Japanese Encephalitis Guideline Searo 2006

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region (with focus on SA 14-14-2 JE Vaccine)

Operations Guidelines

SEA-Vaccines-136 Distribution: Limited

Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region (with focus on SA 14-14-2 JE Vaccine)

Operations Guidelines

© World Health Organization Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. For rights of reproduction or translation, in part or in toto, of publications issued by the WHO Regional Office for South-East Asia, application should be made to the Regional Office for South-East Asia, World Health House, Indraprastha Estate, New Delhi 110002, India. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. October 2006

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

Contents 1. Introduction ......................................................................................... 1 1.1 Background ...................................................................................................... 2 1.2 Recognizing the extent of the JE problem ......................................................... 2 1.3 Different approaches to control JE .................................................................... 3

2. Vaccines against Japanese Encephalitis .................................................. 7 2.1 Type of vaccines ............................................................................................... 7

3. Immunization strategy for the control of JE ............................................ 9 3.1 Mass campaign ................................................................................................. 9 3.2 Conducting the mass campaign ...................................................................... 11 3.3 Ensuring injection safety and adverse events following immunization (AEFI) during a campaign ......................................................... 15

4. Routine immunization with JE vaccine and surveillance for JE .............. 17 4.1 Routine immunization .................................................................................... 17

5. Vaccine procurement ........................................................................ 19 5.1 Vaccine licensing or registration ...................................................................... 19 5.2 Vaccine procurement and management ......................................................... 19 5.3 Important considerations in the procurement and management of JE vaccine are as follows ........................................................ 20 5.4 Considerations for vaccine supply and allowable wastage rates ....................... 20 5.5 Receiving vaccines and supplies ..................................................................... 21 5.6 Vaccine administration ................................................................................... 22 5.7 Cold chain requirements ................................................................................ 23 5.8 WHO opened-vial, multi-dose policy ............................................................. 23

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6. Surveillance for Janpanese encephalitis ............................................... 24 6.1 Clinical case definition of Acute Encephalitis Syndrome ................................. 24 6.2 Types of surveillance for JE .............................................................................. 25 6.3 JE outbreaks and outbreak response ............................................................... 26 6.4 Other aspects of JE surveillance ...................................................................... 29

7. Laboratory aspects of surveillance for JE .............................................. 31 7.1 Laboratory criteria for confirmation ................................................................ 31 7.2 The JE laboratory network .............................................................................. 33 7.3 Specimen collection ....................................................................................... 33 7.4 Transport of specimen .................................................................................... 34

8. References ......................................................................................... 36 Annexes 1. Checklist for planning a mass campaign with JE vaccine ...................... 37 2. Detecting and reporting AEFIs ............................................................. 40 3. SAMPLE: Japanese encephalitis virus laboratory request and report form ...................................................................... 42 4. Stock management ............................................................................. 43 5. Packaging and shipping of vaccine ...................................................... 48

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

Introduction

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What this guide is NOT These guidelines are not meant to be a reference document on the epidemiology, clinical features and the different control measures for Japanese Encephalitis (JE). These are practical, hands-on operations guidelines for the introduction of JE vaccine in a country. The guidelines assume that the disease epidemiology has been defined, appropriate national consultations have taken place, necessary funding and other administrative and policy decisions for the introduction of JE vaccine have been taken. The guidelines do not purport to provide the decision analysis framework for the introduction of JE vaccine into national immunization programmes.

The purpose of the guidelines is: • To guide countries who wish to introduce JE vaccine to control and prevent JE; • To guide the planning of mass campaigns as well as routine immunization with JE vaccine; and • To ensure the establishment of a functioning routine reporting and monitoring system, including laboratory surveillance and adverse events following immunization with JE vaccine

The guidelines are for: • The National Expanded Programme on Immunization (EPI) Programme Manager; • The District Medical Officer; and • Field workers involved in immunization activities who may not need the entire guidelines, but to whom appropriate sections may be provided.

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1.1 Background Japanese encephalitis (JE) is the leading viral cause of disability in many countries of Asia. The virus is a Flavivirus transmitted by mosquitoes and is related to dengue, yellow fever, and west nile virus. In endemic areas across Asia the disease primarily infects children, leaving approximately 70% of those who develop clinical illness either dead or neurologically disabled. Public health authorities have long concluded that vaccination is a necessary tool to control JE. While an effective vaccine has existed since 1941, and is recommended for routine use in endemic countries, it has not reached the poorest countries in Asia. Its value as a control tool has been proven by its successful use to control JE in Japan, Korea, and Taiwan. Control of JE in the Region has been limited by inadequate disease surveillance, a limited and inconsistent vaccine supply, lack of guidance and programmematic support for immunization, and limited advocacy. But recent advances have increased the feasibility of effective JE control. There are new efforts aimed at defining the disease burden and impact in JE-endemic countries which include, inter alia, new WHO surveillance standards and new diagnostics. More importantly, affordable, single-dose new vaccines compatible with routine immunization have been developed.

1.2 Recognizing the extent of the JE problem The endemic areas for JE have been defined for many years. However, the actual JE disease burden has been poorly defined in many parts of Asia. Many countries, although considered endemic, have had no data on disease prevalence to demonstrate JE to be a public health issue. During the 60 years that the vaccine has been available, JE virus has infected an estimated 10.5 million children, resulting in more than 3 million deaths and more than 4 million children living with long-term disabilities. Ecosystems alter with changing land use patterns and irrigation. A recent review shows that 1.9 billion people live in JE-prone areas and the number of people living in irrigated rice growing areas has continually increased since the 1960s. Outbreaks in peri-urban and urban settings are well documented and, outbreaks not associated with the traditional pig-amplifying host clearly demonstrate the importance of other multiple animal species in the transmission and over-wintering of the JE virus. In addition, JE virus has been isolated from no less than 16 different species of mosquito in India and from 19 species in Indonesia.

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Some of the challenges of disease recognition have been lack of diagnostic tools and no uniform guidelines for reporting of JE cases. Some measures put in place to address some of these shortcomings are the release of the first surveillance standards for JE by WHO in January 2006. In the SEA Region encephalitis and JE are now reportable diseases. In addition, three new commercial diagnostic kits, based on IgM ELISA technology, have been developed and are undergoing field testing for integration into laboratory networks. These laboratory networks will be built on the existing infrastructure of measles and polio surveillance.

1.3 Different approaches to control JE Control programmes for JE have focused on three major areas: (1) mosquito control, (2) amplifying host (pig) control, and (3) vaccination. However, neither mosquito control nor amplifying host (pig) control have proven to be reliably effective public health measures to control JE disease in humans.

Mosquito control Mosquito control can include spraying, draining mosquito habitats, personal protection and the use of bed nets. Spraying is both resource intensive, expensive and frequently ineffective. To be effective the control measures must cover all mosquito habitats, which include rice paddy fields, puddles and drainage areas. This is difficult anytime, but especially difficult during the monsoon season and in rural rice-growing areas where JE is most common. The time it takes a Culex mosquito to develop from an egg to an adult is 10-12 days. Therefore, in addition to the large area to be included in control programmes, spraying must also be repeated very frequently (every 10-12 days) to control mosquito populations. An average rice paddy field can produce 30,000 mosquitoes in one day which presents an incredible challenge. Indoor residual spraying has not been shown to be effective and fogging has only resulted in decreases of mosquito populations for one day with complete recovery in four days. With increasing resistance to pesticides, it is now recognized that chemical control of JE mosquito populations for disease control is not effective. Similarly, non-chemical options, including alternative wet/dry irrigation and biological

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control measures, have shown temporary decreases in mosquito populations but none have been linked to a decrease in JE cases. Regardless of its effectiveness against JE, vector control is important for the control of many vector-borne diseases and should be maintained for the control of those diseases. Bed nets are only effective for young children who may be in bed in the early evening as the Culex mosquito bites in the twilight hours. The population at-risk for JE is 1-15 years of age, and usually this population is still active during these peak hours. So a large portion of the at-risk population will still be exposed despite the use of bed nets.

Amplifying host control As the vector of JE is hard to control, additional efforts have been directed to the main amplifying host, the pig. Pig control has been attempted in three ways: segregation, slaughtering or vaccination. Segregation is not practical in many settings. Slaughtering has a high economic impact and affects the livelihood of many families. Vaccination of pigs is costly, difficult and very time consuming. The window of opportunity for immunization is limited as pigs are often slaughtered at 6-8 months of age and vaccination too early has interference from maternal antibodies. Pig vaccination, therefore, has not been shown to significantly impact human cases of JE. In addition to the challenges of controlling pigs, multiple other animal hosts exist in the life cycle of JE virus. For example, birds have been implicated in several outbreaks in different settings. So, even with excellent control measures of pigs the risk of JE virus transmission is still present.

Environmental control It has been suggested that urbanization and economic development have led to decreases in JE transmission but this has not been well documented. In Singapore the urbanization of the entire country has stopped viral transmission. However, this model is hard to replicate elsewhere. Recent viral transmission in wild pigs on outlying islands has raised concern about the potential of human exposure. Prior to the availability of vaccines, vector and environmental control were the only options to control JE. Multiple reviews have shown that these measures are neither sustainable, nor cost-effective and have a limited temporary impact. As JE virus is a part of the ecosystem with multiple hosts and vectors, eradication is not possible.

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Prevention of JE with vaccination JE control through vaccination has been well established in many countries. The success of this intervention is best illustrated through the experience of Thailand. From 1973 until 1983, a vertical control programme for JE with vector control, case detection and outbreak response was used without much effect on disease burden. Since 1983 this programme has been integrated with the primary health care system as a horizontal control programme which also had little effect. However, when JE vaccine was introduced in a phased manner and as coverage increased, the incidence of JE fell dramatically. At a bi-regional consultation on JE, held in 2004 in Bangkok, control strategies were reviewed for all countries from both the South-East Asia and Western Pacific Regions. One of the main conclusions of this consultation was the general agreement that preventive campaigns in high risk populations followed by introduction of JE vaccine into the routine EPI in endemic regions are an appropriate strategy. This strategy mirrors the approach used for yellow fever which is also a mosquitoborne flavivirus. Recent work has shown that JE immunization is not only costeffective but also cost -saving. More cost effective and safe vaccines are now available and technical support through WHO and partners can help countries control JE throughout Asia. One vaccine, the live attenuated SA 14-14-2, now has a specific public sector pricing available for the JE endemic countries of Asia with GNP less than 1000USD to allow increased access. With the availability Figure 1: Japanese encephalitis control in Thailand 1970-1997*

* Graph form Thai MOPH presentation at JE bi-regional meeting 2002

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of safe, effective and affordable vaccines, JE control is now possible as an integrated part of the public health system. Vaccination now provides an effective and reliable public health intervention.

Treatment options There is no specific therapy for JE so the care of JE patients though only supportive, requires excellent critical care and careful attention to early rehabilitation. By providing diligent care, case fatality rates can be greatly reduced. In India in a retrospective study of 12,506 cases, the main causes of death were aspiration, hypoxia, hypoglycemia and uncontrolled seizures. Supportive care, therefore, focuses on airway management, seizure control, decreasing cerebral edema, fluids and nutrition, fever control and managing secondary infections.

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Vaccines against Japanese encephalitis

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2.1 Type of vaccines Three types of JE vaccine are currently in use in several JE endemic countries within the Asia-Pacific region. They are namely: (1) mouse brain-derived inactivated vaccine; (2) cell culture-derived live attenuated vaccine, and (3) cell culture-derived inactivated vaccine.

Mouse brain-derived inactivated vaccine The mouse brain-derived inactivated JE vaccine is produced in several Asian countries. This is the only type of JE vaccine that is commercially available on the international market. The commercially available mouse brain-derived JE vaccine is based either on the Nakayama strain, which was isolated in Japan in 1935, or on the Beijing-1 strain. Currently, the mouse brain-derived vaccine is used in China, India, Japan, South Korea, Sri Lanka, Thailand and Viet Nam. The mouse brain-derived JE vaccine is given subcutaneously in doses of 0.5 ml or 1 ml, the lower dose being for children aged 1-3 years. Due to likely interference of maternal antibodies, children are usually not vaccinated before the age of 1 year. The manufacturers of the internationally marketed vaccine recommend that primary childhood immunization involve 2 injections at an interval of 1-2 weeks. In several Asian trials, primary immunization has a diseasepreventing efficacy of > 95%; 91% efficacy was achieved in a placebo-controlled trial. There is no reduction in seroconversion rates when other childhood vaccines are given simultaneously. However, the primary vaccination schedules vary considerably among different Asian countries.

Cell culture-derived live attenuated vaccine This Chinese vaccine is based on a stable neuro-attenuated strain of the JE virus (SA-14-14-2). In non-endemic areas, a single dose of this vaccine induced an

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antibody response in 83%-100% of children aged 6-7 years, and older children when immunized twice at intervals of 1-3 months, 94%-100% showed a serological response. Side-effects are reported to be minimal. Although at least two doses are recommended, there is evidence that even a single dose can stimulate adequate immune response in the recipient of the vaccine as demonstrated more recently in Nepal. Apart from hundreds of millions of doses used in China, India began introduction of this vaccine in 11 high endemic districts in five states in 2006.

Cell culture-derived inactivated vaccine This vaccine is manufactured in China and is based on the Beijing P-3 strain of JE virus. Primary immunization of infants with this formalin-inactivated vaccine results in about 85% protection. The vaccine is inexpensive, and 90 million doses are distributed for internal use in China every year. However, in China this vaccine will be gradually replaced by the cell culture-derived live attenuated vaccine.

JE vaccines in development Other vaccines are in development and in late stage clinical trials in adults. For up to date information please see: http://www.who.int/vaccine_research/ diseases/japanese_encephalitis/en/

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Immunization strategy for the control of JE

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At the bi-regional meeting on JE held in Bangkok, (30 March to 1 April 2005), after reviewing the experiences from all countries that have successfully controlled JE with vaccination, the consensus statement on future strategies stated: “A proven immunization strategy for JE control seems to be to initiate a preventive campaign in high-risk areas and age groups followed by introduction of vaccine into the routine EPI Programme.” Therefore, the strategy for JE vaccination should include a combination of mass campaign followed by introduction into routine, EPI programme or introduction into routine EPI programme without mass campaign. The latter will be appropriate only in those areas where the disease prevalence is low (or areas considered as low endemic) and the likelihood of an outbreak minimal. For all JE endemic countries, it is necessary to ‘develop a basic minimum data set that countries require for a decision on vaccine introduction. Such information may include disease burden, age, and geographic distribution of cases.

3.1 Mass campaign Planning for mass campaign (See Annex 1: Checklist for planning a mass campaign with JE vaccine) It is important for countries to carefully review the criteria used to decide which geographic areas to include in the campaign and what age group to consider; not all areas need to be covered and age groups immunized. Some key considerations that must be taken into account to guide a decision on the selection of areas and age groups to be included in a mass campaign are: • Review information from the past on cases, deaths, outbreaks reported etc. to make a decision on which areas to include for the mass campaign. • Identify reliable source of data to provide accurate population size estimates for different age strata in defined geographic areas.

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• Assess the cold chain space and equipment to ensure that the large quantity of vaccines and injection equipment can be accommodated. • Assess the health system delivery infrastructure, particularly logistics such as transport, storage, and human resources needed to conduct the campaign. • Put in place a procurement plan that ensures there is sufficient vaccine for the campaign. •

Ensure sufficient funds to meet the cost of vaccines, equipment, and operations.

Defining high risk geographic areas for mass campaign JE is a focal disease with seasonal patterns impacted by agricultural activities, variation in rainfall, animal husbandry and bird-rearing practices of that locality. Peak seasons may vary from state to state in large countries; for example, the peak season for JE is the summer months July to September in Northern India whereas, in the Southern parts, the JE season starts from about August to peak during the winter months. Seasonality is an important consideration for the vaccination campaign as vaccination must precede the onset of the JE season; vaccination during an outbreak usually has minimal impact on the progress and outcome of that outbreak. While all places that report even one case of JE are at risk of future JE outbreaks, due to the sheer cost and the logistics challenges of immunizing everyone, particularly in large population countries, some prioritization is necessary. There are no clear-cut rules for this decision and every country must make that judgment based on the considerations as outlined above. Countries have used different approaches based upon availability of data or pressure brought on by outbreaks. • Thailand initiated routine JE vaccination in children 18-24 months old in eight Northern Provinces with a JE morbidity rate of more than 1.5/100,000 population. Catch-up campaigns were conducted for children aged 7 to 9 years. Both routine immunization and catch-up campaigns were expanded in a phased manner to reach 34 provinces by 1999. JE vaccine is offered nationwide as of 2000 due to continued risk and population migration. •

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In the planning for JE vaccination in India, 10 years data on case reports and outbreaks were reviewed. Due to the difficulty in establishing either an incidence or a prevalence rate, the total cases reported during the

Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

period 1993-2004 were compiled. Five states with the maximum number of cases reported in this period were listed as priority. Further, within the selected states, district-wise data were reviewed and 11 districts with the highest number of cases or outbreaks reported were selected to be targeted in the first phase in 2006.

Defining age group for mass campaigns Ideally, anyone living in JE-endemic areas should be immunized. However, mass campaigns are logistically complex and very expensive to carry out. Therefore, it is essential to assess which age groups are to be targeted for maximum impact on the epidemiology of the disease. • Data from Thailand show that of the cases reported from 1993 to 1997, 60% were in children below 15 years of age, with maximum morbidity in these below 10 years. The catch-up campaign was limited to only those between 7 to 9 years of age. • In a major outbreak in 1988 in the same area where the 2005 outbreak occurred in Uttar Pradesh, 60.4% of the reported cases and deaths were in children below 10 years of age, with only 10.3% reported in those aged 19 years or above. In the years between 1978 to 2001, 60% to 80% of reported cases were in children below 15 years of age. •

In Sri Lanka, when JE vaccine was introduced into the routine immunization programme, campaigns targeted at children aged 10 years or less were carried-out with a major impact on the disease in the immunized districts.

Where JE is endemic, the vast proportion of cases occurs in children aged 10 years or less. Although some countries have carried out campaigns targeting children up to 15 years of age, most countries that have carried out mass campaigns targeted children aged 10 years or less. The decision on the age group to be included for campaigns should be based on local epidemiological data and available resources.

3.2 Conducting the mass campaign Conducting a mass campaign requires meticulous planning and careful coordination to make it a success. An exercise of such a magnitude requires

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the involvement of many sectors and the administrative authorities at different levels. In order to guide the planning of a mass campaign, a ‘Checklist for planning a mass campaign with JE vaccine’ as attached at Annex 1. Please ensure that you go through the checklist before you hold your final preparatory meeting on the day prior to the actual launch of the campaign.

Final preparatory meeting The District Coordinating Team or District Task Force (DTF) must meet at least 24 to 48 hours prior to the actual launch of the campaign to assess the readiness for the campaign. The DTF should check the following: • District microplans have been developed and discussed in detail. • Responsibilities have been defined with clear tasks assigned to individuals and departments. • Clear lines of communication established; clear command and control structure in place. • Vaccines, injection supplies and cold chain equipment (vaccine carriers, cold box, freezers, refrigerators, icepacks) in place and in sufficient quantities. • Ice packs prepared; if insufficient, ice blocks requisitioned from private ice factories. • Information and communications (through banners, posters, radio, TV) etc. commenced. Announcements being aired from mosques, temples, and public address systems in villages, towns etc. • Medical centres and medical officers identified to deal with AEFI should any occur during the campaign. • Daily reporting plans in place and instructions given on how to provide daily feedback at the end of each day. • T-shirts, caps, other advocacy materials (if available) distributed to health workers and supervisors. • District level, micro-planning map developed.

The immunization team It is recommended that each team should ideally comprise of at least five members; of these, at least two must be health workers or nurses who have experience with giving injections. The team composition may be as follows:

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

• Two health workers/nurses; • One assistant to manage the crowd; • One assistant to do the registration and filling of forms, and • Another one to mark tally sheets as the child receives the injection.

Setting up the immunization post Since mass campaigns need to be conducted in the heart of the community to get maximum coverage, it is essential to identify central locations such as schools, mosques, temples, community halls etc. Once the place is identified, the immunization centre can be established. The centre should be used in such a way that children enter from one direction and leave for the opposite direction; avoid entry and exit through the same door. A long table should be set up. If this is not possible, at least two to three small tables are needed. The first table should be used for issuing the immunization card. The central table should have the vaccine, syringes and safety boxes. The third and last place or table should have the tally sheets. Keep unopened vaccine carriers or cold box under the table and not on top of the table. (see figure 2) Figure 2: A sample sketch of a typical layout of an immunization session

Source: WHO/IVB/04.06

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Administering the vaccine • Use common-sense to decide if the child seems to be in the age group identified for the vaccination; DO NOT waste time trying to get proof of age. • Keep children in single file. • The SA 14-14-2 vaccine comes as either a single dose or in 5-dose vials. At present the vaccine does not come with vaccine vial monitors (VVM). • Reconstitute only one vaccine vial at a time. Once reconstituted, place the vaccine vial on top of an ice pack, but make sure that the ice pack is not frozen solid. Allow the ice pack to warm up, i.e. ‘conditioned.’ A conditioned ice pack has water around the ice in the pack. Otherwise, separate the reconstituted vial from the frozen ice pack either by a piece of cardboard, or the foam often found in vaccine carriers. • DO NOT expose the reconstituted vaccine to direct sunlight. • DO NOT fill multiple syringes and keep them lying around; fill one syringe at a time, use one before filling another. • There is NO need to clean site of injection; DO NOT use alcohol to clean the cap of the vial or injection site. • Used needles should be disposed of in accordance with national guidelines. • Only after the child receives the injection should the tally sheet be marked.

Ending the immunization session • Make sure that the immunization team waits till the end of the stipulated working time for the day so that late comers are not missed. • Once the decision to close the immunization post is taken, several things need to be done. These include: − Checking the number of immunization cards issued against the number ticked in the tally sheet; sort out if there are differences. − Make sure that the tally sheet markings are complete, total the final numbers and record it. − Count the number of vials used, check the unused balance and compare with the number of children immunized.

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− If possible, note the wasted vials (in terms of doses of vaccine used and wasted). − If any unopened vials are left and if they have stayed in the vaccine carrier or the cold box, return them to be used the next day. But discard all reconstituted vaccines that are NOT used. − Has there been any adverse event during the immunization session? If any, make note of it after carefully checking the facts about the event. − Compile and communicate the day’s result to the supervisor on the same day. − Check for missing population and plan for reaching the unreached. Do’s and Don’ts of vaccine management •

If the vaccine and diluent are not packed together, it does not matter if the lyophilized vaccine vial is kept at sub-zero temperature. If the vaccine and diluent are packed together, make sure that the icepacks are conditioned prior to putting them in the vaccine carrier to avoid freezing of the diluent. Wrap the diluent container in brown paper before putting it in the vaccine carrier.

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If diluent containers are packed separately, ensure that an equal number of diluent containers are packed as that of vaccine vials.

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To reconstitute the vaccine; the diluent should be stored at the same temperature as the vaccine (+2 to + 8 degrees centigrade and not frozen).

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Reconstituted vaccine should not be exposed to direct sunlight; it also should not be placed directly on solid ice or frozen ice packs.

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Never use alcohol to clean the rubber stopper of the vial.

3.3 Ensuring injection safety and adverse events following immunization (AEFI) during a campaign (See Annex 2: Detecting and reporting AEFIs) Countries must have an AEFI monitoring system even for routine immunization programmes. This becomes even more important when a new vaccine is being introduced. Many countries already have national guidelines which should be followed. Although vaccines are safe, there is no vaccine that is entirely without

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risks. It is important to have in place a monitoring system that includes early detection, rapid investigation and appropriate and timely management of such events. While AEFI should be integrated into the routine surveillance system in the national EPI Programme, injection safety concerns must be addressed a little differently when an injectable vaccine is used on a mass scale. Special consideration with JE vaccine: • It is essential to perform a lumbar puncture (LP) on any patient with a neurological event following immunization and is especially important within the 28 days following immunization. • AEFI surveillance provides an opportunity to monitor for programme errors as well as ensuring the safety of injections.

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Routine immunization with JE vaccine and surveillance for JE

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4.1 Routine immunization Following the mass campaign, JE vaccine needs to be introduced as part of routine immunization to maintain immunity in the new birth cohort. Therefore, JE vaccine should be treated like any other antigen with regard to forecasting, procurement, distribution and management. As known endemic areas receive immunization, JE cases will appear in adjacent or other areas. People in those areas will demand vaccination. Therefore, a country introducing JE vaccine in high-risk areas must be prepared to introduce progressively in other areas where JE is known to be endemic or where JE may spread. Routine immunization is a long-term investment and careful consideration must be given to its sustainability.

Immunization schedule Vaccination should be administered according to the national immunization schedule with attention to contraindications and co-administration as appropriate. The WHO recommended schedule for the inactivated vaccine is three doses: one dose given at 6 months of age or later, followed by a second dose 1-4 weeks later with the third dose given at one year of age. However, the schedule of vaccination varies from country to country: in Thailand two doses of the inactivated mouse-brain-derived vaccine are administered between 18 to 24 months, and a booster dose at 2.5 to 3 years of age. Sri Lanka currently uses the inactivated mouse-brain-derived vaccine and three doses are administered at 12, 13 and 24 months of age. The live attenuated SA 14-14-2 vaccine is recommended to be given as a single dose to children older than 8 months of age followed with a second opportunity at 2 years of age. However, at present it is not recommended to give the vaccine to children below one year of age till further evidence of its safety in infants is available. Please follow package insert and national recommendations for the most up-to-date information. The age at which the

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first dose is to begin, should be based on local age distribution of cases and immunization schedule. The live JE vaccine has no additional contraindications to other live vaccines.

Cold chain and logistics In the management of JE vaccines, given that both the inactivated and the live vaccines are lyophilized, their management and logistics aspects should not be any different from how measles vaccine is handled; all countries have extensive experience with measles vaccine. Should further specific information regarding management of the live vaccine become available, adjustment to the guideline will be made as appropriate.

Monitoring and reporting The monitoring and reporting, be it on vaccine stock or immunization coverage, should be integrated into routine EPI activities and JE should not be treated as something different. In addition, vaccine impact on disease transmission should be followed to justify impact and follow programme effectiveness.

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Vaccine procurement

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5.1 Vaccine licensing or registration Currently, no JE vaccines are WHO pre-qualified. However, WHO prequalification is not required for use of vaccines in countries as long as the vaccines are known to be of assured quality. Such an assurance comes when a country has a functional National Regulatory Authority (NRA). Countries should consider and license JE vaccine through their NRA. The WHO document, Regulation of vaccines: building on existing drug regulatory authorities (WHO/B&B/99.10) is available on the web at http://www.who.int/vaccinesdocuments/DocsPDF/www9846.pdf.

5.2 Vaccine procurement and management (See also Annex 4: Stock Management) The WHO document, ‘Guidelines for the international procurement of vaccines and sera,’ (WHO/VSQ/98.05) is also accessible on the web at http:/ /www.who.int/vaccines-documents/DocsPDF/www9846.pdf. The general guidelines for vaccine supply and stock management are provided in Annex X. In general, vaccine management has several important issues that are not specific to JE vaccine but are important to highlight as many countries may not have extensive experience in vaccine procurement. Some of these include: • Manufacturers require significant lead time to produce vaccines. In general, vaccines are produced after they are ordered so programmes need to be planned early allowing approximately six months for production and quality testing of the vaccine. • Multi-year contracts can help with the stability of vaccine supply and can be considered an important tool where available. For example, UNICEF engages in three year contracts with manufacturers.

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• In the management of vaccine supply, particularly for routine administration, countries could consider setting a value for minimum stock levels that trigger re-ordering.

5.3 Important considerations in the procurement and management of JE vaccine are as follows: • Seasonality of epidemics of JE frequently results in attempts to order vaccine just prior to the JE season. This frequently does not allow enough lead time for the manufacturer. It also does not account for the production process that occurs year round and, therefore, cannot have the surge capacity to meet demands for vaccine for all countries at the same time. In addition to planning ahead, countries should consider phased delivery of the vaccine supply round the year. • Specifically with the SA 14-14-2 live attenuated vaccine, the shelf life of the vaccine needs to be considered in programme planning and while ordering the vaccine. The shelf life of the vaccine upon delivery to the country is 10-12 months. This may have implications for stock management.

5.4 Considerations for vaccine supply and allowable wastage rates: • Wastage rates will differ depending on the number of doses per vial and on the settings in which the vaccine is used, i.e. either in campaign or in routine infant immunization. • In outreach clinics where the number of children attending the clinic is small, a higher wastage may be expected. Use of single dose vials should be considered for routine programme, but this will have a major impact on the cold chain space requirement. • Currently, the manufacturer of live JE vaccine produces both single dose and five-dose vials. Therefore, at times single dose vials or a combination of single and multi-dose vials may be the only formulations available. • Estimating vaccine needs should be based on the target population for campaigns plus the birth cohort in areas previously covered with preventive campaigns.

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Allowable maximum wastage rates for vaccines For multi dose vials, eg. DTP or HepB in 10-dose vials, wastage can be high. In the past, WHO used a 40% wastage for multi dose vials. However, with the launch of the Global Alliance for Vaccines and Immunization (GAVI), the target for reduction of vaccine wastage rates were set at 25% for multi dose vials such as HepB or HepB-DTP combination vaccine, and at 10% for the two-dose pentavalent (DTP+HepB-Hib). Since the SA14-14-2 vaccine is shipped in single-dose and five dose vials, the allowable wastage should be 10% for the single-dose vials, and at least 20% for the five dose vials. In a campaign setting, it may be possible to reduce the wastage to around 5% for the single-dose, and 15% for the five-dose vial.

5.5 Receiving vaccines and supplies At all levels, qualified personnel should receive the vaccines and supplies. The following steps are recommended to be followed: • Check all accompanying documents to ensure they are properly filled. • Check the delivery address and external marking indicating the contents of the box. • Check the condition of packaging (to see if opened, damaged or otherwise tampered with). • Once the boxes are opened, check if the content is the same as labeled and as written on the delivery slips. • Check if the diluents are correct for the vaccines; ensure that equal quantities of diluents are shipped along with the vaccine. • Check the shipping indicators/temperature monitors in all boxes. • Check the date of expiry. For all vaccines supplied through UNICEF or other UN Procured systems, a Vaccine Arrival Report (VAR), designed to monitor international shipment of vaccines and to ensure that shipping guidelines are followed, is required to be filled in and distributed as appropriate.

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5.6 Vaccine administration The administration of the SA 14-14-2 vaccine is no different from that of measles vaccine. Although there is data that the live attenuated vaccine can be safely given to children as young as 8 months, the current recommendation is NOT to use it in children younger than one year. Also, it is recommended NOT to administer measles and the SA 14-14-2 vaccines together or on the same day (co-administration). Data may be available by the end of 2006 to demonstrate if co-administration is appropriate. The characteristics of the inactivated and the live attenuated vaccines are given in Table 1. Table 1: Characteristics of mouse-brain-derived and SA 14-14-2 vaccines

For both vaccines, age of first immunization should be based on epidemiological data on transmission and the local immunization schedule.

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5.7 Cold chain requirements The general cold chain rule is to store all vaccines at +2°C to +8°C. A lyophilized vaccine can be stored at low temperatures for long periods, but diluents are not recommended to be frozen. Further, once the vaccine is reconstituted it should NOT be frozen. At the central and regional vaccine stores, if the vaccines and diluents are packaged separately, the lyophilized vaccine can be stored in freezers or a walk-in freezer room, but not the diluent. At the district level, vaccine can be stored at +2°C to +8°C.

5.8 WHO opened-vial, multi-dose policy WHO’s policy for reconstituted vaccine is to discard the reconstituted vaccine at the end of the session or after six hours, whichever comes first. However, currently the SA 14-14-2 vaccine is recommended to be used within one to two hours once it is reconstituted. Therefore, it is important that this special requirement for the SA14-14-2 is kept in mind, particularly if a programme uses the 5-dose vial for their routine immunization programme.

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6

Surveillance for Janpanese encephalitis

6.1 Clinical case definition of Acute Encephalitis Syndrome Clinically, a case of Acute Encephalitis Syndrome (AES) is defined as a person of any age, at any time of year with the acute onset of fever and a change in mental status (including symptoms such as confusion, disorientation, coma, or inability to talk1) AND/OR new onset of seizures (excluding simple febrile seizures2).

Case classification Suspected Case: A case that meets the clinical case definition for AES. Suspected cases should be classified in one of the following four ways: Laboratory-confirmed JE: A suspected case that has been laboratoryconfirmed as JE. Probable JE: A suspected case that occurs in close geographic and temporal relationship to a laboratory-confirmed case of JE, in the context of an outbreak. “Acute encephalitis syndrome” – other agent: A suspected case in which diagnostic testing is performed and an etiologic agent other than JE virus is identified. “Acute encephalitis syndrome” – unknown: A suspected case in which no diagnostic testing is performed or in which testing was performed but no etiologic agent was identified or in which the test results were indeterminate.

Other early clinical findings may include an increase in irritability, somnolence or abnormal behaviour greater than that seen with usual febrile illness. 1

A simple febrile seizure is defined as a seizure that occurs in a child aged 6 months to less than 6 years old, whose only finding is fever and a single generalized convulsion lasting less than 15 minutes, and who recovers consciousness within 60 minutes of the seizure. 2

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While the above classifications are useful for clearer definitions of AES cases, for practical purposes, the two key definitions to use are “suspected JE cases” for those that meet the criteria for AES, and “confirmed JE cases” for those AES cases which have laboratory confirmation for JE.

6.2 Types of surveillance for JE At the peripheral and district level health facilities where diagnostic capacity for JE does not exist, JE surveillance takes the form of surveillance for acute encephalitis syndrome (AES). Such surveillance should be conducted throughout the year. Where feasible, surveillance for and reporting of JE should be performed within the context of integrated disease surveillance, supported by synergistic linkages with similar on-going surveillance activities such as those for acute flaccid paralysis (AFP) or meningitis. In such situations, reporting of JE cases and deaths should be part of the national health management information system (HMIS) or integrated into communicable diseases reporting systems. However, in many countries it may not be possible to conduct a nationwide surveillance system for JE; it may not even be necessary as JE is often localized to specific geographic areas. Further, JE is a virulent agent resulting in severe illness leading to self-referral. The need for active case detection is, therefore, unlikely to be beneficial. In such a situation, it may be reasonable or more practical to consider passive health facility-based sentinel surveillance for the detection and reporting of AES on a routine basis. Sentinel surveillance may aim to include all hospitals in JE-endemic areas or select the ones where most cases are usually seen. Thus, such a system cannot be expected to provide information on AES from all JE-endemic areas. However, sentinel surveillance systems when used systematically over time will be able to provide information on the trend of the disease; such a system can also provide early warning systems for potential outbreaks of JE. On the other hand, given the nature of the disease, an AES case would ultimately turn up in a health facility sooner or later. Thus, a sentinel surveillance system may, in fact, pick up most AES cases that may be occurring in that area. Based on the endemicity and the current control status for JE, and in accordance with WHO surveillance standards, surveillance systems may be broadly considered as follows:

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(1) In all Asian countries Comprehensive syndromic surveillance for acute encephalitis syndrome (AES) with aggregate reporting is recommended where feasible. In sentinel hospitals, surveillance should be case-based with specimens collected for laboratory confirmation3. The number of sentinel hospitals can be gradually increased if feasible logistically.

(2) In Asian countries where a high level of JE control has been achieved. Surveillance should be case-based throughout the country and include laboratory confirmation of all suspect cases. Regardless of the type of surveillance, reporting should be weekly or monthly and include “zero-reporting” (i.e. no blanks should be left in the reporting forms, a zero should be indicated when there are no cases detected). Outbreak investigations should be initiated if there is a sudden increase in cases or if cases reported are different from historical information, in terms of season, geographic area, age group, or case fatality.

6.3 JE outbreaks and outbreak response Japanese Encephalitis outbreaks are serious as lives are lost and severe disability caused to those that survive the disease. Any outbreak should be investigated thoroughly and an intersectoral approach adopted in the response to an outbreak of suspected JE.

Defining an outbreak There is no single definition. In areas where JE endemicity is low, every case may trigger an investigation. Where JE is endemic, the term outbreak is misleading, unless this applies to an abnormal increase in suspected JE cases as compared with normal transmission. It is difficult to define “abnormal increase”it should be defined as an increase above and beyond the “normal range” of seasonal variation in reported cases, along the lines of the epidemiological analysis of influenza outbreaks. The “normal range” will differ for different countries.

During epidemics, laboratory testing can be limited to confirmation of the first 5-10 cases per geographic area per epidemic. 3

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Outbreak response Once an outbreak is deemed to have occurred, immediate steps need to be taken to conduct a rapid investigation of the outbreak and appropriate control measures effected in time. In most countries, communicable diseases departments have outbreak response teams. The immunization programme must link closely with such teams and have established routes of communication and agreed rules of procedure in responding to such events. An outbreak response should include the following steps/actions • Assessment to confirm the outbreak. • Information, education and communication (IEC). • Options for response. Assessment to confirm the outbreak • Establish that the ‘suspect’ cases actually fit the definition of JE. Obtain information with regard to onset of illness, place of residence of the patient, recent travel history, etc. • Send a team to the locality from where the ‘suspect’ cases have come and conduct a rapid search for similar cases that may have occurred but not reported to the health facility. To what extent such a rapid assessment should be expanded will depend on the population density and the nature of settlements. • Determine if there have been any deaths that have not been reported or deaths for which no cause has been established. Information, education and communication (IEC) • Launch an IEC campaign for the general public so that all cases with AES symptoms are taken to the nearest health facility for supportive care. • Explain to the community leaders of the outbreak and the potential threat of the disease. • Encourage the separation of human dwellings from close proximity to animals such as pigs and wading birds. • Establish a line of communication with the local media, appoint a focal person for the media to refer to, and release information as regularly and as accurately as possible.

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• Encourage people to sleep under mosquito nets, preferably under insecticide-treated nets. • Encourage people to bring the patient early to the nearest health facility. Options for response • Reinforce local physicians’ capacity to provide supportive care for cases with AES symptoms; provide physicians with simple ‘do’s’ and ‘don’ts’ and quick reference materials for clinical care. Emphasize that all treatable should be ruled out prior to labeling a case as AES. • Conduct a quick survey of the environment- rice fields, other likely places where water can collect, presence of pigs or other likely amplifying hosts for the virus. • Link up with the integrated vector-borne diseases unit or malaria control programme to explore possibilities of studying vectors known for transmitting the disease. • Get malaria or vector-borne diseases departments to conduct fogging using space sprays. • Conducting larviciding in areas with stagnant surface water and periodic draining of rice fields may be possible, but requires a high degree of sophistication in agricultural practices to be effective without risk of damage to crops. • It is an excellent opportunity to review immunization coverage if JE vaccine is already being used, and if not, it is also an opportunity to advocate for introduction of JE vaccine.

Data collection, analysis and reporting during a JE outbreak When an outbreak occurs, there is usually tremendous pressure to start immunizing. It is generally agreed that once an outbreak starts, immunizing the population only has a limited impact. However, outbreaks provide excellent opportunities to impress on national policy makers the importance of introducing JE vaccine as part of routine immunization if it is not already integrated into the National Immunization Programme (NIP). In countries where JE vaccine is already a part of the routine programme, a thorough review of the immunization coverage with the aim to improve access in subsequent months is an important and necessary exercise. During an outbreak investigation, the data collection tools must be simple, data collected minimal and most relevant, and rapid analysis and transmission

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of information made central to the purpose of the investigation. A few key things to keep in mind include: • Two basic forms need to be developed: a case investigation form and a line list. A case investigation form will have more detailed information with regard to the patient’s personal history, the onset and progress of the disease and its outcome, and other related information. The line list should have only the minimal information necessary: eg. age, sex, locality (address), time of onset and outcome. • Case investigation should be limited to establish an outbreak of JE; at least 5 to 10 samples from suspect JE cases need to be collected for laboratory confirmation in order to limit wastage of laboratory reagents. Once confirmed, if there are many cases in the locality, it is essential only to line list the suspect cases as no further resources and energy should be expended to conduct case-based investigation of all suspect cases. • The minimum data to be collected in the line list are age, gender, vaccination status, and address. • In the analysis of the data, age should be grouped as 0-11 months, 12-59 months, 10-14 years, and >15 years.

Polio surveillance network and its relevance to JE surveillance Several countries already have well established polio surveillance networks that carry out on integrated vaccine preventable disease surveillance including measles, rubella, neonatal tetanus and, more recently, JE. The regular surveillance work for the surveillance medical officers (SMO) for acute flaccid paralysis (AFP) requires them to visit health facilities on a regular basis to check if any AFP cases have been seen. Therefore, adding AES surveillance does not require any additional visits to heath facilities, as search for AES can be conducted during the same visit for AFP cases. In Nepal the polio SMO network is already reporting JE and the Government of India has requested the National Polio Surveillance Unit (NPSU) of India to assist in JE surveillance in the states of Uttar Pradesh and Bihar.

6.4 Other aspects of JE surveillance Japanese Encephalitis virus is transmitted to humans by a mosquito bite. The main transmission cycle involves animals and mosquitoes, with humans only

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infected incidentally. Humans are also “dead end” hosts, meaning the virus cannot be spread from human to human. The principal vector is Culex tritaeniorhynchus, but a large number of other mosquitoes are known to carry the virus including C. pipiens-pallens and C.quinquefasciatus in urban areas. Pigs are known to be the key amplifying host, but aquatic birds also play an important role in the transmission of the disease. Although other domestic animals such as cattle, dogs, sheep, cows, chicken and peridomestic rodents get infected, they do not achieve sufficient viremia to support further viral amplification. Surveillance can include entomological activities such as vector density monitoring, larval density and breeding site surveys. In most cases, it is difficult even for the malaria programme or the vector borne diseases control programme to conduct such activities in a meaningful way, despite having an infrastructure for entomological services as well as trained entomologists. It would be almost impossible for an immunization programme to carry out such activities without strong support from entomological units. Assessment of pig density in relation to human habitation and evaluating rearing practices of aquatic birds may provide some interesting information, but with minimal utility for control activities. Serological surveillance, where feasible, in domestic pigs might provide useful information with regard to continuing viral activity, particularly in countries where JE vaccination may have reduced the prevalence of JE in humans to insignificant levels. Serological surveillance of immunized cohorts of children over successive years may provide useful information on the rate at which protective immunity wanes following primary immunization. Such information may help national programmes to determine the need for booster doses. However, in most programmes this would be difficult to implement due to cost and logistics reasons.

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Laboratory aspects of surveillance for JE

7

7.1 Laboratory criteria for confirmation Clinical signs of JE are indistinguishable from other causes of AES. Epidemiological data can provide supporting information for the diagnosis. However, laboratory confirmation is essential for accurate diagnosis of JE. Laboratory confirmation of a JE virus infection includes: Presence of JE virus-specific IgM antibody in a single sample of cerebrospinal fluid (CSF) or serum, as detected by an IgM-capture ELISA4 . OR ANY ONE OF THE FOLLOWING which may be done in specialized laboratories: (1)

Detection of a four-fold or greater rise in JE virus-specific antibody as measured by hemagglutination inhibition (HI) or plaque reduction neutralization assay (PRNT) in serum collected during the acute and convalescent-phase of illness. For these tests the two specimens should be collected at least 14 days apart; OR

(2)

Detection of JE virus genome in CSF5, serum, plasma, blood, or tissue by reverse transcriptase PCR or an equally sensitive and specific nucleic acid amplification test; OR

(3)

Isolation of JE virus in CSF5, serum, plasma, blood or tissue; OR

(4)

Detection of JE virus antigens in tissue e.g. by immunofluorescence assay (IFA) or by immunohistochemistry.

Further confirmatory tests (e.g. looking for cross-reactivity with other flaviviruses circulating in the geographical area) should be carried out: (a) when there is an ongoing dengue or other flavivirus outbreak; (b) when vaccination coverage is very high; or (c) in cases in areas where there are no epidemiological and entomological data supportive of JE transmission. 4

Detection of virus genome or virus isolation in serum, plasma or blood is very specific for JE diagnosis; however, it is not sensitive as virus levels are usually undetectable in a clinically ill JE case. Therefore a negative result by these methods should not be used to rule out JE in a suspected case. Similarly detection of virus genome or virus isolation in CSF is usually only found in fatal cases and therefore not very sensitive and should not be used for ruling out a diagnosis of JE. 5

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The large majority of JE infections are asymptomatic. Therefore, in JE endemic areas it is possible to have AES due to a cause other than JE virus and have JE virus-specific IgM antibody present in serum. To avoid implicating asymptomatic JE as the cause of other AES illnesses, sterile collection and testing of a CSF sample from all persons with AES is recommended when feasible.

Because a serum sample collected on admission may not yet be positive in a JE-infected person, a second serum sample should be collected at discharge or on the 10th day onset or of illness of the time of death and tested for presence of JE virus specific IgM by ELISA.

Note: • For persons vaccinated with Japanese encephalitis vaccine within six months of illness onset, testing a single serum sample for Japanese encephalitis IgM may not be diagnostic because it may give a false positive result. In such cases, a diagnosis can only be confirmed by demonstrating JE IgM in the CSF, JE virus isolation, a positive nucleic acid amplification test, immunohistochemistry, IFA, or a four-fold or greater rise in antibody titre in acute and convalescent phase serum samples. • To confirm if a seasonal outbreak is due to JE, suspected cases should be tested until 5-10 are laboratory-confirmed as JE. If the outbreak is not an expected seasonal outbreak, or there are unusual epidemiological features (e.g. age distribution of cases not consistent with pattern of JE infection), testing of CSF is especially important, as an encephalitis outbreak could be due to other aetiologies (eg. Nipah virus). In a nonJE outbreak, sporadic cases of JE are still likely to occur, so the percentage of specimens confirmed as JE positive also should be considered. For example, in previous large JE outbreaks, typically about 30% cases have been JE positive, so confirmation of a much smaller percentage of cases may prompt further investigations into the aetiology of the outbreak. As a JE outbreak continues, all samples may not need to be tested. For example, 5%-10% could be tested on an ongoing basis.

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7.2 The JE laboratory network Samples should be sent for JE testing to designated first level laboratories. At these laboratories the preferred test for JE diagnosis is the IgM-capture ELISA (enzyme linked immunosorbent assay). These laboratories may also carry out other investigations or send the specimens to other levels as necessary. In some cases, the hospital laboratory may be a designated JE laboratory. For laboratories in the JE network, systematic and regular supervision and quality control should be ensured.

7.3 Specimen collection Cerebrospinal fluid and blood (serum) are the specimens to be collected for JE diagnosis. These samples should be collected on admission. If it is a serum sample, it is important that a second serum sample is collected at discharge or on the 10th day of onset or of illness at the time of death. Initial processing of samples should be in hospital laboratories. Samples for subsequent virological testing should then be sent to designated laboratories. Patient information should be recorded on a laboratory request and report form (see Annex x) that must accompany the specimen when it is referred to the laboratory. Information should include: patient name, age (or date of birth), province/district/town of residence, JE vaccination history (and date of last JE vaccination), date of onset of symptoms, types of specimen and date of specimen collection. In the case of an outbreak, a laboratory request and report form in the form of a line list may be prepared (Annex 3 ). All specimen tubes should be labeled with the patient’s name or identifier number, date of collection and specimen type.

Cerebrospinal fluid (CSF) collection • The collection of CSF should be a routine procedure when a patient is suspected of having meningitis or encephalitis. However, it is an invasive technique that should only be performed by experienced personnel under aseptic conditions. • CSF should be collected into separate aliquots for examination for cells, biochemistry, microbiology and virology. It should be collected in a dry, sterile, screw cap container. For virological investigations, 0.5 to 1.0 ml of CSF is required.

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• CSF should be transported to the local hospital laboratory as soon as possible (ideally within 1 hour). Before arrival at the laboratory, the CSF specimens for routine investigations should not be refrigerated or exposed to extreme cold, excessive heat or sunlight. However, if there is likely to be a delay beyond 1 hour, specimens for virology should be refrigerated. In the laboratory priority should be given to ruling out treatable (usually bacterial) aetiological agents. • CSF samples for virological testing should be sent to the designated laboratory as soon as possible. Before transport, in the hospital laboratory, they should be kept at +4oC for short term storage (1 to 3 days) or at or below –20oC for longer term storage. If a –20oC freezer is not available, they should be stored in the freezer section of the refrigerator. If specimens have been frozen, they should be transported frozen. Repeated freezing and thawing of CSF should be avoided as this may lead to instability of IgM antibodies.

Blood specimen collection • Blood should be collected by venepuncture and placed in a dry, sterile vial. The volume of specimen should be approximately 5 ml for older children and adults and 1 ml for infants and younger children. • Blood should be allowed to clot at room temperature and then should be stored in a cold box or refrigerator and maintained at +4oC to +8oC and not frozen. It should be transported to the hospital laboratory within 24 hours. • In the hospital laboratory, serum will be separated for subsequent transfer to a designated laboratory. For serum, shorter term storage (13 days) should be at +4oC, but longer term storage should be at -20oC. If a –20oC freezer is not available, samples should be stored in the freezer section of the refrigerator If specimens have been frozen, they should be transported frozen. Repeated freezing and thawing of serum should be avoided as this may lead to instability of IgM antibodies.

7.4 Transport of specimen • Ensure the availability of specimen collection containers, laboratory request forms and secondary transport containers at health care facilities.

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• A designated person (or persons) should be responsible for storage, packing and transport of samples according to national or international guidelines. • In principle a “triple packaging system” (refer to laboratory manual for details) should be used when transporting samples from place to place.

Transport planning Successful shipment of materials requires advanced planning, appropriate packaging, labelling, and documentation. Coordination and communication are required between all parties involved – the sender, carrier, and receiver. It is the responsibility of the sender to ensure the correct designation, packaging, labelling and documentation of all shipped materials to ensure that the material is transported safely and arrives on time and in good condition. The basic steps to follow are as follows: • Make advance arrangement with the receiver. • Make advance arrangement with the carrier. • Label the package to be shipped as Category B, “Patient’s Specimen”.

Documentation and sending the package The documentation required to be completed for shipping materials is determined by the nature of the materials being sent. In general, each shipment should be accompanied with the following documents: • Shipper’s Declaration of Dangerous Goods (only those goods classified as infectious substances, see Figure 3). • A packing list / proforma invoice / customs declaration / commercial invoice which includes the receiver’s address. • Number of packages, detail of contents, weight, value (a minimal value should be indicated for customs purposes if the items are supplied free of charge). • Airway bill if shipped by air. • Export / import permit if required.

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8

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References

(1)

WHO Position Paper on Japanese Encephalitis. WER, 1998;73:337-343.

(2)

Core information for development of immunization policy, 2002 Update. WHO/V&B/02.28.

(3)

Immunization in Practice, A Practical guide for health staff, 2004 update. WHO&UN Foundation.

(4)

Mid-Level Management Course for EPI Managers, Module 9, Block IIILogistics. WHO/AFRO. March 2004.

(5)

Introduction of hepatitis B vaccine into childhood immunization services. Management Guidelines, including information for health workers and parents. WHO/V&B/01.31 November 2001.

(6)

Surveillance of adverse events following immunization. Field guide for managers of immunization programmes.

(7)

http://aim-e-learning.stanford.edu/en/vaccines/je/index.html.

(8)

WHO recommended standards for surveillance. Japanese Encephalitis, pages 46-51. WHO/V&B/03.01.

(9)

WHO. Surveillance of adverse events following immunization. Field guide for managers of immunization programmes. WHO/EPI/TRAM/93.02.REV.1.

Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

Annex 1

Checklist for planning a mass campaign with JE vaccine While planning for a mass campaign, the following aspects of planning should be kept in mind:

Coordination/planning • Is there need to establish a national committee for the planning and conduct of the mass campaign? If Yes, has it been formed? • Is there need to establish a district coordinating committee? • Is there need to develop a national guideline that defines geographic areas and age groups to be included, along with time line for activities, including overall strategy and policy for the campaign? Has a team leader to coordinate national activities been identified? • Has funding been secured? Has discussion with the Ministry of Finance taken place and approval from relevant ministries sought? • Has district level micro-planning been completed? If not, is there a time frame within which it will be finalized?

Vaccine procurement • Which vaccine will be used- inactivated mouse-brain-derived or live attenuated SA 14-14-2 vaccine? • Have you checked vaccine availability? For example, a letter of intent is especially important where there is a sole supplier. • What size vials (number of vaccine doses) of the vaccine will be used? • Has the procurement process been completed? When is the first shipment expected to be delivered? Is there a plan of distribution from the central level to provinces and districts? • Have appropriate quantities of auto-disable syringes, re-constitution syringes, safety boxes and diluents for the vaccine been accounted for and ordered?

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Cold chain • Is there adequate space at the central and provincial cold stores to accommodate the large quantities of vaccines likely to arrive soon? • Has transport been organized and a distribution plan, along with time lines, developed? • Is there sufficient cold chain space and cold chain equipment at the district level? Has an assessment been carried out or is there a need to conduct a quick review? • Is there need to develop a DO’s and DON’Ts list for cold store managers and field workers who will handle the vaccine?

Injection safety • Is there an injection safety plan? • Is there a guideline on the use and disposal of auto disable syringes at different levels of health facilities? • Is there a plan for monitoring injection safety during the campaign? • Does the country have an Adverse Events Following Immunization (AEFI) monitoring system in place? If not, has a plan been developed for AEFI monitoring during and after the campaign?

EPI forms and materials • Will the recipients of vaccine be given a card? If Yes, have the cards been printed? • Have tally sheets been printed? • Has a supervisory checklist been developed and printed?

Training • Which staff needs to be trained? How will the training be carried out? • Who will provide the training? • Is there a training plan or training schedule? • Has any training material been developed? If Not, what plans are there to start doing it?

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Advocacy, communication and information • Is there any need for advocacy targeted at decision makers, influential community members and religious groups? • What sort of advocacy materials need to be developed? What messages need to be developed and communicated? • Who will develop them? • Is there a comprehensive plan on the use of existing media (TV, radio, etc.) and community channels for communication (eg public address system, religious gathering and festivals)? • Have banners, posters, T-shirts etc. been ordered?

Supervision • Have supervisors been identified at all levels? • Has a supervisory checklist been developed and tested? • Has a supervision plan been developed as an integral part of the overall plan for the mass campaign?

Microplans • Does the microplan map out accurately the distribution of dwellings, and likely centres where immunization sessions are to take place? • Is there accurate population data and is the estimated number of target group for vaccination reflected on the activity map in the microplan? • Does the microplan contain details of vaccination sites, vaccination teams, social mobilization plans and team, time table for activities etc? • Does the microplan clearly indicate the various supplies needed for each of the planned session posts?

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Annex 2

Detecting and reporting AEFIs Which AEFIs should be reported? During a campaign, the period up to which the system will monitor for adverse events should be specified. Generally, it should be less than 48 hours after the immunization session; anything occurring later than that should be part of the regular AEFI system of the programme and not really that of the campaign. The events, therefore, are also of immediate and sudden nature. They include all deaths that are thought by health workers or the public to be related to immunization, all cases requiring hospitalization that are thought to be related to immunization, and any other severe or unusual medical events that are thought to be linked to immunization.

Reporting the AEFI As soon as a suspected adverse event is reported, the health worker must contact the focal person identified for investigating AEFIs. If the health worker is not sure, the information must be relayed immediately to the next level supervisor. Immediate investigation must be initiated at the local level without waiting for the AEFI Investigation Team to arrive.

Responding to the AEFI The health worker must provide all supportive care as long as the child remains within his area of influence. Every attempt must be made to shift the child to a hospital and contact immediately the doctor identified as the focal person for managing AEFI cases. The health workers must collect all information regarding the suspect case and make sure that the parents are kept well informed of the status and progress in the management of the case. The health worker must be prepared to face questions from local media or the community. Communicate the facts clearly, honestly and as calmly as possible. Establish a line of communication and

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information flow and let the parents and the community know who to contact and how to contact for further information.

Investigating AEFIs As soon as a suspected AEFI is reported, the investigation team must proceed to the locality where the event occurred. Collect relevant information on the patient data, time and activities immediately prior and after the immunization. Obtain patient’s past history, history of any similar events in the past or any known reaction to any drugs or other antigens. Review the child’s immunization history and obtain results of laboratory investigation done, if any. Review the vaccine (lot number, expiry, manufacture date) and the injection equipment (for possible contamination, poor handling practices, re-use etc.). Establish the circumstance and the persons who administered the injection. Review the vaccine handling and storage practices, particularly reconstitution, duration left unused after reconstitution, diluent (whether it was the right one or not). Have similar illness reports been received from the same locality or the community? If any, investigate further. Collect samples of whatever is available of the vaccine, syringes and needles (usually not available as they would have been discarded).

Communicating the results of the investigation and taking corrective action Once the investigation is completed and all facts have been collected and verified, a conclusion must be reached as to the nature of the adverse events. A report must be made with the conclusions and communicated to all concerned. If the event is related to immunization, be it programme errors or quality of vaccine, all possible corrective measures must be taken. The health worker should not wait for the final conclusions of the investigation for taking corrective action at the local level should such corrective actions be warranted.

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Annex 3

SAMPLE: Japanese encephalitis virus laboratory request and report form

*Sample is good if: • There is no leakage • Of adequate quantity • Brought in cold chain • Documentation is complete

42

If sample is bad specify Add in the following information: Fever at onset: Yes [ ] No [ ] Duration: ___________ Seizures: Yes [ ] No [ ] Altered level of consciousness: Yes [ ] No [ ] Neck rigidity: Yes [ ] No [ ] Any other information:_______________ Results of any laboratory investigations:_________________

Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

Annex 4

Stock management Defining vaccine supply period It is important to plan vaccine procurement well in advance to ensure timely arrival of vaccine supply. Most manufacturers need at least six months lead time to prepare for supplies, and this is even more important if a large-scale mass campaign is planned in a country. The general principles for vaccine stocks and their period of storage at different administrative levels in the country are as shown in Table 1. The main idea is to ensure that there is no overstocking or stock-out at any administrative level. Table 1: Generally recommended standard periods for vaccine supply Location of store

Supply period

Central store

Six months

Regional/provincial store

Three months

District store Health centre

One month One month

Health post/dispensary level*

One week

*In many places, no vaccine is actually stored at the health post or dispensary level, and even at the health centre level vaccine may be stored only for a week. The final determinant for a decision to store or not to is the availability of electricity at that level.

There are sophisticated methods to calculate vaccine requirements based on supply periods. However, for most programmes the vaccine supplies are made either half yearly or on a quarterly basis, at least at the national and provincial levels. More frequent supplies, for example, on a monthly basis may be made from the provincial to district levels. The important thing to keep in mind is the concept of minimum stock.

Minimum stock The ‘minimum stock’ represents the minimum vaccine doses (or vials) that should be in the store till the arrival of the next supply. For practical purposes, this is fixed at 25% of the total estimated vaccines required for the given supply period. The ‘minimum stock’ concept helps ensure that vaccine supplies are estimated and supply planned so that there is no risk of a stock-out at any time.

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Maximum stock Sometimes stores also run the risk of overstocking. The “maximum stock” that should be in the store is equivalent to the total vaccine doses required for that period plus the “minimum stock.” If we take the above example, the “maximum stock” is (36,000+9,000) = 45,000. Overstocking runs the risks of vaccine expiring on the shelf. For example, if say, 144,000 doses of vaccines are required for a place “X” for the whole year and supplies are made on a quarterly basis, then the “minimum stock” level should be; Total vaccine doses required for the whole year Number of times supplies are made Quantity of vaccine needed during each supply period Minimum stock level needed to be maintained

144,000 4 36,000 (36,000 X 0.25) or 9,000 doses

Critical stock At the district level, the vaccine stocks may be replenished every month. Also, the time required for supply from the provincial store to the district store may not be long enough to worry about. However, when supply delivery time is an important consideration, another concept to keep in mind is the “critical stock or time to order” notion. Mathematically, this can be expressed as, Scritical = Sminimum + (QperiodxLeadtime)/Psupply where Qperiod is the quantity required for that period, Leadtime is the time required for delivery, and Psupply is the supply frequency. Using the above figures, the calculations are as follows if the supply delivery time is, say, 2 weeks: Scritical = 9,000 +[36,000x(2/52)]/4 = 9,000+ [1,440/4] = 9,000+360 = 9,360

Estimating vaccine needs There are several methods to estimate vaccine need and different countries use different methods as appropriate to their settings and practices.

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

• Estimating vaccine needs based on target population • Estimating vaccine needs based on past consumption • Estimating vaccine needs based on the size and number of immunization sessions.

Estimating vaccine needs based on target population The important parameters required for estimating vaccine needs based on target population are: • Target population • Estimated coverage to be achieved • Number of doses in the immunization schedule, and • Wastage rate Wastage rate need to be converted to wastage factor in order to account for vaccine that may be “wasted.” Such wasting could occur due to: • Discarding of opened vials at the end of the session • Discarding of unused vaccine in a multidose vial where WHO’s opened vial policy is not followed • Accidental breakage of vaccine vials during immunization session • Damage in the vaccine carrier during transport • Discarding of un-opened vials returned from an outreach session • Theft or loss of vaccine vials The way to calculate the wastage factor is as follows: for a 25% wastage rate, the wastage factor is calculated as 100/(100-25) or 100/75 or 1.33 To ease the need for such calculations, the following tables provide equivalent wastage factor for estimated wastage rates Wastage rate in %

10%

15% 20% 25% 30% 35% 40% 50%

Equivalent wastage factor

1.11 1.18 1.25 1.33 1.43 1.54 1.67

2

Estimating vaccine needs based on past consumption The important parameters required for estimating vaccine needs based on past consumption are:

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Estimating vaccine needs by target method Example, vaccine needed for a target population of 12,000 with a vaccine administered in three doses, at a wastage rate of 25% and a projected coverage of 85% Vaccine needed = 12,000 x 3 doses x 1.33x 0.85 = 40,698 doses

The main drawback of the population target based method is that in most countries it is hard to get accurate population figures on the different target age groups. For smaller countries and rural settings, it may be relatively easy to estimate the target population, but in large metropolitan cities it is difficult to get accurate estimates. Depending on fertility and mortality patterns in a specific country, the proportions can either be higher or lower than what is given below as an example. Example of population estimates for different age groups Age group

Percent of total population

0 - 11 months

2.5%

12 - 59 months

13.0%

5 – 9 years

14.5%

10 – 14 years

12.1%

Source: Statistical Yearbook of Bhutan 2003. National Statistical Bureau, Royal Government of Bhutan, Thimphu. March 2004

• Stock available at the beginning of the supply period • Stock received during the supply period • Stock available at the end of the supply period • Stock known or considered ‘wasted’ (for example, destroyed, frozen, expired etc.) Mathematically it can be represented as follows: Vneeded = [(Sbeginning + Sreceived) – (Send + Swasted)] Where, Vneeded is vaccine stock needed for the period of supply, Sbeginning is stock available at beginning Sreceived is stock received Send is stock available at end of year Swasted is stock wasted

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

Appropriate adjustments will be needed to account for the natural increase in the birth cohort based on growth rate for that population, as well as if there is either immigration or emigration of a large number of people in that area. This method is useful where stock management is good and reliable stock management data are available. However, this method does not provide information on immunization objectives and targets to be achieved in the given period.

Estimating vaccine needs based on the size and number of immunization sessions Sometimes the nature of the programme delivery infrastructure is such that the only appropriate way to estimate is to base it on the size and number of immunization sessions. In general this entails a higher rate of wastage, particularly if an opened-vial policy is not or cannot be adopted. This is primarily due to the small number of target children at each session in a programme where multidose vials are in use. A vial needs to be opened even if there is only one child at that session. An example of vaccines needed/estimated, based on size and number of immunization sessions, Bangladesh No. of wards in the country

14,027

No. of sessions in each ward

8 (fixed)

Total number of sessions in a year (14027x8x12)

1,346,592

Average number of new children per session

3

Minimum number of vials (multidose) to be opened

1

Total number of vials needed for the whole year

1,346,592

At 30% wastage and 25% buffer, the total vials needed for the year is

2,390,200

With a 10-dose vial, the doses of vaccines needed

23,902,001

The projected surviving infants for Bangladesh for 2005 are 3,865,070. If the target population method is used with the same wastage rate and buffer, the number of doses (3 doses/child) of vaccines required, (3,865,070 x3 x1.42)+25% buffer = 20,581,497 doses. Therefore, this would result in vaccine stock-outs.

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Annex 5

Packaging and shipping of vaccine

Packaging volume information for the SA 14-14-2 live attenuated JE vaccine 1. The packaging of JE vaccine with diluent is below: One dose vial vaccine packaged with diluent. Small box:72mm X55mm X21mm Middle box:215mm X75mm X58mm 2. Vaccines and diluent packaged separately. 2.1 The packing size for 1dose vial and 5 doses vial vaccine is the same because the same size vial is used. Small box: 83 mm X40 mm X 35 mm Middle box: 185 mmX 85 mm X 83 mm Each small box contains 10 vials and one package insert. Ten small boxes are put into a middle box. Twenty middle boxes are put into one plastic bag with quality certifications. The plastic bags are placed into a foam box with ice pack and then put into one big box. 2.2 The following is the packing size for diluents. The diluent for one dose vaccine is water for injection WFI small box for 10 vials: 83mm x 35mm x 40mm WFI middle box for 10 small boxes: 185mm x 85mm x 83mm The diluent for five dose vaccine is PBS PBS small box for 10 vials: 83mm x 35mm x 51mm PBS middle box for 10 small boxes: 185mm x 85mm x 104mm Each small box contains 10 vials and one package insert. Ten small boxes are put into a middle box. Twenty middle boxes are put into one plastic bag with quality certifications. The plastic bags are placed into a foam box and then put into one big box. Source: Chengdu Institute of Biological Products, Chengdu, China

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Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region

e

Introduction of Japanese Encephalitis Vaccine in the South-East Asia Region (with focus on SA 14-14-2 JE Vaccine)

Operations Guidelines