Report of the AEFI committee


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Report of the AEFI committee

  1. 1. REPORT OF THE NATIONAL LEVEL COMMITTEE OF EXPERTS “TO REVIEW The State investigation reports and to investigate the Adverse Events followingImmunization (AEFI) following Japanese Encephalitis(JE) vaccination in high risk districts covering 4 States of the country” Immunization Division Department of Family Welfare Ministry of Health and Family Welfare Government of India 1
  2. 2. Preface Japanese encephalitis has been plaguing the country over severaldecades. Since its discovery in the North Arcot district (now bifurcated intoVellore and Tiruvannamalai districts) in Tamil Nadu in 1955, its prevalencespread to neighboring south and southwest Karnataka and south and east-central Andhra Pradesh in the 1960s, to West Bengal, Assam and nearbyregions in the early 1970s and to Uttar Pradesh in late 1970s, and finally tocentral and south western parts of India – Maharashtra, Goa and Kerala in the1990s. Considerable scientific investigations on its vector identification and vectorbiology and bionomics, host species, human risk factors of disease,epidemiology, virology, diagnostic parameters, reagent-development and fieldapplication, and laboratory work towards vaccine development have beenconducted under the leadership of the Indian Council of Medical Research. Yet,a comprehensive plan for JE control was not made on account of variousreasons. With assistance from Japan India established a vaccine manufacturingunit at Central research Institute Kasauli. However, the vaccine, made in infantmouse brain did not become widely accepted or popular. In the 1990s the Chinese live attenuated JE virus vaccine became knownto the scientific world and since then its safety and efficacy had been discussedin several national and international forums. In 2005, there was an unusually large outbreak of JE in eastern UP,resulting in death of over 1500 children. Consequently the Government of India(GoI) examined the potential of the Chinese live attenuated JE virus vaccine andall assessments were essentially positive. Consequently it was registered inIndia and procured in large quantity. The intention was to begin administering thevaccine in high risk areas prior to the next annual season of JE. In 2006 May, 2
  3. 3. June and July it was used in mass campaigns in 11 districts in 4 States. In oneState (Assam) cases of JE had already started to occur when vaccine becameavailable. After discussing the pros and cons of vaccination, it was decided tointroduce JE vaccine in Assam also, for the benefit of children not yet infected. All vaccines may cause some unwanted reactions in some children. Alllicensed vaccines have gone through safety assessments, yet, it is wise andessential to monitor adverse events following vaccination in order to detect anyunknown adverse effects that may arise due to the vaccine. Thus, the fourStates that distributed and inoculated the JE vaccine in children had conductedadverse events monitoring procedures. Such events were brought to medicalattention. From such data one must differentiate background noise from events dueto the vaccination and also differentiate minor or inconsequential reactions fromserious and life-threatening reactions. The term ‘adverse events followingimmunization’ (AEFI) denotes events within a selected time interval aftervaccination, but such sequence and temporal association does not necessarilymean causal relationship. The data base on AEFI consisted of 533 specificchildren with illnesses that were reported within two weeks of vaccination. Amongthem 65 were considered severe, among which 22 children had died. The taskof the Committee was to examine these cases to differentiate causal associationfrom temporal but coincidental association. The findings of this examination ofevidences will have an impact on the further future use of this vaccine. The Committee and its members feel privileged to be in a position to be ofassistance to the GoI in the nation’s efforts in containing the problem of JE. Thisreport is divided into chapters and several of them will provide comprehensivebackground information so that it becomes valuable for policy makers,programme planners and project implementers. We place on record our appreciation and gratitude to several members ofthe Immunization Division under the Ministry of Health and Family Welfare and of 3
  4. 4. the Program for Appropriate Technology in Health for their assistance and support to the work of the Committee. As Team Leader it is my duty to thank the members of the Committee who have patiently and diligently gone through all the available data and helped in arriving at clear conclusions as well as for drafting several chapters.;; ~ T Jacob John 5 October, 2006 Team leader t 4
  5. 5. Executive summary The Committee has scrutinized the details of all cases of Adverse EventsFollowing Immunization (AEFI) with SA-14-14-2 JE Vaccine that were reported inthe 11 districts of the 4 States in which 9.308 million children were given the liveattenuated Japanese encephalitis vaccine. A total of 533 children with AEFIoccurring within 2 weeks of vaccination were reported. Among them 438 childrenhad very minor symptoms and were seen in the outpatient clinic and treated withsymptomatic treatment as needed. Of the remaining 65 children 43 werehospitalized and 21 among them died. One more child died on the way to thehospital. Thus 22 children died. The frequency of 22 deaths among 9.308 million vaccinated children aged1-15 years works out as 0.236 / 100000 (0.00024%). Based on the population(Census 2001), annual growth rate, estimated number of children and agespecific death rates we arrived at the probable frequency of death in 1-14 yearage group in the general population in the districts in which JE vaccination (SA-14-14-2 JE Vaccine) campaign was conducted comes to 8.63 / 100000 (0.009%).The number of death in the two weeks after JE vaccination (SA-14-14-2 JEVaccine) has not exceeded this background rate. Thus there seems to be noprima facie evidence that AEFI has contributed any excess mortality. Two prominent clusters of illnesses and a number of miscellaneous onesconstituted the 65 “serious” events – 43 hospitalized and recovered and 22 died.One cluster was obviously acute encephalitis, in Assam, where JE had alreadystarted as an outbreak. We conclude that the cases of encephalitis reported aswere causally unrelated to JE vaccine. Epidemiologically, JE vaccine campaigndid not induce any spurt of the number cases – indeed, following vaccinationcases rapidly declined. The second cluster of cases was due to an acute encephalopathysyndrome, a disease that occurs among young children in UP. It is characterizedby sudden onset, rapid progression and high case-fatality. Such cases havebeen occurring annually in different parts of UP and occasionally in neighboringStates as well. We do not know what causes such illnesses and without anunderstanding of specific case criteria and etiology, it is not possible to ask or 5
  6. 6. answer retrospectively whether JE vaccination (SA-14-14-2 JE Vaccine) has inany way contributed to its triggering in predisposed children. We do not considerthat the available evidence suggests causal relationship with JE vaccine (SA-14-14-2). The following are the committee’s recommendations to the Government ofIndia.. Recommendations 1. No direct causality has been established between the reported illnesses and the SA-14-14-2 JE vaccine. Therefore no stricture on the further use of the vaccine is warranted. 2. As has been observed case investigations and laboratory tests conducted following an AEFI have been inadequate. Standard case records and reporting formats, sample collection and investigation at designated laboratories, data collection and analysis, epidemiological investigations and causality assessment following AEFI need to be strengthened and reinforced by the State and National authorities. 3. The protective efficacy and vaccine effectiveness should be measured and monitored in those JE-endemic areas where the vaccine is used on a long term basis using epidemiological skills and expertise. 4. As the vaccine contains live attenuated JE virus, neuro-virulence studies in suitable animal models should be conducted in order to develop in- country information on this vaccine. 5. One general observation of concern is the poor quality of hospital case records. Improved case records will stimulate better clinical investigation and diagnosis. The Government may address this problem through appropriate channels. 6. In view of the frequency of acute encephalopathy syndrome in some JE endemic areas further studies using epidemiological methods to identify risk factors that may provide clue to the nature of the disease should be addressed. 6
  7. 7. Chapter I The Establishment of the CommitteeA National level committee of experts was formed on 13th July 2006 “to review Stateinvestigation reports & to investigate the Adverse Events following Immunization (AEFI)following vaccination with live attenuated SA-14-14-2 vaccine against JapaneseEncephalitis (JE) in high risk districts covering 4 States of the country” (Vide letter No.T-13020/05/2006-CC&V. see Annexe 1).Members: 1. Dr. T Jacob John, Vellore, Tamil Nadu – Team Leader 2. Dr. Ramteke, Joint Drugs Controller General of India 3. Dr. Dipali Mukharjee, Senior Deputy Director, ICMR 4. Dr. Shah Hossain, Epidemiologist, NICD 5. Dr. Pradeep Haldar, Asst. Commissioner (UIP) – CoordinatorTerms of Reference • The committee will review the State investigation reports & will investigate the AEFI following JE vaccination with live attenuated SA-14-14-2 vaccine in High risk Districts Covering 4 States of the Country • The committee members may visit the concerned districts as and when required or as required by the State to review the State investigation reports and to investigate AEFI cases. • Committee is required to submit the report to Government of India (GoI).Brief Background In the first half of 2006 The GoI made and implemented decisions to licensepurchase and import the live attenuated JE vaccine from China, after the due processesof procedures. Against the background of large outbreak of JE in eastern Uttar Pradeshin 2005 and the continued endemicity of JE in other States, the vaccine was given tochildren in 11 selected high risk districts in 4 States in mass campaigns, during mid-Maythrough July. The adverse events following vaccination form the data base for thiscommittee to evaluate causal relationship versus co-incidental temporal relationship.Meetings held: (Minutes attached in Annex 2) 1. First meeting of the committee was held on July 28th 2006. 2. Second meeting was held on Sep 11th 2006. 3. Third meeting was held on Sep 25th 2006. The Committee arrived at conclusions on the question of causal relationship of AEFI with JE vaccination and formulated its final recommendations, as presented in the final chapter of this report. 7
  8. 8. Chapter II Japanese Encephalitis in IndiaIntroductionJapanese encephalitis (JE) is caused by the JE virus, a member of the Flavivirus family.It is the most important and serious viral cause of encephalitis and consequent mortalityas well as disability in surviving children, in most of Asia. The disease affects primarilychildren under the age of fifteen, leaving up to 70 percent of those who develop illnesseither dead or with long-term neurological disabilities. JE has spread beyond its earlydomain, spreading as far south as northern Australia and as far west as Pakistan fromits early geographic detection in Japan in the late 19th century. To date JE has notappeared in Africa, Europe, or the Americas.The three main activities for JE management and control are:• Problem definition: Efficient surveillance with case detection and reporting (including age and geographic location of patient as well as laboratory confirmation of outbreaks).• Secondary prevention of death/disability: Improved case management to decrease case fatality rate (CFR) and rehabilitation of surviving children with disability.• Primary prevention: Protection of host through immunization and risk-reduction of vectors and human-vector contact.Experience of JE control in the SE Asian Region:With JE, a problem throughout most of South and East Asia, it is useful to consider the considerable amount of experience with JE control in the region. Based on such lessons, in 2005, after reviewing the use of immunization and its impact, WHO consensus on the JE immunization strategy was achieved. For JE control, vaccine should be used in one- time campaigns in the at-risk age groups followed by routine vaccine introduction in new child cohorts at-risk areas.1 This strategy is the cornerstone of all successful JE control programsin South East Asian countries. Following a review of JE control programs in all countriesendemic for JE it was found that JE control efforts with vector control alone was withoutthe desired effect. They then moved to introducing JE vaccination in the program (e.g.,Japan, Korea, Thailand, and China). Due to this program review, vector control is notrecommended as an effective strategy for JE control, although integrated vector controlfor all vector-borne diseases remains a necessity irrespective of vaccination status.JE disease and control in India:Key events in history of JE in India• 1954: First evidence of suspected JE viral activity in Tamil Nadu and Pondichery1 Bi Regional JE Conference, March, 2005 8
  9. 9. • 1955: JE virus isolated from brain biopsy at Vellore. Virology conducted at Virus Research Center at Poona (now National Institute of Virology, Pune)• 1950s and 1960s. Identification of vectors as Culex vishnui complex; pigs found to be amplifier host; cattle and humans found to be non-amplifier hosts.• 1960s. JE detected in Andhra Pradesh and Karnataka• 1973: Outbreak reported from Burdwan & Bankura districts, West Bengal.• 1980s. JE caused outbreaks in Assam Bihar and eastern UP, moving westward in subsequent years to Delhi and Haryana.• 1990s. JE in Maharashtra, Goa and Kerala.Disease burden and reporting:JE has since been reported in 26 States and Union Territories (UTs), especially since1978. In the last decade cases have been reported almost annually in 12 States andUTs. The surveillance system is not complete or comprehensive. However, thenumbers of clinically diagnosed cases are cumulated in Government hospitals, formingthe basis of national statistics.From 1998-2005: • Average annual suspected JE cases reported: 2316 • Average annual deaths reported: 524 • Average case fatality rate from JE in India : 23 %Data Source: National Vector Born Disease Control Program (NVBDCP)Sl. Affected States / 2002 2003 2004 2005No. Union Territories C D C D C D C D 1 Andhra Pradesh 22 3 329 183 7 3 0 0 2 Assam 472 150 109 49 235 64 145 52 3 Bihar 8 1 6 2 85 28 192 64 4 Chandigarh 4 0 0 0 0 0 0 0 5 Delhi 1 0 12 5 17 0 2 0 6 Goa 11 0 0 0 0 0 3 0 7 Haryana 59 40 104 67 37 27 0 0 8 Karnataka 152 15 226 10 181 6 75 6 9 Kerala 0 0 17 2 9 1 10 Maharashtra 119 16 475 115 22 0 66 30 11 Manipur 2 1 1 0 0 0 1 0 12 Punjab 10 2 0 0 0 0 0 0 13 Tamil Nadu 0 0 163 36 88 9 8 1 14 Uttar Pradesh 604 133 1124 237 1030 228 6096 1511 15 West Bengal 301 105 2 1 3 1 6 1 Grand Total 1765 466 2568 707 1714 367 6594 1665C = Cases D = Deaths 9
  10. 10. Prevention and controlPrevention and control of JE was not given priority in the National Health Policy (2002)and the then expectation was that it would be addressed by the concerned States.Subsequently, JE control was included in the expanded version of malaria control underthe integrated scheme for National Vector Borne Disease Control Programme(NVBDCP), as approved by the Cabinet Committee on Economic Affairs (CCEA) onOctober 15, 2003. Under this scheme: • States are responsible for implementing actions of the program. • Government of India support is need-based (mainly insecticides, diagnostic kits, technical support in outbreak investigation, and training for capacity building). • Ad hoc vaccination was done in Assam, Tamil Nadu, Goa, Uttar Pradesh, Bihar, and West Bengal, using the Kasauli-made inactivated vaccine made in infant mouse-brain. Sustained vaccination in specific localities has been undertaken in Tamil Nadu (since 1995) and AP (since 2000), with highly encouraging result • Vector control methods aimed at controlling JE have been planned as part of the integrated vector control strategy under the enhanced vector control strategy (EVBDCP) aimed at controlling malaria, filariasis, dengue, kala-azar and JEEpidemiology of JE in IndiaSettingJE is a disease predominantly of the rural population, on account of the vectorprevalence and densities. Culicines breed mainly in irrigated paddy fields and similarsurface bodies of water and they are more in rural than in urban locales. However caseshave been reported from urban areas like Lucknow and Bangalore in recent past.2 Inplanning control initiatives it should also be considered that in most of the endemicdistricts in states like Uttar Pradesh and Bihar the demarcation between urban and ruralpopulation is unclear particularly in the context of lack of quality data from surveillance.JE outbreaks have also been reported in peri-urban areas.Age groupClinical encephalitis occurs in one in 300-500 infected individuals. Silent infectionconfers life-long immunity. In southern India, JE almost exclusively affects childrenbelow 15 years, the vast majority below 10, while in north India (e.g., UP, West Bengal)all age groups are affected with the majority of cases below 15 years of age. 3 Thereason is epidemiologically explainable. In endemic areas adults are mostly immune onaccount of past infection, whereas in newly introduced areas both children and adultsare susceptible. Over time the new locations become endemic and cases occurexclusively under 15. Overall, children 1 to 15 years of age should be considered the “at-risk” group for JE vaccination in India. If individual states have good quality data on agedistribution, this information could be used for planning purposes in that state. of surveillance data for the last decade (1990-2000) had helped planningimmunization in the age group of 2-12 years in AP2 In another instance 58 hospitalized children (0-15 year) suffering from AES (Acute Encephalitis Syndrome) wereinvestigated between July 2001 and February 2002 in the known endemic district of Cuddalore in Tamil Nadu. Spatial 2clusters of cases were evident in three different municipalities’ viz. Chidambaram, Virudhachalam and Thittakudi.3 ICMR report on Japanese Encephalitis 10
  11. 11. SeasonalityTransmission of JE typically begins in Assam in March through April with peaks in latermonths. As one goes south, onset of the disease occurs in later months. The outbreak ofJE in Kerala in 1996 was also in the first quarter of the year. Mosquito breeding isimpeded by heavy rainfall although vector abundance, and hence high rates of virustransmission, is associated with rainfall. It is the rainfall pattern, rather than total rainfall,which is more important. Mosquitogenic conditions are created if water accumulates forlong periods. Flooding and receding water lines in the Brahmaputra river basin innortheast India create enormous pools and puddles leading to high mosquitogenicconditions that often do not correlate with rainfall. Canal fed ditches and paddy fields areanother breeding source of mosquitoes outside the monsoon season, and outbreaksoccur regularly in predominantly canal-irrigated regions like Mandya district ofKarnataka. In northern India, the shift from dry land wheat cultivation to wet paddycultivation using ground and canal water emerged as an important risk factor for highmosquitogenic conditions leading to outbreaks of JE.Month 1 2 3 4 5 6 7 8 9 10 11 12As √WB √UP √ √ √ √ √ √ √AP √ √ √ √ √Ka Mandya √ √ √ √ √TN √ √ √ √Goa √ √ √ √ √ √VectorsCulex tritaeniorhynchus and Cx. vishnui are the principal vectors of JE in India. The virushas been isolated from 15 species of mosquitoes in India belonging to genera Culex,Aedes, and Anopheles. In Kerala Mansoniodes has been suspected to be the vector.Animal hosts• Pigs: monitoring of antibodies in sentinel pigs in Kolar has demonstrated transmission of virus & presence of enzootic cycle in pigs almost throughout the year• Birds: based on laboratory evidence birds are considered to be important hosts in the enzootic cycle. Outbreaks associated with birds have been reported in India.4• Mammalians. Paddy cultivation encourages breeding of Culicines and clustering of water birds and together the stage will be set for amplification and spread of JE virus to mammalian hosts such as pigs, cattle and humans. Cattle and humans are blind ends for virus amplification in Nature.In summary, a typical case of Japanese Encephalitis in India would be an unvaccinatedmale child between the ages of 1 and 15 years living in a rural/peri-urban area withpaddy cultivation in the vicinity. Close proximity to pigs/pig sties would increase the risk.At risk population: For programmatic considerations, the epidemiological data from JE inIndia indicates that all children in the age group 1-15 years living in endemic districtsmust be considered to be at risk of JE4 Soman RS, Rodrigues FM, Guttikar SN, et al. Experimental viraemia and transmission of Japanese encephalitis virus bymosquitoes in ardeid birds. Indian Journal of Medical Research. 1977;66:709–718. 11
  12. 12. JE Control Strategy:The goal in JE control in India is to reduce incidence of JE by more than 50% by 2010.5The three “pillars” of JE control will be utilized. In addition, although measures of vectorcontrol have a limited role in controlling JE, integrated vector control (NVBDCP) for allvector-borne disease will need to continue.JE Control in India:• Case identification - Strengthening surveillance with special attention to program monitoring and case identification from silent areas.• Case management – Improved case management with training at specified treatment centers with early diagnosis and improved management of JE cases to reduce case fatality.• Immunization and plan for sustainable vaccine supply – Preventative campaigns in at-risk areas with vaccine integration into routine EPI. – Defined plan to create a sustainable supply of vaccine using India’s strong capacity in vaccine production.Vector control in India is a part of the integrated vector control strategy for the five vectorborne diseases viz. malaria, kala-Azar, filariasis, JE and dengue - Insecticide spraying is not considered a major tacticy in JE control.6 – NVBDCP-India provides guidelines for vector control methods as a part of the integrated vector control approach which is explained in their strategic plan. – During+ outbreaks some specific short-term methods for immediate intervention are adopted by NVBDCP.Surveillance StrategyIndia has a surveillance system based on public sector institutions. In order to supportimmunization, particularly to monitor the success of immunization, the system will needto be further strengthened. Effective surveillance with laboratory support when neededwill help to both monitor the impact of immunization as well as identify new areas oftransmission. Reporting should regularly include age of patient and district they are fromas the immunization strategy and risk-stratification relies on this data. Laboratoryconfirmation of cases based on collection and testing of cerebral spinal fluid (CSF) aswell as blood sera will become increasingly important in areas where vaccination isimplemented. If a case of encephalitis happens around the time of vaccination, testingCSF can determine if it was actually due to naturally acquired infection.In areas without vaccination, attention to new or emerging JE virus transmission withoutbreak response will be essential. Depending on the scenario adopted forimmunization, attention will need to be paid to areas where routine immunization isstarted without covering the total at-risk population. These sites will be likely areas foroutbreaks to occur and will require close monitoring. Unfortunately by the time anoutbreak is detected, viral amplification in Nature and transmission to humans would be5 Draft proposal for World Bank assisted ( 2005-06 to 2009-10 ) Enhanced vector Borne Disease Control Program(EVBDCP)6 SEA/RC55?7- Prevention and Control of Dengue , Japanese Encephalitis and Kala-Azar in SEA Region 12
  13. 13. well established in the community. At that time, immediate outbreak response may havelittle or no effect to to limit or stop transmission. JE has an incubation period of up to 2weeks and antibody levels take 7-10 days after onset of illness to be reliably detectedthrough the IgM ELISA. This results in about 3 weeks of gap from the time of exposureto detect an outbreak with lab confirmation. Outbreak response with immunization is nothelpful with inactivated vaccine as it takes 2 doses and one month (total of 5 weeks) tohave a protective immunity. The live vaccine has been used just prior (1 week) to anoutbreak in Nepal with good immunity (99% efficacy).Summary surveillance strategy• Patient reporting including age, district of residence, and immunization status• Samples for confirmation including CSF from any patients with history of vaccination• Sensitization and training in silent areas geographically related to known high-risk areas• Lab training and specimen transport establishedCase managementIn Andhra Pradesh the setting up Encephalitis Treatment Centers (ETCs) in endemicdistricts has helped to reduce the case fatality rate in the State over the past 5 years.ETCs have been set up by upgrading the Community Health Centres (CHCs) in the mostendemic districts of the state with ‘manpower-medicine–equipment’ to provide clinicalmanagement of acute encephalitis syndrome (AES). The centers are also equipped withadequate referral support to higher centers of treatment. Enhanced care and treatmentfacilities are supported by intensified surveillance7 and diagnostics or AES in thesedistricts. To improve patient outcome, similar training and site identification in endemicdistricts would be started. This model is worth replication in other JE endemic regions.JE vaccination:The consensus statements from global meetings of WHO on JE control in 1995, 1998and 2002 have emphasized that “human vaccination is the only effective long-termcontrol measure against JE. All at-risk residents should receive a safe and efficaciousvaccine as part of their national immunization program.”In the Weekly Epidemiological Record, No. 44, 1988 of WHO it had been stated that“Where affordable, JE vaccination should be extended to all endemic areas where JE isconsidered a public health problem”Only two vaccines are currently available globally for JE control. They are: (i) The mouse brain derived inactivated vaccine (ii) The live attenuated SA-14-14-2 vaccineThe next chapter will review vaccines against JE.7 In addition to intensified surveillance in the endemic districts in AP following NVBDCP guidelines through line listing &mapping of cases, training and intensified IEC, the State Government in collaboration with JE Project, PATH and technicalsupport from VOXIVA established a real time web& telephone based reporting of AES cases from identified Public andPrivate facilities (5+5) in Kurnool in 2005. The system is currently under evaluation. 13
  14. 14. Chapter III Japanese Encephalitis Vaccines We quote below the most recent World health Organization (WHO) PositionPaper on JE vaccines.WHO Position Paper. 25 AUGUST 2006, No. 34/35, 2006, 81, 325–340,, World Health Organization, GenevaIn accordance with its mandate to provide guidance to Member States on health policymatters, WHO is issuing a series of regularly updated position papers on vaccines andvaccine combinations against diseases that have an international public health impact.These papers, which are concerned primarily with the use of vaccines in large-scaleimmunization programmes, summarize essential background information on therespective diseases and vaccines, and conclude with the current WHO positionconcerning their use in the global context. The papers have been reviewed by a numberof experts within and outside WHO and since April 2006 they are reviewed andendorsed by WHO’s Strategic Advisory Group of Experts on vaccines and immunization.The position papers are designed for use mainly by national public health officials andimmunization programme managers. However, they may also be of interest tointernational funding agencies, the vaccine manufacturing industry, the medicalcommunity and the scientific media.Summary and conclusionsJapanese encephalitis (JE) is the most important form of viral encephalitis in Asia. It isestimated that the JE virus causes at least 50 000 cases of clinical disease each year,mostly among children aged <10 years, resulting in about10 000 deaths and 15 000cases of long-term, neuro-psychiatric sequelae. In recent decades, outbreaks of JE haveoccurred in several previously non-endemic areas. Infections are transmitted throughmosquitoes that acquire the virus from viraemic animals, usually domestic pigs or waterbirds. Only about 1 in 250–500 infected individual smanifest clinical disease. There is nospecific antiviral treatment for JE. Although the use of pesticides and improvements inagricultural practices may have contributed to the reduction of disease incidence insome countries, vaccination is the single most important control measure. Currently, thethree types of JE vaccines in large-scale use are (i) the mouse brain-derived, purifiedand inactivated vaccine, which is based on either the Nakayama or Beijing strains of theJE virus and produced in several Asian countries; (ii) the cell culture-derived, inactivatedJE vaccine based on the Beijing P-3 strain, and (iii) the cell culture-derived, liveattenuated vaccine based on the SA 14-14-2 strain of the JE virus. Drawbacks of themouse-brain vaccine are the limited duration of the induced protection, the need formultiple doses, and, in most countries, the relatively high price per dose. The cellculture-derived vaccines are manufactured and widely used in China, where theinactivated vaccine is gradually being replaced by the live attenuated vaccine. Severalother promising JE vaccine candidates are in advanced stages of development.The need for increased regional and national awareness of JE and for internationalsupport to control the disease is urgent. JE vaccination should be extended to all areaswhere JE is a demonstrated public health problem. The most effective immunizationstrategy in JE endemic setting is a one time campaign in the primary target population,as defined by local epidemiological data, followed by incorporation of the JE vaccine into 14
  15. 15. the routine immunization programme. This approach has a greater public health impactthan either strategy separately.Both the mouse-brain derived and the cell culture-based vaccines are consideredefficacious and to have an acceptable safety profile for use in children. However, withthe mouse-brain derived vaccine, rare cases of potentially fatal acute disseminatedencephalomyelitis and hypersensitivity reactions have been reported among vaccinatedchildren in endemic regions and in travelers from non endemic locations. Because of therarity of these adverse events, and the high benefit-to-risk ratio of routine vaccination,the introduction of immunization against JE in public health programmes should not bedeferred.The mouse-brain derived, inactivated vaccine has been used successfully to reduce theincidence of JE in a number of countries and is likely to be used nationally andinternationally for some more years. The cell culture-based, live attenuated vaccineappears to require fewer doses for long term protection, is in most cases less expensive,and seems to represent an attractive alternative to the mouse brain derived vaccine.However, more needs to be known on its safety and efficacy when used in immunodeficient people, as well as on the impact of co-administrating this vaccine with othervaccines.The immunization schedules of the 3 licensed JE vaccines that are currently in large-scale use vary with the profile of the respective vaccines and depend on localepidemiological circumstances and recommended schedules of other childhoodvaccines. When immunizing children 1–3 years of age, the mouse brain-derived vaccineprovides adequate protection throughout childhood following 2 primary doses 4 weeksapart and boosters after 1 year and subsequently at 3-yearly intervals until the age of10–15 years. Equally good childhood protection is obtained by a single dose of the cell-culture based, live attenuated vaccine followed by a single booster given at an interval ofabout 1 year. The importance of achieving long-term protection is underlined by theobservation that in some areas an increasing proportion of the JE cases occur inindividuals older than 10 years of age.There is a need for safe and effective JE vaccines of assured supply. All manufacturersof JE vaccines should comply with the international standards for Good ManufacturingPractices and meet the WHO requirements for production and quality control. Whetherlocally produced or purchased from outside the country, the safety and immunogenicityof the vaccine must be assessed by independent national control authorities before itmay be approved for use.Improved methods of JE surveillance including standardized, JE virus-specific laboratorytests are critical for characterizing the epidemiology, measuring the burden of disease,identifying high-risk populations and documenting the impact of control measures. Therecommended standards for JE surveillance are discussed in a separate WHOdocument.2BackgroundJapanese encephalitis (JE) is a vector-borne, viral zoonosis that may also affecthumans. JE occurs in practically all Asian countries, whether temperate, subtropical, ortropical, and has episodically intruded upon areas without enzootic transmission such asthe Torres Strait Islands off the Australian Mainland.Nearly 3 billion people live in JE-endemic regions, where more than 70 million childrenare born each year. However, the annual incidence of clinical disease differs 15
  16. 16. considerably from one country to the other as well as within affected countries, rangingfrom <10 to >100 per 100 000 population. The disease periodically becomes hyperendemic in areas such as northern India, parts of central and southern India, southernNepal, northern Viet Nam as well as in areas of South-East Asia where vaccinationprogrammes have not yet been instituted, e.g. in Cambodia.Anthropophilic culicine mosquitoes transfer the virus to humans from animal amplifyinghosts, principally domestic pigs and wading birds. Culex tritaeniorhyncus, the mostimportant vector species, breeds in water pools and flooded rice fields. Although themajority of the human cases occur in rural areas, transmission can also occur in peri-urban and urban centres.In temperate locations, the period of transmission typically starts in April or May, andlasts until September or October. In tropical and subtropical areas, transmission exhibitsless seasonal variation, or intensifies with the rainy season. Where irrigation permitsmosquito breeding throughout the year, transmission may occur even in the dry season.In many Asian countries, major outbreaks of JE occur at intervals of 2–15 years. So far,no evidence that JE epidemics follow major floods, including tsunamis, has been found.Several aspects of the JE epidemiology require further studies.Whereas all age groups have been affected in regions where the virus has beenintroduced recently, serological surveys show that most people living in JE-endemicareas are infected before the age of 15 years. Only 1 in 250–500 JE viral infections aresymptomatic. In hyper-endemic areas, half the number of JE cases occurs before theage of 4 years, and almost all before 10 years of age. Some endemic regions wherechildhood JE vaccination has been widely implemented have experienced a shift in theage distribution of cases towards an increasing proportion of cases occurring in olderchildren and adults.In countries such as Japan and Korea, and in some regions of China, the incidence ofJE has decreased during severaldecades, primarily as a result of extensive use of JEvaccines. Improved socioeconomic conditions, changed life styles and control measuressuch as centralized pig production and the use of insecticides may also have contributedto this development. Permethrin-impregnated mosquito nets have been shown toprovide some protection against JE in one study. However, mosquito nets and otheradjunctive interventions should not divert efforts from childhood JE vaccination. WhereasJE is believed to be grossly underreported among residents of endemic regions, thedisease is very uncommon among short-term visitors and tourists to such areas.Clinical JE follows an incubation period of 4–14 days and is mostly characterized bysudden onset of fever, chills, myalgias,mental confusion and sometimes nuchal rigidity.In children, gastrointestinal pain and vomiting may be the dominant initial symptoms andconvulsions are very common. JE may present as a mild disease, leading to anuneventful recovery, or may rapidly progress to severe encephalitis with mentaldisturbances, general or focal neurological abnormalities and coma. Out of theapproximately 50 000 cases of JE that are estimated to occur each year, about 10 000end fatally, and about 15 000 of the survivors are left with neurological and/or psychiatricsequelae, requiring rehabilitation and continued care.Reports of JE disease in pregnant women are limited, as most infections occur inchildhood, but studies from Uttar Pradesh (India), indicate a high risk of JE- associatedabortion during the first two trimesters. The potential impact of concurrent infections, inparticular HIV, on the outcome of JE virus infection is not yet established. 16
  17. 17. The pathogenJapanese encephalitis virus belongs to the mostly vectorborne Flaviviridae, which aresingle-stranded RNA viruses. JE virus is antigenically related to several otherflaviviruses that are prevalent in Asia, including dengue virus and West Nile virus. Theenvelope glycoprotein of the JE virus contains specific as well as cross-reactive,neutralizing epitopes. The major genotypes of this virus have different geographicaldistribution, but all belong to the same serotype and are similar in terms of virulence andhost preference.Following an infectious mosquito bite, the initial viral replication occursin local and regional lymph nodes. Viral invasion of the central nervous system occursprobably via the blood.Confirmation of a suspected case of JE requires laboratory diagnosis. The etiologicaldiagnosis of JE is mainly based on serology using IgM-capture ELISA which detectsspecific IgM in the cerebrospinal fluid or in the blood of almost all patients within 7 daysof onset of disease. Other methods include conventional antibody assays on paired serafor the demonstration of a significant rise in total JE-specific antibody, as well as a dot-blot IgM assay, suitable for use in the field. The virus is rarely recovered in tissue culturefrom blood or CSF, but may be found in encephalitic brains at autopsy. JE-viral RNA israrely demonstrated in the CSF.Protective immune response:Protection against JE is associated with the development of neutralizing antibodies.Based on animal models as well as on clinical vaccine trials, a threshold of neutralizingantibodies $ 1:10 has been accepted as evidence of protection. A role for cell-mediatedimmune mechanisms in protection against JE virus has been demonstrated inexperimental studies on mice.Vaccines against Japanese encephalitisCurrently, the most important types of JE vaccines in large scale use are: • the mouse brain-derived, purified and inactivated vaccine, which is based on either the Nakayama or Beijing strains of the JE virus and is produced in several Asian countries; the cell culture-derived, inactivated JE vaccine based on the viral Beijing P-3 strain, and • the cell culture-derived, live attenuated vaccine based on the SA 14-14-2 strain of the JE virus.Mouse brain-derived inactivated vaccineHistorically, the mouse-brain derived, inactivated JE vaccine has been the most widelyavailable JE vaccine on the international market. In the Republic of Korea, Thailand, andin areas of Malaysia, Sri Lanka, and Viet Nam, mouse brain-derived JE vaccine hasbeen incorporated into the routine immunization programme. Liquid and lyophilizedvaccines are both available for use. Current formulations of this vaccine arestandardized in terms of immunogenicity and following extensive purification, its contentof myelin basic protein has been reduced to minute amounts (<2 ng per ml). WHOtechnical specifications have been established for vaccine production3 Lyophilizedmouse brain-derived vaccine is stable at 4 °C for at least 1 year.Although the Nakayama strain protects against JE virus strains from different Asianregions, other JE virus strains, such as the Beijing-1 strain, have induced stronger andbroader neutralizing antibody responses in experimental, preclinical studies. For thisreason, and because of the higher antigen yield in the mouse brain following inoculationof the Beijing strain, the Nakayama strain has been replaced in several mouse brain- 17
  18. 18. derived JE vaccines. No evidence has been found of significant differences betweenthese vaccine strains in protective efficacy in humans.The mouse brain-derived JE vaccine is given subcutaneously in doses of 0.5 or 1 ml(with some vaccines: 0.25 ml or 0.50 ml) the lower dose being for children aged <3years. In several Asian trials, primary immunization based on 2 doses given at aninterval of 1–2 weeks has induced protective concentrations of neutralizing antibodies in94–100% of children aged >1 year. Although experience from Thailand shows that JEvaccination of children aged 6–12 months may be highly efficacious as well, in mostepidemiological settings primary immunization should be given at the age of 1–3 years.Given the mostly infrequent occurrence of JE in infancy and the likely interference withpassively acquired maternal antibodies during the first months of life, vaccination is notrecommended for children before the age of 6 months. In immunogenicity studies in theUSA, seroconversion occurred only in approximately 80% of adult vaccines following anequivalent 2-dose schedule. In contrast, in US soldiers, a schedule based on vaccinationon days 0, 7 and 30 resulted in 100% seroconversion. Following a booster injectionapproximately 1 year after the primary 2 doses, protective antibody levels have beenachieved in practically all children and adults, regardless of geographical region. Inpeople whose immunity is unlikely to be boosted by natural infection, repeated boostersare required for sustained immunity.Since the optimal number and timing of booster doses depend on the frequency ofnatural boosting with JE virus and possibly with related flaviviruses, the schedule forroutine JE immunization has been difficult to standardize. Many Asian countries haveadopted a schedule of 2 primary doses preferably 4 weeks apart, followed by a boosterafter 1 year. In some countries, subsequent boosters are recommended, usually atabout 3-year intervals up to the age of 10–15 years.Australian studies following the outbreak of JE in the Torres Strait demonstrated that inthe majority of children the level of neutralizing antibody declines to non-protectiveconcentrations within 6–12 months following primary immunization. About 3 years afterthe primary series of 3 doses, or the last booster, only 37% of adults and 24% of childrenhad protective antibody levels.For travelers aged >1 year visiting rural areas of endemic countries for at least 2 weeks,the established current practice is to administer 3 primary doses at days 0, 7 and 28;alternatively 2 primary doses preferably 4 weeks apart. When continued protection isrequired, boosters should be given after 1 year and then every 3 years.Current experience, primarily from Taiwan (China) and Thailand, does not suggestreduced seroconversion rates or an increase in adverse events when mouse brain-derived JE vaccine is given simultaneously with vaccines against measles, diphtheria–tetanus–Pertussis (DPT) and polio as part of the Expanded Programme Immunization(EPI) programme. However, the possible impact of co-administration of the mouse brain-derived vaccine with other vaccines of the childhood immunization programme has notbeen systematically studied.In general, the mouse brain-derived JE vaccine has been considered safe, althoughlocal reactions such as tenderness, redness and swelling occur in about 20% ofvaccinated subjects. A similar percentage of vaccines may experience mild systemicsymptoms, including headache, myalgia, gastrointestinal symptoms and fever. Acutedisseminated encephalomyelitis (ADEM) temporally coinciding with JE immunizationusing the mouse brain-derived vaccine has been reported at frequencies corresponding 18
  19. 19. to 1 case per 50 000–1 000 000 doses administered, but no definitive studies areavailable. Based on observations of a case of ADEM temporarily associated with JEVaccination, the recommendation for routine childhood JE vaccination has beenwithdrawn in Japan. However, the Global Advisory Committee on Vaccine Safety4concluded recently that there was no definite evidence of an increased risk of ADEMtemporally associated with JE vaccination and that there was no good reason to changecurrent recommendations for immunization with JE vaccines.Occasionally, hypersensitivity reactions, in some cases serious generalized urticaria,facial angio-oedema or respiratory distress, have been reported, principally in vaccinerecipients from non-endemic areas. The reported rates of such reactions in prospectiveand retrospective studies are usually in the range of 18–64 per 10 000 vaccinatedsubjects. A complicating factor is that such reactions may occur as late as 12–72 hoursfollowing immunization. Sensitization to gelatine, a vaccine stabilizer, has beensuspected in some cases in Japan, but the underlying cause remains uncertain.The only contraindication to the use of this vaccine is a history of hypersensitivityreactions to a previous dose. However, pregnant women should be vaccinated onlywhen at high risk of exposure to the infection. Mouse brain-derived vaccine has beengiven safely in various states of immunodeficiency, including HIV infection.Cell culture-derived, inactivated vaccineManufactured and available only in China, this vaccine is based upon the Beijing P-3strain of JE virus, which provides broad immunity against heterologous JE viruses, andhigh viral yields when propagated in primary hamster kidney cells. A more recent versionof the vaccine produced on Vero cells is licensed in China. Primary immunization ofinfants with this formalin-inactivated vaccine results in about 85% protection, butimmunity wanes relatively rapidly. The vaccine has been used mainly in annual Chineseimmunization campaigns before onset of the transmission season. Transient localreactions are reported in 4%, mild systemic reactions in <1%, and hypersensitivity in1:15 000 of the vaccinated subjects. No case of acute vaccine-associated encephalitishas been reported. The vaccine is inexpensive, and previously, 75 million doses weredistributed each year for internal Chinese use. This cell culturederived, inactivatedvaccine is gradually being replaced by the cell culture-derived, live attenuated vaccine.Cell culture-derived, live attenuated vaccineThis vaccine is based on the genetically stable, neuroattenuated SA 14-14-2 strain of theJE virus, which elicits broad immunity against heterologous JE viruses. Reversion toneurovirulence is considered highly unlikely. WHO technical specifications have beenestablished for the vaccine production.5 As the vaccine is produced on primary cells, themanufacturing process includes detailed screening for endogenous and adventitiousviruses. The live attenuated vaccine was licensed in China in 1989. Since then, morethan 300 million doses have been produced and more than 200 million children havebeen vaccinated. Currently, more than 50 million doses of this vaccine are producedannually. Extensive use of this and other vaccines has significantly contributed toreducing the burden of JE in China from 2.5/100 000 in 1990 to <0.5/100 000 in 2004.The cell culture derived live, attenuated vaccine has also been licensed for use in India,Nepal, Republic of Korea and Sri Lanka.Case control studies and numerous large-scale field trials in China have consistentlyshown an efficacy of at least 95% following 2 doses administered at an interval of 1 year.Observational studies on children in China, Nepal and Thailand have suggested thateven 1 dose of this vaccine can induce significant long-term protection (11 years in 19
  20. 20. China). Carefully planned studies are required to establish firm recommendations on theoptimal immunization schedule.In a prospective, randomized study involving more than 13 000 children activelymonitored for 30 days, no cases of encephalitis or meningitis were observed, and nodifference in hospitalization or prolonged fever was found between those who hadreceived the SA 14-14-2 vaccine and the controls. In a study in the Republic of Korea,fever exceeding 38 °C and cough were observed in approximately 10%, whereasredness and swelling at the site of injection occurred in <1%. Neither hypersensitivityreactions nor acute encephalitis have been associated with this vaccine. However, forimmunization of pregnant women or immunodeficient individuals, the live attenuatedvaccine should be replaced by one of the inactivated JE vaccines until further evidencehas been generated.JE vaccines in advanced stages of developmentA promising genetic approach is the construction of a chimeric live attenuated vaccinecomprising neutralizing antigen-coding sequences of the SA 14-14-2 strain of the JEvirus inserted into the genome of the 17 D yellow fever vaccine strain. The resultingrecombinant virus is cultivated on Vero cells. So far, the prototype of this vaccine hasdemonstrated an acceptable safety profile and a seroconversion rate of more than 97%following administration of a single dose. Vero cells are also used in Japan to develop aninactivated JE vaccine based on the Beijing P-1 strain. Furthermore, the SA 14-14-2 viralstrain has been adapted to Vero cells and the resulting experimental inactivated vaccinecandidate has shown promising results in clinical trials.General WHO position on vaccinesVaccines for large-scale public health interventions should meet the current WHO qualityrequirements;6 be safe and have a significant impact against the actual disease in alltarget populations; if intended for infants or young children, be easily adapted to theschedules and timing of national childhood immunization programmes; not interferesignificantly with the immune response to other vaccines given simultaneously; beformulated to meet common technical limitations, e.g. in terms of refrigeration andstorage capacity; and be appropriately priced for different markets.WHO position on JE vaccinesThe need for increased regional and national awareness of JE and for internationalsupport to control this disease is urgent. With increasing availability of efficacious, safeand affordable vaccines, JE immunization should be integrated into the EPI programmesin all areas where JE constitutes a public health problem. The most effectiveimmunization strategy in JE-endemic settings is one time catch-up campaigns includingchild health weeks or multi-antigen campaigns in the locally-defined primary targetpopulation, followed by incorporation of the JE vaccine into the routine immunizationprogramme. This approach has a greater public health impact than either strategyseparately.The three types of JE vaccines that are currently in large scale use are consideredefficacious and acceptably safe for use in children. However, following immunization withthe mouse brain-derived vaccine, rare cases of potentially fatal ADEM andhypersensitivity reactions have been reported among children in endemic regions and intravelers from non-endemic locations. An increased awareness of these specific adverseevents is recommended, for example when assessing the actual risk of JE for theindividual traveler. However, because of the rarity of these adverse events, and thegreater benefit to risk ratio of routine vaccination, the introduction of immunizationagainst JE in public health programmes should not be deferred. 20
  21. 21. The now widely available cell culture-derived, live attenuated vaccine based on the SA14-14-2 strain of JE virus and possibly the novel cell culture-derived, inactivatedvaccines may offer suitable replacements for the mouse brain derived vaccine. The liveattenuated vaccine induces protection for several years after 1 or 2 doses, whereasdurable protection by the mouse brain-derived vaccine may require 2–3 initial dosesfollowed by boosters at intervals of approximately 3 years. As the price per dose of themouse brain-derived vaccine in most countries is higher than that of the live attenuatedvaccine, the need for repeated doses renders the former vaccine unaffordable in manyJE-endemic countries.Optimal national vaccination strategies depend on reliable information concerning theduration of protection and, additionally, whether repeated exposure to natural infection isrequired for long-term protection. Similarly, further information is needed on possibleimpact of cross-reacting flavivirus antibodies (e.g. dengue virus antibodies) on theoutcome of primary JE immunization. All the currently used vaccines appear to protectequally well against infection by JE virus of different genotypes.For epidemiological, programmatic and economic reasons, JE immunization schedulesdiffer widely from one country to the other. In general, using the mouse brain derivedvaccine, adequate childhood protection is achieved following immunization of children asof 1 year of age with 2 primary doses 4 weeks apart followed by boosters after 1 yearand subsequently at 3-yearly intervals up to the age of 10–15 years. Using the cellculture-based, live attenuated vaccine, equally good childhood protection is provided bya single dose of vaccine followed by a booster given at an interval of about 1 year. Moreinformation is expected to become available on possible interference between JEvaccines and simultaneously administered vaccines, as well as on the duration ofprotection.The principal Japanese manufacturer of mouse brain-derived JE vaccine has recentlydiscontinued its production, and the quantity of this vaccine produced by othermanufacturers is limited. Although ideally, the mouse brain-derived vaccine should begradually replaced by new generation JE vaccines, short supply of JE vaccines ingeneral will probably require continued production also of the mouse brain-derivedvaccine for several more years. The rare, but potentially dangerous, adverse eventsassociated with this vaccine make strict attention to current international qualityrequirements crucial for its continued production. Whether locally produced or purchasedfrom outside the country, the safety and immunogenicity of the vaccine must beassessed by independent national control authorities before it may be approved for use.One of the manufacturers of the live attenuated vaccine is currently expanding itsproduction capacity. In addition, new vaccines based on cell culture methods or modernrecombinant technologies are now being introduced into immunization programmes orare in advanced stages of development.JE surveillance is critical for characterizing the epidemiology, measuring the burden ofdisease, identifying high-risk areas and areas of new disease activity, as well as fordocumenting the impact of control measures. Realizing the need to harmonizesurveillance efforts in different countries, WHO has developed surveillance standardsthat also include specific recommendations on JE surveillance. 21
  22. 22. Chapter IV The live attenuated JE virus SA-14-14-2This chapter examines available information on the attenuated live virus vaccine againstJE. The first paragraph is sourced from the Drugs Controller General of India.“The most widely used JE vaccine in China, the live attenuated JE virus strain SA 14-14-2 was obtained after 11 passages in weanling mice followed by 100 passages in primaryhamster kidney cells at National Institute for Control of Pharmaceutical and BiologicalProducts (NICPPP) I Beijing in early 1970’s. This strain was shown to be safe andimmunogenic in mice, pigs, horses and humans. Expanded field trials in Southern Chinainvolving more than 200,000 children confirmed the strain safety and yielded efficaciousof 88-96% over 5 years. The SA 14-14-2 stain also elicits seroconversion rates of 99-100% in non-immuno subjects. This is live attenuated , lyophilized SA 14-14-2 vaccineproduced on primary hamster kidney cells and is being marketed in China since 1990’salso approved in Korea, Srilanka & Nepal etc. The said vaccine is allowed to import inthe country after ensuring its safety and efficacy and other technical details as per normsand examined by panel of experts under DG ICMR, New Delhi. The vaccine is NOTrecombinant derived vaccine, therefore GEAC was not consulted and moreover JE SA114-2 strain is attenuated, which is not hazardous.”The following section is adapted from the brochure on the vaccine, obtained from themanufacturer, namely, the Chengdu Institute in China.[Constituents and characters]Japanese Encephalitis live vaccine is a preparation of live attenuated JE virus (strain SA14-14-2) grown on the monolayer of hamster kidney cell cultures. After cultivation andharvest an appropriate stabilizer is added in the virus suspension, which is thenlyophilized. The product looks like a light yellow crisp cake. After reconstitution, it shallturn into a clear, orange-red liquid.[Eligible’s]Healthy children above 8 months of age and those including children and adults whointend to enter the endemic area from non endemic area.[Function and uses]The product can induce immunity against JE virus in recipients following immunization. Itis used to prevent Japanese encephalitis.[Specifications]2.5ml of reconstituted vaccine per container 0.5ml per single human dose containing notless than 5.4lg PFU of live JE virus.[Administration and dosage](1) Reconstitute the freeze-dried vaccine with the accompanying vaccine diluent as stated on the label, and do not use the vaccine until it is reconstituted completely,(2) Injection s.c. 0.5mlof he vaccine at deltoid insertion area of the lateral upper arm.(3) A portion of 0.5ml of the vaccine shall be given for a child at the age of8 months, 2 years and 7 years respectively. No more inoculations a needed henceforth. 22
  23. 23. [Adverse reaction]Transient fever any occur I few recipients, which normally does not last longer than 2days and could be relieved spontaneously. Occasionally, sporadic skin rashes mayappear and commonly no particular treatment is needed. In case of necessity,symptomic treatment might be helpful.[Contraindications](1) Subjects with fever, acute infectious disease, otitis media, active tuberculosis, cardiac, renal or hepatic disease.(2) Constitutional weakness, subjects with an allergic or epilepsy history.(3) Subjects with congenital immunodeficiency and those who are receiving or received immunodepressant therapy recently.[Precautions](1) Care should be taken to avoid contacting the vaccine by disinfecting during opening the container and in the course of injection.(2) Do not use the vaccine if any leakage of container or clumps not dispersed on shaking are found, or the color of the vaccine turned into red before reconstitution.(3) The vaccine shall be used up within one hour after reconstitution at the ambient temperatures of 2-8 o C; discard the remaining vaccine afterwards, if any.(4) Do not use the vaccine on e month or after administrating another live vaccine.[Storage]Store and ship at or below 8oC, protected from sunlight[Packaging]Vial, 5dose/vial[Expiry date]The vaccine shall be used before the expiry date stated on the label.[Standard for implementation]Pharmacopoeia of the Peoples’s Republic of China (Edition 2005), Volume III[Product license number]S10900004[Import license number]SV-52-7313[Manufacturer]Manufacturer:Chengdu Institute of Biological Products, Chengdu, CHINAAddress: Baojiang Bridge, Chengdu, Sichuan, ChinaZip code:610023Telephone:86-28-84418968Fax:86-28-84419941Homepage:http// 23
  24. 24. Chapter V The licensing and procurement of the vaccineThe live attenuated JE vaccine is a biological agent/product, not previously used in India.Therefore the GoI took initiatives to explore the feasibility of its licensing andprocurement through the established channels of the National Regulatory Agency(NRA). The matter was presented to the Directorate General of Health Services, and inparticular the Drugs Controller General of India (DCGI). A request was made to theNRA for registering the product in India. The question was referred to the Indian Councilof Medical Research for technical advice.ICMR recommended the licensing of SA-14-14-2 live JE vaccine. (Letter dated 08/01/06 No. 30/3/2004-ECD-I) Anx -3 The Director General of Health Services called a meeting of independent experts andrepresentatives of ICMR and the expert group endorsed the plan of action to license,procure and use the vaccine as planned for the next pre-outbreak period. • DCGI had processed the registration of the new drug and issue of license for importing the SA-14-14-2 after the test batches of the samples of SA-14-14-2 have been declared of Standard quality by CDL Kasauli. • Hindustan Latex Limited, Thiruvananthapuram, held negotiations for agreement to act as agents of Chengdu Institute of Biologicals and procure the vaccine. • For implementation of the JE vaccination campaign prior to the next outbreak season, namely vaccination from 15th May 06, the procurement of vaccine and logistical support had to be arranged. The Ministry placed a firm order with the vaccine manufacturer / supplier and finally the vaccine was imported in time under the following protocol. Storage / Shipment / Supply of the live vaccine (SA-14-14-2) • The selection and proposal for JE vaccination campaign in 11 high risk districts was approved by Standing Finance Committee chaired by Secretary (Health & FW) on 18th January, 2006. • Criteria for prioritization / selection of districts for JE vaccination o Total number of JE cases reported (NVBCP) o Incidence of JE in the district o Recent JE outbreak o Serological evidence of the disease ( ICMR) o Epidemiological evidence • After reviewing the available data on the epidemiology, incidence of the disease availability of vaccine the following districts are being proposed for implementation of JE vaccination during 2006 using SA-14-14-2 live attenuated vaccine. • The Chief Secretaries of 5 States were apprised of GoI’s intention to introduce Japanese Encephalitis vaccine in 11 endemic districts of 5 States during 2006. 24
  25. 25. • An operational guide and training module was developed. • A Sensitization & Planning workshop with representatives from five States (UP, Assam, West Bengal and Karnataka and CMOs and DIOs of 11 districts was held on 30-31st January, 06 under the Chairpersonship of AS (J). • A time line for implementation of vaccination campaign was worked out and the vaccination campaign started from 15th May, 2006. • District level task force meeting, chaired by the District Collectors of all 11 districts was held. • Micro-plan for JE vaccination campaign at the district level was prepared.State / Dates for Campaign District Kushinagar Gorakhpur MaharajganjUttar Pradesh Deoria(15th May 06) Kheri Sidhartnagar Saint KabirnagarWest Bengal (18th June 06) Bardhaman DibrugarhAssam (2nd July 06) SibsagarKarnataka (2nd July 06) BellaryVaccine Supply Protocol: NDL/CDL for QC National Vaccine (Parallel) testing of dose in samples) Million 12- Apr 12-May 5.2 19- Apr 19-May 2.5 09-May 09-June 4 30-May 30-June 1.8Shipment Schedule: No. Quantity (×1,0000doses) Shipment before 1 520 May 12, 2006 2 250 May 19,2006 3 400 June 09,2006 4 180 June 30,2006 Total 1350Vaccine requirement:State Vaccine Requirement Vaccine Requirement (Doses) (Doses) in MillionUttar Pradesh 6140616 + 2225916 6.14 + 2.3West Bengal 2957133 2.95Assam 955663 0.95Karnataka 865488 0.86 25
  26. 26. Chapter VI The vaccine use in the fieldIn this chapter a brief account of the implementation of the programme is given. Thismassive programme was implemented after much ground preparations, and a coalitionof partnership consisting of the Government of India (Immunization Division), StateGovernments, UNICEF, WHO and Program for Appropriate Technology in Health(PATH). PATH had been assisting Andhra Pradesh for JE control activities over severalyears and was helpful in conceptualizing the present programme of JE vaccination in the4 States. The monitoring of adverse events following immunization was a built-incomponent of implementation. At the end of the chapter the numbers of childrenvaccinated by geographic area and the numbers of reported AEFI are given in summarytables.Strategy in Brief • Target population : 1-15 year age group • Vaccine : Live attenuated SA-14-14-2 vaccine from CDIBP, China • Dose : Single dose • Campaign: Village to villageKey components • Center site selection • Estimation of beneficiaries • Manpower • Training • Vaccine, logistics and cold chain • Route chart for distribution of vaccine and logistics • Supervision • Recording and reporting • IEC • Referral in case of AEFIUnits • Planning : PHC • Implementation : Sub center • Vaccination site : VillageGeneral guidelines • Each village including its hamlets in the sub center area will have a immunization center assigned specifically for the village and located within the village. • Two or more villages should not be clubbed together for one immunization center • The activity should always be carried out from Booth designated as the “vaccination center” • Timing of activity – 9 AM to 5 PM • Selection - Rural o The village primary school will be the preferred site of vaccination activity o In the absence of a school , the ICDS center or a fixed site which is easily identifiable, approachable and acceptable to the community may be selected • Selection-Urban o School will be the preferred vaccination site o School site should be selected strategically to cover all children 26
  27. 27. • Coordination o Specific instructions and date of activity in the village/ ward should be communicated to school authorities at least 14 days prior to the activity by the District Education Department o Instruction must include specific job responsibilities of school teachers & students in the activity o Respective departments should intimate their functionaries at the village level of the date of the campaign for that village and assign specific responsibilities two weeks prior to the program o DTF will ensure that instructions and guidelines have been sent out from the District level o BTF will ensure that the instructions have reached the target functionaries.Estimation of Beneficiaries o All children between the age group above 12 months and below 15 years should be estimated for vaccination with JE vaccine o It is estimated that the above age group will constitute about 33 % of the populationVaccinating Team Composition o Each team will have at least 4-5 members o One team shall be assigned only one village at a time o MO, PHC shall be overall responsible for team selection o Team supervisor will assist the MO, PHC in identifying team members where possible o The team will be supported by local volunteers ( students/ club members/ community persons/ school personnel)Micro Planning: Role of vaccinator / Supervisor (planning stage) o Develop micro plan for activity in her sub center area ( local sub center ANM ) o Ensure completeness of micro plan o Vaccination site selection in the village o Identify the third and fourth member of the team o Orientation of the third and fourth member o Assist in vaccine and logistic transportation planning for her sub center areaRole of Vaccinators o Vaccinate children o Give specific instructions to parents on AEFI o Take appropriate measures in case of any AEFI o Ensure completeness and reporting of day’s activity in the designated format o Overall responsible and accountable for planning , training and conducting the activity in the centerRole of other Team Members o Mobilize children from the village to the vaccination center o Assist in identification of absentee children• It is estimated that each vaccinator will vaccinate 125-150 children per day• One team ( 2 vaccinators ) will vaccinate 250-300 children per day• No. of days of activity in a village = (Expected number of beneficiaries in he village)/ (250-300)• Both vaccinators and person involved for recording in the team must receive training on o National Guidelines on JE vaccination 27
  28. 28. o JE Vaccine o Reporting coverage o AEFI – actions to be taken, referral & reporting o Waste disposal following vaccination o JE Vaccine - Freeze dried, Needs to be reconstituted with the diluents provided with the vaccine (Phosphate Buffer Solution) - Heat sensitive. - Storage and transport at 2-8°C - To be used within 2 hours of reconstitution - Single dose – 0.5 ml ( irrespective of age group) - Subcutaneous injectionCold Chain o Vaccine should be stored and transported at 2-8°C in a vaccine carrier with 4 frozen ice packs o Vaccine and diluents should be stored and transported at the same temperature o Once reconstituted the vaccine needs to be utilized within 2 hour time o Planning for replenishment of icepacks/ice is an essential component of micro plan o One vaccine carrier with 4 frozen ice packsTeam to carry o Adequate number of JE Vaccine vials o Adequate number of AD syringes o Adequate number of syringes for reconstitution o Adequate cotton swab o Adequate number of vaccination record cards o Tally sheets - multiple o Banner to mark location site o Emergency medicinesTransportation of vaccines and logistics o Ensure quick replenishment of vaccines and icepack / ice o Identify from existing vehicles o Separate route chart plan for each vaccination siteSupervision o Supervisors will be selected from existing health supervisors, block level ICDS functionaries and other key block level government officials. o One supervisor will supervise 3-5 teams o All supervisors must be - trained before the activity - familiar with his/her area and team - able to travel independently to the field o Good supervision is key to good quality program o Supervisor will advise the PHC MO in ensuring quality of the program o Before the activity the Supervisor will assist in team formation, site selection, preparation and completeness of micro plan o Will develop a plan of supervision during the activity and share he same with MO, PHC o Will provide on job training/orientation o Will report daily on quality and completeness of program in his/her area o Responsible for compilation and reporting from designated area daily 28
  29. 29. Recording and reporting o All formats to be used as mentioned in operational guideline.Coverage data Target Children No. of Children % Beneficiaries (1-15 years) vaccinated vaccinated 99.01Koshi Nagar 1095877 1085055 97.03Gorakhpur 1390307 1349047 103.93Maharajganj 776500 806996 99.86Deoria 1074219 1072683 102.95Lakhimpur-Kheri 1183481 1218364 94.35Sant Kabir Nagar 542062 511417 94.35Siddharth Nagar 775934 792944 99.97UTTAR PRADESH 6838380 6836506 56.12Burdwan 2190690 1229404 56.12WEST BENGAL 2190690 1229404 90.49Dibrugarh 409611 370653 74.25Sibsagar 372356 276487 82.76ASSAM 781967 647140 82.67Barelli 720517 595648 82.67KARNATAKA 720517 595648 88.39INDIA 10531554 9308698 29
  30. 30. Report of Adverse Events following Immunization (AEFI)As a part of the monitoring of routine immunization program, any untoward events duringthe JE vaccination campaign was also monitored so as to fully investigate any adverseevents that may have had occurred , even if insignificant or minor. The time interval ofmonitoring was 2 weeks from the day of injection. Completely AEFI Children recovered cases Hospitalized Death vaccinated without reported hospitalization 4Koshi nagar 1085055 18 11 7 2Gorakhpur 1349047 85 71 14 1Maharajganj 806996 50 42 8 0Deoria 1072683 55 54 1 0Lakhimpur-Kheri 1218364 10 10 0 0Sant Kabir Nagar 511417 4 4 0 0SiddhartNagar 792944 0 0 0 7UTTAR PRADESH 6836506 222 192 30 6Burdwan 1229404 24 16 7 6WEST BENGAL 1229404 24 16 7 3Dibrugarh 370653 49 38 11 4Sibsagar 276487 66 53 13 7ASSAM 647140 115 91 24 2Bellary 595648 143 140 2 2KARNATAKA 595648 143 140 2 22INDIA 9308698 504 439 63 30
  31. 31. Chapter VII AEFI Reports: Magnitude and Spectrum.Vaccination campaign with the live attenuated JE vaccine was conducted in 11 districtsof 4 states during May to July 2006. The campaign began on 15 May 2006 in the Stateof Uttar Pradesh in the districts of Gorakhpur, Maharajganj, Kushinagar, Deoria andKheri. The campaign in the UP districts of Sant Kabirnagar and Siddharthnagar beganon 20 May 2006. The campaign in Burdwan, West Bengal began on 18 June 2006 andthe campaign in Dibrugarh and Sibsagar districts in Assam as well as in Bellary district inKarnataka began on 2 July 2006.Cases of Adverse Events Following Immunization (AEFI) were reported in nearly alldistricts except the district of Siddharthnagar in UP. Very few AEFI were reported in thedistricts of Sant Kabirnagar and Kheri in UP.In various pre-campaign preparatory meetings the importance of AEFI detection andreporting was emphasized. Also in the advisories issued during the campaign and againafter the campaigns – all concerned officers in States and districts were requested toensure that reports regarding AEFI cases were collected and forwarded to theImmunisation Division under the Ministry of Health and Family Welfare, New Delhi.During the campaign there was a team from the implementation partnership – GoI, StateGovernments, UNICEF, WHO and the Program for Appropriate Technology for Health(PATH) that visited the programme sites and helped both the implementation and themonitoring of AEFI. After the completion of the campaign, another team was sent by theGoI to collect information on AEFI and it visited institutions where children with reportedAEFI were hospitalized. Thus the data set on AEFI was the result of all these efforts puttogether. The reports thus received were analyzed in the Division. The combined line listgives a total report of 533 AEFI cases, including 22 deaths. The details are given in table1 below. Table 1 : Line List and Source S No. AEFI list No. 1. Non Serious 438 2. UIP Section Serious Recovered 43 3. Death 22 4. GOI team in UP Additional names from Gorakhpur Line List 30 Total AEFI 533 AEFI cases and deaths in 11 districts and 4 states following JE immuniz ation AEFI de aths , 22, 4% AEFI r e quir ing hos pitalization but im pr ove d, 43, 8% AEFI r e quir ing no hos pital car e , 446, 88% 31
  32. 32. The campaign in the respective districts began as in table 2 and the approximateduration of the campaign was as given. The campaign continued from 1 to 2 weeks. Theperiod covered was from May 15 to 15 July, 2006. Table 2 : Duration of Vaccination Campaign District Vaccination start Vaccination end Period in days Burdwan 18-Jun 29-Jun 12 Maharajganj 17-May 29-May 13 Kushinagar 15-May 25-May 11 Kheri 15-May 26-May 12 Sant Kabirnagar 23-May 29-May 7 Siddharthnagar 20 May NA NA Deoria 15-May 29-May 15 Gorakhpur 15-May 27-May 13 Bellary 10-Jul 15-Jul 6 Dibrugarh 2-Jul 15-Jul 14 Sibsagar 2-Jul 14-Jul 13The GoI (Immunization Division) prescribed a format for reporting of AEFI during and for14 days after this campaign. The reports were generally in this format at 2 levels – theFirst Information Report (FIR) by Health Workers or Peripheral Health Personnel and thePreliminary Information Report (PIR) by the Medical Officer investigating an FIR. TheDivision had access to the PIRs and also the photocopies of case records of childrenwho were hospitalized for AEFI. However, among all reports, there was no clinicalinformation recorded for 47 children. They have been excluded from furtherconsideration in this report. That leaves 486 cases of AEFI, available for analysis. Thebroad clinical features of these cases are summarized in Table 3. (The table includesmultiple entries, in case of more than one clinical feature, for which reason the totalsmay not tally.) Table 3 : Clinical Features of AEFI Cases Other Fever Fever Fever NeuroDistrict immediate < 3 d > 3 d Vomiting Convulsion Sign ARI RashBurdwan 12 2 1 9 3 2 5 3Maharajganj 14 7 3 16 4 3 0 3Kushinagar 5 3 4 4 7 5 1 2Kheri 1 10 1 1 0 0 0 7Sant Kabir 2 0 0 2 0 0 0 0SiddharthnagarDeoria 24 0 1 12 1 0 9 0Gorakhpur 25 15 8 26 12 4 4 10Bellary 54 1 1 20 3 2 1 26Dibrugarh 10 7 10 19 8 3 1 2Sibsagar 17 34 9 16 8 7 2 0 164 79 38 125 46 26 23 53 32