virus developed by Acambis as a diagnostic tool was noted. Dr Monath indicated that the company had provided the virus to CDC for distribution under Material Transfer Agreements (MTAs) for this purpose, and that CDC staff had noted that international shipping of the virus was time- consuming, but possible. While the SC has no active programme on WNV, it was suggested that research on animal models, e.g. primates, should be endorsed.


YF vaccine safety 20002005

Dr Bentsi-Enchill (WHO) gave an update on vaccine safety issues in relation to the YF vaccine. She summarized the CDC vaccine adverse event reporting system (VAERS) data from 20002005, which included both passive and stimulated reporting and post-marketing surveillance. There were 682 YF vaccine-related AEs reported, of which 103 (15%) were serious; 188 occurred after administration of YF vaccine only, of which 23 (12%) were graded as serious. In this latter group, there were three deaths, five life-threatening AEs, and 15 hospitalizations. Two vaccineassociated syndromes have been defined viscerotropic disease and neurotropic disease. Cases of vaccine-associated viscerotropic disease have been reviewed by a vaccine safety working group, and case definitions for suspected, probable, and definite cases have been established. All cases have been associated with primary vaccination and had onset 25 days after vaccination. Of 25 cases reported between 1996 and 2005, 60% have been fatal, and the ages of subjects has ranged from 4 to 79 years, with 44% over 60. Cases have been reported from multiple countries and have been associated with both the 17D-204 and 17DD strains. Four (17%) of 23 patients have had a history of thymectomy. In summary, the risk factors for viscerotropic disease appear to include older age, primary immunization, and thymic disease, and estimates of risk are very wide, ranging between 0.4 and 3.5 cases per million vaccine recipients. Current recommendations are to carefully consider the risks and benefits of vaccination in the elderly, and to query subjects about prior thymic disorders; these recommendations have been incorporated into the product monographs and CDC vaccine information sheets. Case definitions have also been established for neurotropic disease. In the United States, 11 cases were reported between 1995 and 2003, with onset between four and 23 days after vaccination. The estimate for the risk of disease is approximately 4.5 cases per million vaccinations. The working groups are continuing their activities, and, in collaboration with CDC, are pursuing evaluation of cases as well as improvements in surveillance.



Discussion: It was noted that there is no apparent gender effect in the observed serious AE following YF vaccination. It was suggested that the increased risk in the elderly could relate to thymic involution, but there is a need to better understand host factors in immune responses to YF vaccine. It was further noted that data from HIV+ vaccine recipients showed mutations in vaccine viruses isolated from the recipient, although safety appears not at risk. It was suggested that the switch to active immunization instead of previous immune globulin administration for hepatitis A prevention, could have increased the risk for complications from YF vaccine. Overall, a strong plea was made that the assessment and investigation of SAE following YF vaccination needed strengthening. As a first measure, the database needed expansion through more AE monitoring and case investigation in endemic countries, as the United States data was not considered to be applicable to those countries. In particular, there is a lack of estimates on incidence rates. More complete case investigations are needed, including virus isolation and characterization, as well as necropsy. Dr Bentsi-Enchill commented that there was a low level of awareness in some countries, and that work was under way to establish networks for surveillance and investigation of cases.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

5. Discussion and recommendations

(session not attended by company representatives)
5.1 Dengue vaccines

Dr Vaughn led a discussion on dengue vaccines. In the area of reference materials and diagnostics, the following discussion points and recommendations were made. The SC endorsed the establishment of the pooled, tetravalent dengue antibody serum as an international reference standard, and recommended the candidate reagent to ECBS for approval. However, the four monovalent dengue antisera were considered unsuitable as international standards, given their overall low titres. With these recommendation the committee followed the proposal made by Dr Morag Ferguson of NIBSC, who had conducted the collaborative study. The Committee also supported WHO efforts through the TDR-led working group to establish regional reference laboratories and work towards defining standardized acute diagnostic tests. Recommendations on functional tests, which are of particular relevance to vaccine evaluation, should be deferred until a dedicated review and discussion has been held with vaccine developers. The point was raised as to whether a dengue vaccine could be designed in such a way so as to elicit an immune response that allows discrimination between vaccine and natural infection-induced response. While this concept of marker vaccine is well established in the veterinary area, it was considered incompatible with regulatory requirements for human-use vaccines.

On the issue of correlates of protection for dengue vaccines, the following recommendations were made. It was recommended that WHO should organize a meeting focused on correlates of efficacy of dengue vaccines. While this consultation would most likely not yield a firm recommendation on correlates, as it was the result of a similar consultation held in 2004 on JE vaccines, it would be a state-of-the-art review, that should provide important orientation on how to define correlates. The correlates meeting should be used for a review of existing model systems for early evaluation of dengue vaccines, including non-human primates and the human challenge model.

In relation to guidelines for the conduct and evaluation of dengue vaccine clinical trials, it was concluded as follows. The existing WHO/TDR document was a solid basis, but there was a need to update and expand the document. However, the group recommended waiting for the conclusions from the correlates meeting before revising the document. A subgroup should be established to draft the guidelines.




JE vaccines

Dr Cardosa led the discussion on JE vaccines. The group was charged to express their views on remaining research needs in relation to JE vaccine efficacy and safety, in the light of the advanced vaccine pipeline that was presented at the meeting. Overall, the group felt that the vaccine pipeline was well advanced, with no specific research areas essential beyond normal vaccine safety and efficacy assessment required for licensure. For consideration for vaccine safety and efficacy in a post-licensure setting, possible research areas should include vaccine efficacy against different viral genotypes, the development of a rational strategy for booster immunizations (in particular for inactivated vaccine), and interaction of live JE vaccines with other flaviviruses. Consideration should also be given to studies of vaccine efficacy in different ethnic groups and different age groups. Studies into the identification and assessment of occasional vaccine failures should be encouraged. Encouragement was given to the study proposed by AFRIMS on the long-term effects of JE vaccination using inactivated vaccine at Kamphaeng Phet site, Thailand, particularly with regard to susceptibility to dengue disease.

With regard to correlates of vaccine efficacy for JE vaccines: the group endorsed the recommendations made at the 2004 workshop and supported their presentation to ECBS for formal adoption; with regard to specific virus strains for neutralizing antibody assays, the group felt that this required further study, and so no recommendation was made; the group also recommended that WHO should consider revising the guidelines for production and control of inactivated JE vaccines.


Other flavivirus vaccines

Dr Barrett summarized the discussions in relation to YF and WNV, and the group agreed the following recommendations. With regard to YF vaccine, the group recommended: that WHO seek to obtain autopsy material from patients with vaccine-related AEs in order to fully characterize such cases; that WHO support the development of a reporting network to improve case identification in developed countries. The group recommended these actions with the goal of avoiding unsubstantiated erosion of confidence in YF vaccine. With regard to WN vaccine, the group recommended that surveillance activities be maintained and strengthened, especially for neurological disease.


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

Annex 1:
List of Participants

Dr Mark Beatty, Chief, Epidemiology, Dengue Branch, DVBID, NCID, Centers for Disease Control and Prevention, 1324 Calle Canada, San Juan PR 00920, Puerto Rico Dr Jane Cardosa, Institute of Health & Community Medicine, University of Malaysia, Sarawak, Kota Samarahan 94300, Malaysia Dr Beth-Ann Coller, Hawaii Biotech Inc., 99193 Aiea Heights Drive, Suite 200, Aiea, Hawaii 96701, USA Dr Denis Crevat, Sanofi Pasteur, Discovery Drive, Swiftwater PA 18370, USA Dr Mike Drebot, Chief, Viral Zoonoses, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba R3E 3R2, Canada Dr Francis A. Ennis (could not attend) University of Massachusetts Medical School, 55 Lake Avenue, North Worcester MA 01655, USA Dr Morag Ferguson, National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom Col Robert V. Gibbons, Department of Virology, Armed Forces Research Institute of Medical Sciences, 315 Rajavithi Rd, Bangkok, Thailand Dr Mathias Grote, Intercell Biomedical Research & Development, Campus Vienna Biocenter 2, 1030 Vienna, Austria Dr Duane Gubler, John A. Burns School of Medicine, 3675 Kilauea Avenue, Hawaii, Honoulu 69816, USA Dr Maria G. Guzman, Institute of Tropical Medicine Pedro Kouri, Cuitopista Novia Mediodia P.O. Box 601, Marianao 13, Ciucad de la Habana, Cuba Dr Scott B. Halstead, Department of Preventive Medicine & Biostatistics, Uniformed Services University of the Health Sciences, 5824 Edson Lane, N. Bethesda MD 20852, USA Dr Ned Hayes, Medical Epidemiologist, Arboviral Diseases Branch, Division of Vector-borne Infectious Diseases, Centers for Disease Control and Prevention, PO Box 2087, Fort Collins, Colorado 80522, USA



Dr Elizabeth A. Hunsperger, Chief, Viral Pathogensis & Reference Laboratory, Dengue Branch CDC, NCID, DVBID, Dengue Branch Centers Control and Prevention, 1324 Calle Canada, San Juan PR 00920, Puerto Rico Dr Julie Jacobson, Director, JE Project, CVP/PATH, 1455 NW Leary Way, Seattle, WA 98107, USA Dr Niranjan Kanesa-Thasan, Acambis Inc, 38 Sidney Street, Cambridge, MA 02139, USA Dr Yoichiro Kino, The Chemo-Sero Therapeutic Research Institute (Kaketsuken), Second Research Department , Kaketsuken, Kyokushi, Kikuchi, Kumamoto 8691298, Japan Dr Penelope Koraka, Erasmus University, Dr Molewaterplein 50, P.O. Box 1738, Rotterdam 3000 DR, The Netherlands Dr Ichiro Kurane, Director, Department of Virology 1, National Institute of Infectious Diseases 1-23-1 Toyama, Shinjuku-Ku, Tokyo 162-8640, Japan Dr Jean Lang, Sanofi Pasteur SA, 1541 avenue Marcel Merieux, Campus Merieux, F-69280 Marcy LEtoile, France Dr Mammen Mammen, Armed Forces Research Institute of Medical Sciences, 315/6 Rajavithi Road, Bangkok 10400, Thailand Dr Yaich Mansour, PATH, Btiment Avant Centre, 13 chemin du Levant, 01210 Ferney Voltaire, France Dr Narender Dev Mantena, Senior Vice President, Corporate Development, Biological E. Limited, 18/1 Azamabad, Hyderabad 500020, India Dr Harold Margolis, Director, Paediatric Dengue Initiative, International Vaccine Institute Kwanak PO Box 14, Seoul, Republic of Korea 151-600 Dr Lewis Markoff, Food and Drug Administration, Laboratory of Vector-Borne Virus Diseaes Bg 29A, Room 1B17, NIH Campus, 8800 Rockville Pike, Bethesda, MD 20892, USA Dr Jacques-Francois Martin, PARTEUROP, 41 Quai Fulchiron, 69005 Lyon, France Dr Karen McCarthy, Clinical Operations, Acambis, Peterhouse Technology Park, 1000 Fulbourn Road, Cambridge CB1 9PT, United Kingdom Dr Thomas Monath, Chief Scientific Officer, Acambis, Inc., 38 Sidney Street, Cambridge, MA 02139, USA Dr Junko Namazue, Section Manager, Research Foundation for Microbial Diseases of Osaka University (BIKEN), Section of Clinical Research, D56, 5-16 Tukumo-dai, Suita, Osaka 565-0862, Japan


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

Dr Thi Kim Tien Nguyen, Director, Pasteur Institute, 167 Pasteur Street, Ward 3, Ho Chi Minh City, Viet Nam Dr Albert Osterhaus, Erasmus University, Dr Molewaterplein 50, P.O. Box 1738, Rotterdam 3000 DR, The Netherlands Dr Alan Rothman, Center for Infectious Disease and Vaccine Research, University of Massachusetts, 55 Lake Avenue North, Worcester MA 01655, USA Dr Arunee Sabchareon, Mahidol University, Faculty of Tropical Medicine, 420/6 Rajvithi Road, Bangkok 10400, Thailand Dr Christophe Salanon, Bio-Rad Laboratories, 3 boulevard Raymond Poincar, 92430 Marnes la Coquette, France Dr Tom Solomon, Departments of Medical Microbiology & Neurological Science, Eighth Floor Duncan Building, Daulby Street, Liverpool L69 3GU, United Kingdom Dr Wellington Sun, Chief, Department of Virus Diseases, Walter Reed Army Institute of Research 503 Robert Grant Avenue, Silver Spring, MD 20910-75, USA Mr Hideo Takahara, Supervisor, Production Technology Group, Kanonji Insitute - The Research Foundation for Microbial Diseases of Osaka University, 2941, Yahata-Cho, Kanonji City, Kagawa 768 0061, Japan Dr Erich Tauber, Intercell AG, Campus Vienna Biocenter 2, A-1030 Vienna, Austria Dr Marc Tabouret, Clinical Microbiology Division, Bio-Rad Laboratories, 3 boulevard Raymond Poincar, 92430 Marnes la Coquette, France Dr Stephen Thomas, Department of Virus Diseases & Immunology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-75, USA Col David W. Vaughn, Director, Military Infectious Diseases Research Program, US Army Medical Research and Materiel Command, 504 Scott Street, Fort Detrick MD 21702-5012, USA Dr Li Yuhua, Chengdu Institute of Biological Products, Baojiang Bridge, Chendu, Sichuan Province, 610023, the Peoples Republic of China Dr Ventzislav Vassilev, GlaxoSmithKline Biologicals S.A., 89 Rue de lInstitut, B-1330, Rixersart, Belgium Dr Paul Young, University of Queensland, Brisbane 4072, Australia



WHO Regional Offices/Secretariat:

Dr Harvey Artsob, Tropical Disease Research, World Health Organization, Avenue Casai, 1211 Geneva 27, Switzerland Dr Yang Baoping (could not attend), Regional Advisor EPI, WPRO, World Health Organization, Regional Office for the Western Pacific, Manila 2932, Philippines Dr Adwoa Bentsi-Enchill, Vaccine Assessment and Monitoring (VAM), World Health Organization, 20, avenue Appia, 1211 Geneva 27, Switzerland Dr Thomas Cherian, Acting Coordinator, Parasitics and Other Pathogens Vaccine Research (POP), World Health Organization, 20, avenue Appia, 1211 Geneva 27, Switzerland Dr Joachim Hombach, Parasitic and Other Pathogens Vaccine Research (POP), World Health Organization, 20, avenue Appia, 1211 Geneva 27, Switzerland Dr Marie-Paule Kieny, Director, Initiative for Vaccine Research (IVR), World Health Organization, 20 avenue Appia, 1211 Geneva 27, Switzerland Dr Pem Namgyal, Medical Officer, New Vaccines VAB/EPI, Regional Office for South East Asia, World Health House, Indraprastha Estate, Mahatma Gandhi Road, New Delhi 110002, India


2005 Report of the Steering Committee on Dengue and other Flavivirus Vaccines

The World Health Organization has managed cooperation with its Member States and provided technical support in the field of vaccine-preventable diseases since 1975. In 2003, the office carrying out this function was renamed the WHO Department of Immunization, Vaccines and Biologicals. The Departments goal is the achievement of a world in which all people at risk are protected against vaccine-preventable diseases. Work towards this goal can be visualized as occurring along a continuum. The range of activities spans from research, development and evaluation of vaccines to implementation and evaluation of immunization programmes in countries. WHO facilitates and coordinates research and development on new vaccines and immunization-related technologies for viral, bacterial and parasitic diseases. Existing life-saving vaccines are further improved and new vaccines targeted at public health crises, such as HIV/AIDS and SARS, are discovered and tested (Initiative for Vaccine Research). The quality and safety of vaccines and other biological medicines is ensured through the development and establishment of global norms and standards (Quality Assurance and Safety of Biologicals).

The evaluation of the impact of vaccinepreventable diseases informs decisions to introduce new vaccines. Optimal strategies and activities for reducing morbidity and mortality through the use of vaccines are implemented (Vaccine Assessment and Monitoring). Efforts are directed towards reducing financial and technical barriers to the introduction of new and established vaccines and immunization-related technologies (Access to Technologies). Under the guidance of its Member States, WHO, in conjunction with outside world experts, develops and promotes policies and strategies to maximize the use and delivery of vaccines of public health importance. Countries are supported so that they acquire the technical and managerial skills, competence and infrastructure needed to achieve disease control and/or elimination and eradication objectives (Expanded Programme on Immunization).

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